Microbes Saving Lives and Reducing Suffering
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1 of 61 Microbial Biotechnology, 2025; 18:e70068 https://doi.org/10.1111/1751-7915.70068 Microbial Biotechnology EDITORIAL OPEN ACCESS Microbes Saving Lives and Reducing Suffering KennethTimmis1 | ZeynepCerenKarahan2 | JuanLuisRamos3 | OmryKoren4 | AnaElenaPérezCobas5,6 | KarenSteward7 | Victorde Lorenzo8 | ElisabettaCaselli9 | MargaretDouglas10 | ClarissaSchwab11 | VirginiaRivero12 | RafaelGiraldo13 | JunkalGarmendia14,15 | RaymondJ.Turner16 | JessamynPerlmutter17 | JoséM.BorrerodeAcuña18 | PabloIvanNikel19 | JeromeBonnet20 | AngelaSessitsch21 | JamesK.Timmis22,23 | CarlaPruzzo24 | M. AuxiliadoraPrieto12 | SiavashIsazadeh25 | WeiE.Huang26 | GerardClarke27,28 | DaniloErcolini29 | MaxHäggblom30 Correspondence: Kenneth Timmis ([email protected]) Received: 18 November 2024 | Accepted: 25 November 2024 Funding: The authors received no specific funding for this work. 1 | Introduction Given the overexploitation of the resources of planet Earth, due in large part to the everincreasing human population (https:// www. un. o rg/ s us ta ina bl ed ev e lop me nt/ susta ina bl econsu mptio nprodu ction/ ), which has already compromised vital planetary processes (https:// repor ts. wefor um. org/ docs/ WEF_ Busin ess_ on_ the_ Edge_ 2024. pdf), the limitations of which are encapsulated in planetary boundaries (Richardson etal.2023; Gupta etal. 2024; https:// www. pikpotsd am. de/ en/ news/ lates tnews/ earth - excee dsa felimit sf irst - plane tar yhealt hcheck - issue sredalert ) and climate tipping points (Wunderling etal. 2023; Wunderling, von der Heydt, and Aksenov2024), it would not be unexpected that a visitor from Mars might well be confused, or at least bemused, by our efforts to save lives and reduce morbidity. The Martian might be similarly bemused when it learned that although warfare is a constant feature of biosphere ecology, including human behaviour, with military personnel of opposing armies doing their best to kill one another, military physicians will try their best to save the lives of injured prisoners of the opposing side. But warfare and other activities of individuals and groups aimed at harming others notwithstanding, saving lives and preventing/reducing human suffering is an ingrained moralethicalhumanitarian imperative (https:// www. ohch r. or g / site s/ def au lt / fi le s/ D o c u m e nt s/ Publi ca t io n s/ Facts heet31. pdf). While we cannot prevent death, we try hard to prevent avoidable, premature death and disease. But trying hard is not the same as succeeding (Kruk etal.2018). This is reflected in the United Nations Sustainable Development Goal (SDG) 3 Ensure healthy lives and promote wellbeing for all at all ages which identifies major deficits in global healthcare and provides a roadmap to correct these deficits (https:// sdgs. un. org/ 2030a genda ). The pursuit of saving lives and ameliorating human suffering is arguably the highest calling of humankind. Though generally considered to be the domain of clinicians—the healers—it clearly includes the endeavours of other health professionals, emergency responders, carers, parents–family–friends, the pharmaceutical industry, international organisations and a variety of nongovernmental organisations. More indirectly it includes inter alia those of engineers, educators, the body politic and financial services. Microbial technologies, exemplified by vaccines and microbially inspired and produced pharmaceuticals and diagnostics, play a central role in the prevention, amelioration and curing of disease, saving millions of lives and reducing billions of cases of suffering every year (https:// immun izati ondata. who. int). Moreover, lifesaving microbial technologies play out not only in the healthcare sector but also in wastewater and drinking water monitoring and treatment (Fowler and Smets 2017), food provision, bioremediation, etc. As a consequence, they rank very high among human endeavours to prevent and counter disease. Microbial technologies are thus central to the aims of SDG 3. Moreover, given that new lifethreatening problems, such as diverse impacts of global warming (Lenton et al. 2023), have arisen and appropriate microbial technologies either exist or can be developed to contribute to their mitigation, the scope and scale of lifesaving/− prolonging/−improving microbial solutions will continue to grow (Verstraete etal.2022). For affiliations refer to page 45. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.
2 of 61 Microbial Biotechnology, 2025 Despite this, microbes, if at all discussed in strategy documents, are usually mentioned only in the context of problems they pose (causing disease, food deterioration, materials corrosion, etc.), rarely as solutions they can provide for problems, and consequently are massively underexploited. Reasons for this include germophobia (the prevalent view of microbes as being dangerous germs, to be feared and therefore killed), their invisibility (out of sight, out of mind, which means they are not on the radar screens of most decisionmakers) and the fact that their vital importance to the wellbeing of humanity, food plants and animals, climate, the biosphere is a relatively recent realisation that has not yet permeated the body of general knowledge. While this is slowly changing, time is not on our side in confronting pressing issues and crises which demand immediate implementation of effective solutions. We need to accelerate appreciation of the power of microbes to address problems and the deployment of relevant microbial technologies (Timmis, de Lorenzo, et al. 2017; Timmis, de Vos, etal.2017). In exhorting leaders and policy decisionmakers to exploit microbial technologies to mitigate and solve major problems and global crises, we ask them to step outside of their comfort zones, enter the (for them) new information world of the microbiologist, see the bigger picture and engage in systems thinking. However, in order to be effective in this endeavour, we, the scientists and microbiologists, must also appreciate the wider context, be systems thinkers and communicate the bigger picture. But most of us only feel authoritative in discussing our own narrow field of activity, because our scientific training inhibits us from expressing opinions about issues the rigour of which we are not able to verify. This key element of scientific training, which guides our personal academic activities, can in fact promote ‘silo’ rather than systems thinking, and a reluctance to step outside of the comfort zones of our own specialities. The constant and justified exhortation to engage in interand transdisciplinary research in which some of the most significant discoveries are to be made is only modestly successful, partly because of this and partly because of the difficulty of finding willing and capable assessors of grant applications for such projects and subsequent manuscript submissions, which as aconsequence often result in unwarranted rejection, disappointment and discouragement to engage further in such research. Therefore, if microbiologists want society to take full advantage of the power and potential of currently unfamiliar microbial technologies, and for leaders and policymakers to step outside their comfort zones and take the risk (for them) of implementing new solutions they only incompletely understand, we must ourselves step outside of our comfort zones and take the risk of engaging in conversations of broader issues. This Editorial seeks: • To highlight the diversity, range, interconnectedness and interdependencies of the wide range of very different causes of human suffering and mortality, on the necessity of consideration of individual problems within broader contexts, of viewing them in the context of systems healthcare and of the necessity of systems thinking for solving systems problems, and on the need to address causes and remedies at their roots, not only in the hospital (see also https:// www. goinvo. com/ featu res/ deter minan t sofhea lt h/#: ~: text= Health% 20is% 20 More% 2 0Than% 20Med ical,t he% 20s oc ial% 20det ermin ants% 20of% 20health), • To outline and map on the spectrum of health challenges the exceptional range of available and emerging microbial technology solutions that raise barriers to preventable human suffering, morbidity and premature mortality, that is, that directly address the aims of SDG 3, and thereby raise awareness of some vital problemsolving options that may be inadequately appreciated by decisionmakers, • To present human suffering in the wider context, including policy, lifestyles and behaviour, environmentclimate changeplanetary boundaries, conflicts and technological potentials, in order to identify bottlenecks to progress and focus on plausible countermeasures, and • To provide a framework for the Microbial Biotechnology Special Issue The Contribution of Microbial Biotechnology to Sustainable Development Goal 3: Ensure healthy lives and promote wellbeing for all at all ages, of which this Editorial is a part. 2 | Principal Causes of Human Disease and Key Risk Factors The burden of disease is usually expressed in terms of disabilityadjusted life years (DALYs): one DALY represents the loss of the equivalent of 1 year of full health. ‘DALYs for a disease or health condition are the sum of years of life lost (YLLs) due to premature mortality and years of healthy life lost due to disability (YLDs) due to prevalent cases of the disease or health condition in a population’. (https:// www. who. int/ data/ gho/ indic atormetad ataregis try/ imrdet ai ls/ 158#: ~: tex t = DALYs% 20for % 20a% 20dis e as e% 20or,% 2C% 20Sex% 2 C % 20Cau se% 2C% 20Risk% 20fac tors). According to the World Health Organisation (WHO) report for 2020–21 (https:// www. who. int / ne wsro o m / fac tsheets/ detai l / t hetop10c ause sofdeath ), cardiovascular, respiratory and infectious diseases were leading causes of death globally, with significant differences between low/medium income countries (LMICs) and highincome countries (HICs) (see also https:// ourwo rldin data. org/ burde nofdisease; https:// www. healt hdata. org/ resea rchanaly sis/ l ibra ry/ globa lburde ndisea se - 2021findi ngsgbd2021study ). Cancer and dementia are also important in HICs. Microbes are centrally involved in initiation and progression of disease in some of these classes. However, and crucially, microbes and their activities can be harnessed to reduce disease so, for our discourse, the lens of predisposing parameters/risk factors of disease is of greatest interest because this reveals intervention options for detectionmonitoring, prevention and treatment (Ezzati etal.2002). Often, risk factors fall into the classes of too much (e.g., exposure to air pollution, untreated drinking water sources and unhealthy food) or too little (e.g., food, micronutrients and exercise). According to Ezzati etal.(2002), ‘In the poorest regions of the world, childhood and maternal underweight, unsafe sex, unsafe water, sanitation, and hygiene, indoor smoke from solid fuels, and various micronutrient deficiencies were major contributors 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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3 of 61 to loss of healthy life. In both developing and developed regions, alcohol, tobacco, high blood pressure, and high cholesterol were major causes of disease burden’. It is also important to keep in mind that preventable human suffering also has many other causes, including poverty, abuse, warfare, migrations, trafficking, accidents, lack of education and, especially, global warming, some of which can be addressed with microbial technologies. In this discourse, we review these diverse health risk factors in the context of microbial causes, solutions and mitigation strategies with the aim of providing an integrated healthenvironmenthumanitarian ecosystem perspective to promote a more systems approach to reducing human suffering. 3 | Microbial Barriers to Infectious Diseases 3.1 | The Scale of the Problem of Infectious Diseases Infectious diseases constitute nearly 30% of global disease burden (https:// ourwo rldin data. org/ burde nofdisease). This amounts to an estimated 830 million DALYs globally, 704 million of which are associated with 85 pathogens (IHME Pathogen Core Group 2024). Approximately 15–17 million deaths/year— 25% of deaths due to all causes are estimated to be due to communicable diseases. Infectious illnesses also have considerable impacts on individual earnings and workplace productivity and costs. 50%–60% of all workplace absenteeism is estimated to be due to respiratory infections or gastroenteritis. Approximately 500 million noninfluenza viral respiratory tract infections are estimated to occur each year in the USA, resulting in 70 million lost workdays. In France and Germany, lost productivity related to infectious illnesses in the workplace was found to have cost an estimated $US10–15 billion per year (Blanchet Zumofen, Frimpter, and Hansen2023; Hansen, Zimmerman, and van de Mortel 2018). Gastroenteritis and respiratory infections in children are the major causes of school absenteeism. Moreover, infections, especially of children, often engender the need for caregivers, with the corresponding loss of their earnings and workplace productivity. Some infections can be either chronic or have sequelae that exacerbate all of these burdens. 3.2 | Infectious Diseases Are Typical Ecological Interactions: Healthcare Consists of Ecological Interventions and Raising Barriers Infections are normal ecological interactions in the biosphere: competition for resources, organismal wars, the nature of food chains/webs and predator–prey interactions, and the cycle of birth and death that recycles biological resources along the generations that occur among all freeliving organisms (see also Anderson 1991; Pitlik and Koren 2017; https:// asm. org/ artic les/ 2024/ june/ patho genes isnotatrait - itsanoutcome). These battles involve diverse innate defences and weaponry, including antibiotics, and are influenced by external environmental factors. To confront the challenges of human infections, we have learned to manipulate a number of these natural parameters, in addition to instituting a range of technical processes that do not occur naturally, to create new or elevate existing barriers that reduce infections. Some of these manipulations have their roots in traditional medicine practices developed by early civilisations. For example, although antibiotics were discovered and characterised only at the beginning of the last century (e.g., Hutchings, Truman, and Wilkinson2019), the use of antibioticcontaining preparations of herbs and other materials in infection prevention and treatment by humans was practiced as early as 2500 BC (https:// www. scien celea rn. org. nz/ inter active_ timel ine/ 15antib iotic sandantim icrob ialresis tance - atimeline). It is also worth noting that exploitation of antibiotics to counter infections is not restricted to humans: there are a number of animals and insects that employ antibioticproducing microbes to protect vulnerable offspring from infection by pathogens (e.g., Currie etal.1999; MartínVivaldi etal.2014; Kaltenpoth etal.2014), an ecological practice that goes back in animal evolution to the Cretaceous age (ca. 145 My BP). It is important to note that ecological manipulations in clinical medicine do not always aim to raise barriers; sometimes, they aim to lower them. Examples include the use of blowfly larvae for debridement of necrotic tissue of wounds (maggot therapy): in this case, the necrotic tissue serves as a barrier to body defences where pathogens can proliferate, so its removal by maggots cleanses the wound and allows innate defences to function more effectively. Medicinal leech therapy can be used for a number of different goals but in general to lower functions such as inflammation in inflammatory diseases, coagulation in cases of thrombosis, etc. (Abdualkader etal. 2013; Sig etal.2017; https://biology.anu.edu.u/research/researchstories/ leechesmodernmedicine). 3.3 | Body Surface Barriers and Their Breaching: Portals of Entry In order to infect a host and cause disease, a pathogen must be transmitted to, and either colonise—establish themselves and multiply on surfaces of—and/or invade the host. Colonisation and invasion occur via portals of entry: epithelial surfaces. The surfaces of our bodies are covered by a protective cellular barrier—the epithelium—which includes the skin and the mucosal surfaces of the airway, the gastrointestinal and genitourinary tracts and ocular surfaces. The epithelium impedes the breaching of body surfaces by microbes and other chemical and physical threats, and is the first line of defence against pathogen attack. The epithelial barrier itself is covered by microbes—the microbiome—which is designated the ‘second skin’, because it also acts as a physical barrier and protects against colonisation of and invasion by pathogens (Kim, Covington, and Pamer2017; Byrd, Belkaid, and Segre 2018; Eisenstein 2020; Panwar, Sequeira, and Clarke2021; HarrisTryon and Grice2022; McCallum and Tropini 2024; Wu and Yao2024) by leaving little surface area for colonisation by new microbes, and by fighting off those that would invade its territory. As the primary portal of entry for pathogens, epithelial surfaces are armed with a comprehensive array of immune defences, both innate immunity, which has broad specificity and involves inter alia inflammatory processes, clotting factors, phagocytes, complement, cytokines and antimicrobial proteins and peptides, and 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 of 61 Microbial Biotechnology, 2025 adaptive immunity, which are dedicated to protecting the epithelial barrier (Moens and Veldhoen2012). The surface immune barrier is the third line of defence. Moreover, the epithelium and microbiome also act as (bio)chemical barriers by independently and interactively producing an array of substances, that either inhibit ‘enemies’ or promote the growth of microbiome ‘friends’ (Mukherjee and Hooper2015; Zhang, Merana, etal.2022). These chemicals include antimicrobial lipids and fatty acids, microbially produced compounds such as iron chelating molecules and, in skin, immunomodulatory tryptophan derivatives, and acidifying substances that lower surface pH and are responsible for creating and maintaining the ‘acid mantle’, which plays key roles in skin barrier function (Elias2015). Epithelial chemistry constitutes a fourth line of defence. In turn, the chemical and immune defences shape, protect and nurture the microbiome. In addition, some epithelial surfaces may be ‘patrolled’ by macrophages that eliminate pathogens and other microbes that are not recognised as indigenous. All of the body surface lines of defence, though largely distinct in terms of actors, are highly interactive and integrated and coordinate responses to threats, especially barrier breaches. In general, the skin is the most robust barrier (Eisenstein2020) because a major function is to keep foreign agents out. The internal epithelia are more vulnerable because their function is also to take in—to serve as a portal for—environmental materials, like food and water (gastrointestinal tract) or oxygen (airways). Ensuring that portal activities of internal epithelia are highly selective for needed materials, while keeping enemies out, is more challenging. Some internal epithelia also have an additional defence: production of sticky mucus that binds foreign materials, including microbes, and that is continuously swept to the outside: a conveyer belt physically removing unwanted agents (Turner2009; Hansson2012; Song, Chai, etal.2023). 3.4 | The Gastrointestinal Tract Epithelial Barrier The intestine, with an estimated surface area of 32 m2, is an important portal of entry for foodand waterborne pathogens. Its epithelial barrier function is largely governed by the integrity of the intercellular ‘tight junctions’, and the other defences mentioned above. Pathogens have evolved mechanisms to breach intestinal defences. For example, Entamoeba histolytica specifically binds to mucus via a Galbinding lectin, and subsequently produces a cysteine protease that degrades mucin and allows invasion (SolaymaniMohammadi and Petri Jr. 2008). Other pathogens penetrate the intestinal barrier either opportunistically, by taking advantage of increased gut epithelial permeability (‘leaky gut’), or actively, by creating increased permeability, or though diverse means of invasion of the epithelium (Kim etal.2010). 3.5 | The Respiratory Tract Epithelial Barrier Although the airways also have a mucus layer which serves a similar function of sweeping pathogens and other particulates to the exterior via the mouth (and thereafter the gastrointestinal tract) and nose, it differs in two important but linked respects, namely the airways are a culdesac, not a thoughway, and under certain circumstances mucus can be produced in excess which can clog the airways and hinder pathogen clearance, as is experienced in respiratory infections and diseases like cystic fibrosis (‘mucoviscidosis’). 3.6 | Endogenous and Exogenous Pathogens Sources of infections can be either endogenous—transmission is not necessary, although there will have been a transmission event at some point before the pathogen became endogenous— or exogenous, which involves transmission via something external to the person who becomes infected. 3.7 | Raising/Creating Barriers to Infections: Endogenous Pathogens Healthy microbiomes typically contain small populations of facultative pathogens, microbes such as Clostridioides difficile, that do not generally cause disease because their numbers and hence activities are held in check by ecological controls operating in the microbiomes of healthy individuals, and do not therefore reach infective dose levels. Such controls may be lowered by events that cause microbiome dysbiosis, such as antibiotic treatment, and/or in immunecompromised individuals, allowing pathogen numbers to increase to infective dose levels that enable a pathogen to overwhelm our defences and initiate disease. Microbial technologies to lower pathogen population levels, and thereby raise barriers to disease, include interventions such as probiotics and microbial transplants to increase gut microbiota diversity and the population levels of beneficial microbes. 3.8 | Raising/Creating Barriers to Infections: Exogenous Pathogens and Their Transmission Exogenous pathogens require transmission among hosts and can be acquired by air, water, food, physical contacts, insect vectors, physical injurieswounds and invasive health interventions, the latter three of which involve breaching our natural surface barriers. As a consequence of our inherent barriers to infection, most pathogen transmission events do not lead to disease. In healthy individuals, a large number of pathogenic organisms are needed to overcome our barriers. This number is designated the infective dose and varies according to the pathogenicity of the microbe. Although there are some pathogens, such as shigellae, whose infective dose is low, that is, a few organisms are able to initiate an infection, most pathogens, like salmonellae and vibrios have infective doses in the thousands or millions (Kothary and Babu2001). Thus: infections by exogenous pathogens have both a qualitative component—the transmission event—and a quantitative component—the number of infectious agents in the transmission event in relation to the infective dose. Raising barriers to such infections involves interventions targeting both of these components. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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5 of 61 3.9 | Challenge 1: Settings With High Pathogen Burdens and/or Highly Susceptible Populations High concentrations of pathogens are found in certain settings, which translates into high probability of infective dose transmission to susceptible individuals. The classic and historically one of the most important examples is water contaminated with human wastes. The seriousness of the disease impact of contaminated water led to the development of wastewater treatment processes which substantively reduce pathogen loads of incoming wastes. Other settings where pathogens concentrate, such as hospitals, or where hygiene conditions are suboptimal, such as may be found in some disadvantaged communities, refugee camps, informal settlements, slums, care homes, nurseries, war zones, etc. are more challenging, as are close contacts with animals infected with zoonotic pathogens. Surveillance in such settings must be top priority because epidemics can easily break out, and speed is of the essence to contain them. Concerted efforts are needed to provide the necessary expertise and logistics in particularly vulnerable, lowresource settings. In any case, it is important to avoid situations where pathogens may concentrate, such as swimming in confined freshwaters with high densities of rodents (Leptospira; Haake and Levett 2015) and waterfowl (Cryptosporidium, Giardia; Kuhn, Rock, and Oshima2002). Hospitals are particularly problematic environments for infections by resistant pathogens because they contain high populations of people with low barriers to infections due to disease and treatment issues, such as receiving immune depressants following transplantations, are hightraffic environments where large numbers of people introduce all manner of microbes, and places where diverse pharmaceuticals, including antibiotics, and disinfectants are deployed. These conditions select a robust ‘hospital microbiome’ in which antibiotic and disinfectant resistances are common and where facultative pathogens that may not cause disease in healthy individuals are able to produce lifethreatening infections in vulnerable patients. Of particular concern are the antibioticresistant ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species (De Oliveira et al. 2020; Ayobami etal.2022; Denissen etal.2022; Miller and Arias2024), which are able to colonise hightouch surfaces, like handles, and thence be transmitted to almost anyone, including patients, hospital professionals and visitors, the latter two of which also serve as agents of transmission to patients. Earlier effective barriers to hospitalacquired (nosocomial) infections included hygiene measures based on comprehensive disinfectant use, but their use is now experiencing diminishing efficacy, not least because hospital microbiomes typically include disinfectantresistant AMR pathogens. However, the application of probiotic bacteria and bacteriophages to surfaces that carry high loads of pathogens can be an effective means of reducing such loads and hence their ability to deliver infective doses. This is strategy being tested and rolled out in hospitals and elsewhere. Fomite (surfaces)- toperson and persontoperson contacts are in general significant routes of transmission of infections. Contact transmission can be reduced by avoiding handshaking/kissing/hugging when greeting, and by the use of condoms in sexual encounters. Other barriers include disinfection, sanitation and hygiene but, as already mentioned, pathogens are becoming increasingly tolerantresistant to disinfectants, so these barriers are becoming less effective (Tong etal.2021). Food is a major vehicle for pathogen transmission via the faecaloral route, either contaminated during the supply chain or during preparation. While basic hygiene practices are the mainstay barriers against food contamination, diverse means of processing food materials and food safety controls are key to preventing the consumption of contaminated food. Probiotic technology that creates barriers to pathogen transmission by hightouch surfaces A promising probiotic approach is the application of spores of harmless bacteria effective at colonising regularly touched hospital surfaces, thereby installing an effective ecological barrier for colonisation of such surfaces by the ESKAPE and other pathogens, and their transmission to patients (Caselli 2017; D'Accolti, Soffritti, Mazzacane, etal.2019; Neidhöfer etal.2023). Probioticbased sanitation is essentially based on the ability of selected probiotics to effectively compete with pathogens in the treated environment, displacing and replacing them over time (D'Accolti et al. 2024), increasing environmental microbial diversity and simultaneously decreasing the selection of AMR pathogens (Leistner et al. 2023). This approach has also been shown to be effective against viral pathogens (D'Accolti etal.2021), and has recently been extended to subways and other spaces where large numbers of people and their pathogens concentrate (D'Accolti, Soffritti, Bini, Mazziga, Cason, etal.2023). In addition to probiotics alone, the combined use of probiotics and bacteriophages was also explored for the rapid and specific removal of AMR pathogens in the hospital environment, with promising results (D'Accolti, Soffritti, Lanzoni, et al. 2019, D'Accolti, Soffritti, Bini, Mazziga, Arnoldo, etal.2023). Of note, such microbial technologies are ‘frugal’: economically affordable and easy to use, rendering them applicable in lowincome settings. Microbial technologies that raise barriers against watertransmitted disease Wastewater treatment is a key, largely microbiological process that reduces the environmental load and transmission of human faecal pathogens and constitutes a major barrier to infections transmitted by water, either directly consumed by drinking or indirectly taken in during washing, swimming, etc. Drinking water is usually subjected to microbiological monitoring, treatment and disinfection (Pluym etal.2024) to reduce waterborne infections further and lower the intake of toxic chemicals. A recent study estimates that improving access to safely managed water, sanitation and hygiene services would prevent an additional 1.4 million deaths and 74 million DALYs each year (Wolf etal.2023). Both types of barrier can be breached by stormwaters, poor maintenance, and accidents and, in the case of drinking water treatment, by the development of biofilms housing pathogens such as Legionella in water supply piping (Mondino etal.2020). 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 61 Microbial Biotechnology, 2025 Respiratory infections are common (https:// immun izati ondata. who. int/ , https:// www. ecdc. europa. eu/ en/ datadashb oards - anddatab ases) and transmitted by breathing air with a high pathogen load. Barriers include air filtration systems, sometimes coupled with disinfection (e.g., by UV irradiation), use of masks and personal distancing, avoidance of large gatherings in confined spaces, especially in times of epi−/pandemics, and pathogen dilution with fresh air by ventilation. Breaches of the surface barriers can be nonspecific, like those caused by surgery, transfusions, catheters and other invasive clinical interventions, physical wounds and animal bites, all of which become potential portals of entry for pathogens. Just as humans have evolved sophisticated barriers to infection, so have microbial pathogens evolved ways and means of circumventing or countering our innate defences: their specific mechanisms to breach surface barriers (Hornef etal. 2002). One of the most effective of these is pathogen exploitation of bloodsucking insect vectors (that are often also intermediate hosts for the pathogens), like mosquitoes (https:// ukhsa. blog. gov. uk/ 2024/ 07/ 26/ howyoucanhelp - usresis tthetiger - mosqu itosconqu estofeurope/ ) that can transmit dengue (https:// www. wefor um. org/ stori es/ 2024/ 11/ dengu efever - outbr eakclima techang e/? utm_ sourc e= sfmc& utm_ mediu m= email & utm_ campa ign= 28393 32_ Agend aWeek ly8Nove mber2 024& utm_ term= & email Type= Agenda% 20Weekly) and malaria, and ticks that can transmit Lyme borreliosis and tickborne encephalitis. Such vectors inject pathogens directly into the blood stream during the blood meals needed to provide the nutrients for egg production. Insect vectormediated transmission circumvents all the surface barrier defences. Examples of microbial technologies available to raise barriers in these cases are, on one hand, vaccination (e.g., to prevent tickborne encephalitis) and antibiotics (e.g., to treat Borrelia) and, on the other, the deployment of Wolbachia to reduce transmission of pathogens by female mosquitos. 3.10 | The Wolbachia Technology Barrier Wolbachia is a bacterial endosymbiont of around 50% of the arthropods, and also of many nematodes, that profoundly influences host physiology and behaviour. Wolbachia particularly impacts host reproduction in ways that favour its own propagation and transmission among host populations. One impact on the host includes reducinghost mortality from microbial infections by inhibiting the transmission and virulence of pathogens the host may carry, some of which like dengue and Zika virus also infect humans. In other cases, Wolbachia endosymbionts have become intricately intertwined with host biology and are essential for host survival and reproduction, as is the case for the nematode Onchocerca volvulus, the causative agent of river blindness. These interactions between Wolbachia and its hosts can be exploited to fight disease and have already triggered explosive growth in Wolbachia technology directed at reducing insector nematodevectored infections of both humans and crop plants. 3.11 | Raising/Creating Barriers to Infections: Prophylaxis Since its inception, vaccination has saved countless lives and protected many more from disease (e.g., considering just one vaccine, it is estimated that the measles vaccine saved 31.7 million deaths over a 20year period https:// www. who. int/ newsroom/ spotl ight/ histo ryofvacci nation/ histo ryofmeasl esvacci nation; Venkatesen2022; see also Nandi etal.2019). There are a range of vaccines available to prevent many infectious diseases (e.g., https:// immun izati ondata. who. int; https:// vacci nekno wledge. ox. ac. uk/ home; https:// immun izati ondata. who. int/ ; Croucher2024). Immunisation with vaccines supports the initial host response to infection by significantly elevating the barrier function of adaptive immunity against specific pathogens. Priming the immune system through vaccination to achieve a rapid and massive response to infection can not only protect the Microbial technologies that raise barriers to foodtransmitted disease Microbial fermentations of plant and animal food materials are widely used to produce, for example, bread, cheese and other milk products like yoghurt, and condiments like vinegar and soy sauce, as well as an amazing range of regionally specific fermented foods (Gänzle2022; Harper etal.2022). These fermentations not only add new flavours and textures but, crucially, reduce and hinder transmission of foodborne infections by creating ecophysiological conditions, such as acidity, shortchain carboxylic acids and other antimicrobial compounds, that inhibitpathogens. Such conditions also inhibit the growth of food spoilage microbes (Snyder, Martin, and Wiedmann2024) and hence extend food shelf life (see also Buljubašić etal.2024), thereby reducing wastage, and increase food security. Microbial technologies are also widely used in food safety monitoring and include diagnostic tests for typical food pathogens, toxins like mycotoxins and cyanotoxins, food origin and authenticity. These are often based on PCR and antibody tests for specific biomarkers, especially nucleic acid and antigen signatures. Microbial technologies in food safety enable the removal of contaminated or suspect food from the supply chain, are effective barriers to infection and intoxication by these routes, and prevent a huge number of cases of morbidity and mortality. Microbial technologies that combat infections enabled by barrier breaches through injury In addition to the deployment of prophylaxes (vaccines, e.g., to prevent tetanus, antibodies, e.g., to prevent rabies) and therapies, important measures to reduce pathogen loads, reduce probabilities of infection, and bolster defences related to these types of breaches include probiotic treatment of hospital surfaces to reduce fomitetransmission of pathogens to wounds, pathogen diagnostics for quality control of donated blood, blood products and other materials for intravenous infusions, and pointofcare test (POCT) systems for rapid diagnosis following animal bites, especially in rural and lowresource settings. Moreover, there are a number of promising microbial technologies and products to promote wound healing and hence reduce exposure to pathogens, including topical bacterial therapeutics that release substances like the chemokine CXLC12, which promotes healing, and microbial polymers that provide biocompatible scaffolds for tissue repair and regeneration. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
7 of 61 individual, but also the population, through attainment of ‘herd immunity’ (Fine, Eames, and Heymann2011). The ability to spread in a totally susceptible population, quantified as the R0 number—the average number of people acquiring an infection from a diseased individual—is a pathogenspecific characteristic (https:// www. cebm. net/ covid - 19/ whenwillitbeoveranintro ducti onto - viral - repro ducti onnumbe rsr0andre/#: ~: text= If% 20R0% 20is% 20les s,the% 20data% 20that% 20inf orm% 20it): for example, the R0 number for measles is around 15 (Guerra etal.2017). Immunisation (and recovery from infection) reduces the proportion of susceptible individuals in a population, and we then instead consider the effective reproduction number, Re, which will reduce compared to the R0 value the more individuals are immunised or have recovered from natural infection (https:// www. cebm. net/ covid - 19/ whenwillitbeoveranintro ducti onto - viral - repro ducti onnumbe rsr0andre/#: ~: text= If% 20R0% 20is% 20les s,the% 20data% 20that% 20inf orm% 20it). Once a particular threshold of unsusceptible individuals is reached, for example 95% in the case of measles, the pathogen fails to transmit effectively, and there is a decline in disease incidence. This threshold, which is dependent on the R0 number, is when herd immunity is achieved. Crucially, herd immunity confers a significant degree of indirect protection on unvaccinated individuals (https:// vacci nekno wledge. ox. ac. uk/ herdimmun ity# Peopl e - whodepen donherdimmunity), which is particularly important as populations age and numbers of people with lower immunity, for example, due to treatment with immunosuppressants, coand polymorbidities, etc., increase. Impressively and importantly, vaccination campaigns aimed at achieving herd immunity have eradicated a number of deadly infections, either globally (smallpox, rinderpest) or regionally (polio, rabies) and have the ability to eradicate more (e.g., guinea worm, malaria), if socioeconomic parameters will allow (https:// ourwo rldin data. org/ eradi catio nofdiseases; https:// asm. org/ Artic les/ 2024/ Septe mber/ Polio - sLastStand - TheGloba lFight - forEradi catio? utm_ mediu m= email & utm_ sourc e= rasa_ io& utm_ campa ign= newsl etter ). This represents the alleviation of an enormous health burden. Although rinderpest was a deadly infection of cattle (cattle plague), not of humans, it had an enormous impact on human health because outbreaks caused famines responsible for millions of deaths and created poverty among farmers (https:// ourwo rldin data. org/ howrinde rpest - waseradi cated ). However, vaccine hesitancy (Larson, Gakidou, and CJL2022) tends to reduce vaccine coverage, so that herd immunity is no longer attainable for some infections and the vulnerable are not protected. In 2019, the WHO listed vaccine hesitancy as one of the 10 threats to global health (https:// www. who. int/ newsroom/ spotl ight/ tenthrea tstogloba lhealt hin2019). Even when vaccination levels that provide herd immunity are achieved it can break down because, due to vaccine hesitancy within certain groups (Jäckle and Timmis2023), vaccination levels are not uniform across communities and pockets of unvaccinated individuals can create miniepidemics that can jump to other pockets (Peeples2019). In the context of microbial technologies to raise barriers against disease, vaccine hesitancy is a significant opposing barrier. Wolbachia technology that reduces pathogen transmission by insect vectors Wolbachia is one of the most promising tools we have to fight mosquitoborne disease. According to the WHO, about half of the world's population may be at risk of mosquitotransmitted dengue virus infection (https:// www. who. int/ newsroom/ factsheets/ detail/ dengu e - andsever e - dengue; https:// www. wefor um. org/ stori es/ 2024/ 11/ dengu efever - outbr eakclima techang e/? utm_ sourc e= sfmc& utm_ mediu m= email & utm_ campa ign= 28393 32_ Agend aWeek ly8Nove mber2 024& utm_ term= & email Type= Agenda% 20Weekly). There is no treatment, so control efforts are directed at reducing transmission. Male mosquitoes infected with Wolbachia released into natural populations reduce female fertility. Moreover, the bacterium interferes with dengue virus reproduction in infected mosquitoes, thereby reducing virus loads (Walker etal.2011; Loterio etal.2024). Wolbachia can similarly reduce transmission of Zika and chikungunya viruses, among other pathogens of interest (Ant etal.2022). Wolbachia technology is an important strategy to raise barriers to pathogen transmission and its use for the control of vectormediated infections, including malaria, is being actively explored (Walker etal.2021). Importantly, trials using Wolbachia to fight mosquitoborne disease have already shown significant reductions in dengue virus transmission to humans in multiple test locations around the world. Wolbachia technology is also effective for reduction in plant infections transmitted by insect vectors (Gong etal.2020). This is also of human health importance for several reasons. Firstly, insect control classically involves chemical insecticides, some of which may pollute the environment and poison humans consuming treated crops. Secondly, chemical pesticides often affect nontarget insects that may have beneficial activities, like pollination, which is essential for food production, and hence impacts food security. Wolbachia technology is neither polluting nor affects nontarget insects, so its replacement of chemical pesticides will directly reduce pollutantcaused maladies and indirectly reduce morbidity and mortality resulting from inadequate nutrition. Wolbachia does not always act as an antipathogen and can instead serve as an effective drug target for treating disease. Wolbachia is an essential endosymbiont of filarial parasites causing onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis). In this case, inpatient antibiotic elimination of Wolbachia indirectly kills the adult worms that require the symbiont (e.g., Sulaiman etal. 2019; Wan et al. 2019; https:// awol. lstmed. ac. uk). This is important because, although filariasis infections can now be controlled by the antinematode drug ivermectin, the drug only kills the microfilaria worms that cause disease pathology, but not the sexually mature adult worms that produce the microfilariae. As a result, disease recurs and requires repeated therapy. A combination of treatments with ivermectin targeting the microfilariae, and with, for example, doxycycline targeting Wolbachia, can eradicate filariasis from patients. Wolbachia technology is undoubtedly a powerful means of combatting some important types of infectious disease and has considerable potential for development of new applications. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 of 61 Microbial Biotechnology, 2025 3.12 | Raising/Creating Barriers to Infections: Therapeutics Treatment of infections often involves inter alia the administration of antibiotics which, if the causative agent is sensitive, can be extremely effective, add an additional weapon to the natural defences of the infected individual, and tip the balance of the ongoing ecological war in favour of the host. 3.13 | Challenge 2: Antimicrobial Resistance Antimicrobial resistance (AMR) - has been increasing alarmingly in recent years and is now predicted to restore infectious diseases as the main cause of human mortality, as was the case in the preantibiotic era (Ventola2015a, 2015b; Coque etal.2023). One report forecasts that by 2050 infectious diseases will be responsible for 100 million deaths annually and result in a cumulative loss of economic output worth US$ 100 trillion (https:// amrreview. org/ sites/ defau lt/ files/ 160525_ Final% 20pap er_ with% 20cov er. pdf; Naghavi etal.2024). AMR is considered by the WHO to be one of the most serious threats to human medicine, a concern that was brought into sharp focus by a 2019 study which attributed 1.27 million deaths worldwide directly to AMR and another 4.95 million deaths as associated with AMR (Murray etal.2022). New antibiotics effective against current AMR pathogens are urgently needed but the pipelines of new candidates are almost dry. The revitalisation of antibiotic discovery programmes is hugely important and urgent (e.g., Timmis etal.2014; Anderson etal.2023; Birkelbach etal. 2024; Brüssow2024). However, while there is indeed cause for alarm, and the currently increasing trajectory of morbidity and mortality caused by AMR pathogens constitutes a crisis, this prediction is based on modelling studies that fail to take into account the potential influence of a major revitalisation of antibiotic discovery programmes and the development of alternative microbial technologies based on ecological barriers. While drug prospecting has traditionally focused on microbial sources and continues to do so with increased emphasis on poorly investigated microbes, including uncultured microbes, and on expression of silent or inactive microbial biosynthetic pathways, other sources such as human and animal antimicrobial peptides are also receiving increasing attention. However, in addition to new but classical antibiotics, a number of other options are being actively investigated. These include cotherapies of antibiotics and compounds targeting functions vital to antibiotic resistance (Laborda etal.2024; Wu, Huang, and Xu2024; Wan etal. 2024; Xu and Lin2024) and the use of pathogens of pathogens, such as bacteriophages and bacteriovorous bacteria, like Bdellovibrio, surfaceengineered bacteria (Dahlsson Leitao, Ståhl, and Löfblom2024), antipathogen and antiAMR CRISPRCas systems (Bikard etal.2014; Derollez, Lesterlin, and Bigot 2024), therapeutic antibodies/nanobodies that inactivate pathogens or toxins, use of antimicrobial nanomaterials (Arora, Lashani, and Turner2024) and 'nanobiotics' (Chakraborty et al. 2022; Lashani et al. 2024), and microbiota transplants (Bratkovič etal.2024; Carratalá etal.2024). Bacterial therapeuticsbacteria engineered to inactivate inter alia pathogens, their virulance products, and antibioticinactivating enzymes, or to deliver therapeutic payloads at sites of diseasewould seem to have signficant potential (Srivastava and Lesser 2024). These various approaches, and others, based on microbial technologies, have yet to prove their ability to achieve significant reductions in morbidity and mortality caused by infections by AMR pathogens, but their development and testing needs to proceed at pace. Moreover, new technologies are available and in development that increase the speed and accuracy of antibiotic sensitivity testing, thereby reducing the time during which potentially ineffective antibiotics are administered. These improve disease outcomes and reduce selection pressure for AMR. Importantly, monitoring AMR and its evolution by PCR, sequencing, etc., will be crucial to targeting and raising barriers against it. It is important to note that vaccines also play a crucial role in combating antimicrobialresistant (AMR) pathogens by preventing infections, reducing the reliance on antibiotics and lowering the selection pressure for resistance (Bloom etal.2018; Sevilla etal.2018). New vaccines targeting AMR pathogens will be able to directly reduce the proliferation and spread of resistant strains. Recently developed generic technologies to generate attenuated live vaccines have focused on the creation of Dglutamatedependent variants of pathogens (Cabral et al. 2017), and variants dependent upon an unnatural amino acid (Pigula etal.2024), neither of which proliferate significantly in the host so do not cause disease, but which elicit protective immune responses. Such vaccines were shown to be effective against challenge by multiresistant Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus in animal models, so have considerable promise as an essential technology in the broader strategy to combat AMR. Such vaccines should contribute not only to individual and public health, but also to the sustainability of effective antimicrobial therapies. In addition to the development and deployment of new technologies, there must also be accompanying measures which Vaccine technologies that prevent infectious diseases There is a range of procedures to manufacture vaccines but most have in common the production of an antigen of the target pathogen that induces protective immunity. More recently, with the development of the mRNA vaccine technology, the immunising agent is a nucleic acid coding for the target antigen, which is then produced insitu in the vaccinated individual. This is a ‘nimble’ technology that can create vaccines more rapidly than classical procedures in response to quickly developing epi−/pandemics, respond promptly to the evolution of pathogen variants and, coupled with fast tracking of authorisations, has hugely accelerated the speed of development and deployment of vaccines against serious pandemic infections, and against new variants of rapidly evolving pathogens. These developments saved millions of lives during the COVID19 pandemic and will save many more in future. (e.g., https:// www. who. int/ news/ item/ 14082024whodirec torgener aldecla resmpoxoutbr eakapubli chealt hemerg encyofinter natio nalconcern; https:// www. wefor um. org/ agenda/ 2024/ 09/ pande michealt hcare - healt hmpoxvacci ne/? utm_ sourc e= sfmc& utm_ mediu m= email & utm_ campa ign= 28365 67_ Agend aWeek ly27Sep tembe r2024 & utm_ term= & email Type= Agenda% 20Weekly). One report suggests that the economic benefit of COVID19 vaccines amounted to $US 5.2 trillion (Sevilla etal.2024). 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
9 of 61 ensure the reduction in nonclinical use of antimicrobial agents, to lower environmental selection pressures for evolution and transmission of AMR, and provide the education which will be required to achieve this (e.g., CalvoVillamañán, San Millán, and Carrilero2023). 3.14 | Challenge 3: Chronic and Recurrent Infections Sometimes, even when natural defence barriers are augmented with antibiotics, pathogen clearance is not achieved and infections flare up again, particularly in patients with indwelling devices (one study recorded that > 90% of hospitalised patients have an indwelling device: Chen, O'Malley, and Chopra 2021). This may have different causes, including genetic defects in vital barriers, such as pathogen clearing processes, as is the case in cystic fibrosis (Ribeiro etal.2023), pathogen surface variability that prejudices the efficacy of pathogen recognition by body defences, pathogen localisation in body sites that are poorly accessible to host defences, pathogen creation of protective subcellular location structures and extracellular colony structures like biofilms (Bjarnsholt2013), and development of persister states in which dormancy is induced inter alia by antibiotic treatment or phages (FernándezGarcía etal.2022; FernándezGarcía etal.2024). 3.15 | Raising Barriers to New Infections With the Aid of Artificial Intelligence Microbial pathogens, like all members of the biosphere, evolve to adapt to changing environments. Unlike most visible members of the biosphere, microbial pathogens may evolve very rapidly because most can have very short reproduction times under certain conditions. Evolution includes developing new host specificities, in particular for humans in the case of animal pathogens, and increased virulence. As the 'space' of evolutionarily space for pathogens becomes better known, it will become easier to predict using artificial intelligence what new infection threats may evolve, and hence to be better prepared and take effective measures to counter them (Danchin 2024). 3.16 | Creating Barriers to Infectious Amyloid Neurodegenerative diseases, like Alzheimer's and Parkinson's (a) are major, essentially unpreventable and untreatable lethal diseases of old age, (b) involve progressive buildup of denatured protein—amyloid—plaques in the brain that inhibit normal neurological functions, and (c) are similar in some ways (progressive amyloid buildup) to prion diseases. There is an association between Alzheimer's disease and the gut microbiota (Grabrucker etal.2023; Marizzoni etal.2023; Williams etal.2024). Prion diseases of animals cause transmissible spongiform encephalopathies (TSEs), such as bovine spongiform encephalopathy (BSE; mad cow disease) in cattle and scrapie in sheep (Prusiner 1998). BSE can be transmitted via infected animal products to humans causing variant CreutzfeldtJakob disease (vCJD). A characteristic of the denatured protein in amyloid plaques is the failure of onsite protein quality control systems (i.e., proteases and chaperones) to degrade and recycle it. Prion amyloid is infective, that is, acts as a template to promote misfolding of similar proteins, and thereby reproduces. Bacteria, including gut bacteria, are known to produce and release amyloid proteins (Giraldo 2020), for example, in biofilms, and a possibility that has been raised is that one potential aetiology of human neurodegenerative disease is that gut bacteriaproduced amyloid migrates to the brain and acts as a template that catalyses initiation and propagation of human amyloid in the brain (Jain2024; Elkins, Jain, and Tükel2024). One potential strategy being explored to reduce the incidence of amyloidcaused neurodegenerative disease is the removal of amyloidproducing microbes, or of the secreted amyloid itself, in the gut microbiota. Another relates to the fact that gut microbiotaproduced metabolites have proinflammatory activity on neurons and glia (e.g., see Cattaneo etal.2017), which creates a window of opportunity to intervene in microbial metabolic networks to downregulate production of such metabolites. Prion proteins released into soils from dead animals are long lived and contaminated soils may represent a source of new infections. Moreover, plants are known to take up prion proteins via their roots, transport them to their aerial parts, and thence transmit them to herbivores (Carlson etal. 2023). One possibility to confront this risk may be the deployment of microbial proteases able to degrade animal prions and targeting contaminated soils (and their runoff waters), and/or their ecosystem engineers, like earthworms (Nechitaylo etal.2010; Pritzkow etal.2021) and plant rhizospheres (Elkins, Jain, and Tükel2024). 4 | The Microbiome Barrier The human microbiome consists primarily of microbial populations—microbiota—on the different body surfaces: skin, oral cavity, gastrointestinal (GI) tract, respiratory tract, ocular surface and genital tract. Some internal tissues/organs may also be colonised temporarily (e.g., blood following a cut or graze, after brushing the teeth; see also Tan, Ko, etal.2023; MichánDoña, VázquezBorrego, and Michán2024) or longer term (e.g., tumour colonisation: Nejman etal.2020). Each body site is characterised by unique physiological conditions that select microbiota of different compositions with different activities and interactions with host tissues—functionalities—and health consequences (McCallum and Tropini 2024). Most of these interactions are either positive or essential: they are the basis of the goods and services the microbiome contributes to the humanmicrobiome partnership. Microbial technology strategies to raise barriers against chronic and recurrent infections Important progress is being made in this effort, ranging from the identification of nonor weakly varying epitopes of pathogens with highly variable surfaces, that can serve as targets for effective vaccines and immune therapies, the use of antibiotics/antibiotic carrier systems (e.g., nanocarriers: see Yan etal.2024) that can penetrate body sites, such as the brain, that are poorly accessible by traditional drugs, and the development of antibiotics that attack biofilm and dormant microbes (Lebeaux, Ghigo, and Beloin2014; Petersen etal.2024). 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
16 of 61 Microbial Biotechnology, 2025 choose or are obliged to repartition their daily schedules to reduce the times they allocate to food preparation and consumption (Baker etal.2020; https:// www. nature. com/ artic les/ d4247 302400020 - 7. pdf). Importantly, ultraprocessed foods have a significant impact on gut microbiota composition and function, which is linked to increased intestinal permeability and inflammation, and inflammatory bowel disease, colorectal cancer and irritable bowel syndrome (Du etal.2024; Whelan etal.2024). 6.6 | Microbial Technology Barriers Against Micronutrient Deficiencies Micronutrients are organic or inorganic elements and compounds such as vitamins and minerals. They are crucial for the maintenance of human health: some are components of enzymes that carry out key cellular activities, others regulate biosynthetic cellular reactions essential for immune functions and energy generation, and yet others are essential for biological processes such as growth, bone health, and fluid balance (https:// ourwo rldin data. org/ micro nutri entdefic iency ; https:// www. fao. org/4/ X0245E/ x0245 e01. htm; https:// www. fao. org/4/ X5244E/ X5244 e03. htm; https:// www. bbc. com/ f ut u re/ b e sp o ke/ fol lo wt he - foo d / theh idd e nhu ng e ra f f e c tingbilli ons/ ). Micronutrients also modulate the diversity and composition of the gut microbiome, leading to beneficial or detrimental outcomes for human health. Humans cannot synthesise all the required micronutrients, so they need to acquire them exogenously mainly from three major sources: (a) dietary components, (b) synthesis by commensal gut bacteria and (c) as oral food supplements. One quarter of the world's population, and half of the children, may suffer from micronutrient deficiencies resulting from reduced intake and/or poor absorption that lead to or aggravate many chronic diseases, such as allergies, inflammatory diseases, metabolic and endocrine disorders, cardiovascular diseases and even cancer (Shenkin 2006). Micronutrient deficiencies dramatically impact the quality of life, lead to physical and mental dysfunctions, and increase susceptibility to infectious diseases by impairing immune functions (Barone etal.2022; Noushin etal.2021). As mentioned above, microbes produce a range of nutrients in the gut that are essential for the host. In analogous fashion, microbes can produce in cell factories such nutrients to be used as food supplements. Another promising strategy to reduce micronutrient deficiencies is biofortification: the increase in levels of micronutrients in crop plants. This may involve classical plant breeding, rhizosphere microbiota interventions or genetic engineering. Rhizosphere microbiota interventions are particularly interesting because existing crop plants can be used and applications can be rapid (Dhiman etal.2023; Kumari etal.2023). However, plant:microbe:soil interactions are dynamic and not always reproducible. Another approach being explored relates to phytate, which is a major storage form of phosphorus in cereals, legumes, oil seeds and nuts (Gupta, Gangoliya, and Singh2015). Although phytate may have some health benefits, it is considered an antinutritional factor because it also forms complexes with dietary minerals, especially iron and zinc, and causes mineralrelated micronutrient deficiency in those humans who are primarily dependent upon grainbased foods. For this reason, phytase supplementation of human plant food is under investigation to find the right conditions that maximise benefits of both phytate and phytase (Kumar etal.2010; DersjantLi etal. 2015). The gut microbiota regulates the intestinal levels of essential vitamins (such as vitamins Bgroup, C, D, E, K, etc.), minerals (such as calcium, magnesium, iron and phosphorus), and healthrelated compounds, such as shortchain fatty acids (like acetic, propionic and butyric acids). Importantly, the gut microbiota also influences micronutrient uptake (Barone etal.2022; Noushin etal.2021; Lin and Medeiros2023). Gaining an understanding of the intricate interplay of host, microbiota and nutrition in gut physiology, and the relevant biochemical pathways and their regulation, will undoubtedly help develop microbiome and nutrition interventions that increase levels and absorption of micronutrients and hence barriers against micronutrient deficiencies. 6.7 | Soil Health and Human Health Plants are the base of terrestrial food chains that lead to human nutrition and thus play a major role in nutritionrelated health. They are also pivotal for biodiversity and the services it provides, and for carbon capture (and, with microbial partners, burial) and hence global warming and its threats to health. Therefore, any parameter that generically influences plant health and productivity influences human health. Soil fertility is fundamental to plant productivity and crop yields, and soil availability determines the extent to which crop plants can be grown, hence the soil health:human health relationship. But soil health and food production is only one aspect of the importance of soil (https:// www. w e for um. or g/ agend a/ 2024/ 10/ soi lhealt h - human - he alt h - c onne c tion/ ? utm_ s our c e= sfmc& utm_ mediu m= email & utm_ campa ign= 28370 04_ Agend aWeek ly4Octo ber20 24& utm_ term= & email Type= Agenda% 20Weekly). Besides supporting plant growth, soil functions as a complex ecosystem for animals and microbes, acting as a natural reactor that purifies water, replenishes aquifers and balances surface waters through various chemical and biological processes. It plays an essential role in biogenic cycles pivotal to life. About 20% of the carbon fixed by plants is released into the soil, enriching its organic matter, improving soil quality and vitalising it and the organisms that call it home (Ramos and Timmis 2021; Timmis and Ramos2021; Singh etal.2023; Ulbrich etal.2022). Although sequestration of carbon in soils is crucial for mitigating climate change, poor soil management practices can exacerbate greenhouse gas Microbial technologies to raise barriers against micronutrient deficiencies • Production of micronutrient supplements in cell factories • Fermented foods • Crop biofortification • Phytase • Microbiome interventions 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
17 of 61 emissions. Both the United Nations and European Commission stress the importance of sustainable soil practices to reduce these risks. In response to these vital functions, the European Union launched a mission program to enhance soil health and restore polluted sites (https:// rea. ec. europa. eu/ fundi ngandgrants/ horiz on - europ eclust er6foodbio ec onom y - n a tur alres ou rcesagric ultur eandenvir onment/ soilmissi on_ en). This initiative highlights the importance of maintaining healthy soils, an issue as important as plastic or water pollution. The growing global population, projected to reach 10 billion by 2050 (https:// ourwo rldin data. org/ unpopul ation - 2024revision), demands greater food production, underscoring the need to preserve and build healthy topsoil. Effective soil management is key to tackling global challenges like food insecurity, climate change and biodiversity loss (https:// openk nowle dge. fao. org/ server/ api/ core/ bitst reams/ a4fd8 ac54582 - 4a66 - 91b 055abf 6 42a4 00/ content). Soil biodiversity, which includes an immense reservoir of microscopic life, plays a critical role in these processes. For instance, a single gram of rhizosphere soil (the soil near plant roots) can contain between 10 and 100 million microbes, while bulk soil can hold 10,000 to 1 million microbes per gram. Despite this diversity, < 1% of soil microbes have been successfully cultivated in laboratories and characterised (Lutz etal.2023; Panda and Zhou2023). Recent advances in metagenomics are revealing the extent of this microbial diversity and their interactions, which are essential for sustaining biogenic cycles and restore natural ecosystems (Ramos, de Lorenzo, and López2024; Singh etal.2023). To address the importance of soil health we should take into account that nearly a century is needed to form just 3 mm of topsoil, making it a nonrenewable resource within human lifespans. It is estimated that 33% of the world's land is threatened by desertification, with 25% of European agricultural soils severely damaged. Climate change compounds these issues by reducing rainfall, increasing desertification and threatening agricultural output. Projections suggest a 30% decline in food production due to plant diseases and plagues, potentially leading to hunger, mass migrations, and economic and sociopolitical instability (https :// www. u ndrr. org/ unde r stand ingdi sas t e rr isk/ termi nology/ hips/ en0019; https:// www. wefor um. org/ agenda/ 2024/ 09/ tripl e - cop - yearleade rsalig n - ef for t spla ne taryhealt h/? utm_ sourc e= sfmc& utm _ mediu m= ema il & ut m _ c ampa ign= 28365 67_ A gend aWeek ly27Sep tembe r202 4 & utm_ term= & email Type= Agenda% 20Weekly). Soils also vary in terms of their plant pathogen burdens, which can determine the health and yield of a crop. Repeated cultivation of the same crop in the same soil can enrich for pathogens of that crop and a progressive lowering of yields. On the other hand, some soils—diseasesuppressive soils—can either prevent establishment of relevant pathogens, or allow their establishment but restrict their potential to cause disease (Baker and Cook 1974). Diseasesuppressive soils suppress disease because of microbial activities (e.g., Mendes etal. 2011), characterised by a competitive environment of a high and active microbial biomass, which limits access of the pathogen to available resources, and by production of antimicrobial compounds (e.g., see Schlatter etal. 2017). Importantly, specific suppressiveness can be transferred to and conferred upon disease conducive soils, thereby increasing plant health and yields. Protecting soil is important for rural economies and enhances agricultural sustainability. Initiatives like the European Green Deal promote soil health policies aimed at achieving sustainable agriculture and forestry by 2030 and 2050 (https:// rea. ec. europa. eu/ fundi ngandgrants/ eumissi onsoildealeurope_ en). Healthy soils help mitigate desertification, pollution and biodiversity loss, while also supporting microbial systems that enable plants to tolerate extreme conditions. Microbial technologies can help improve marginal soils, offering a solution to expand cultivable land and boost food security in vulnerable regions (Maestre, Sole, and Singh 2017; Bernal2024). For these reasons, a more proactive approach to preserving soil fertility, slowing the process of desertification, regenerating lowfertility soils and maintaining our ability to produce food for a growing global population has been proposed (Timmis and Ramos 2021; see also Rhodes 2017). This urges adoption of policies that treat soils worldwide as ‘patients in need of healthcare and creation of (a) a public health system for development of effective policies for land use, conservation, restoration, recommendations of prophylactic measures, monitoring and identification of problems (epidemiology), organizing crisis responses, etc., and (b) a healthcare system charged with soil care: the promotion of good practices, implementation of prophylaxis measures, and institution of therapies for treatment of unhealthy soils and restoration of drylands’ (see also Maestre, Sole, and Singh 2017). It further recommends ‘elaboration of internationally agreed laws to protect the environment, to define ecocrimes/ecocide/environmental crimes, including those that deliberately degrade soil health or pollute, and appropriate sanctions, and creation of the International Environmental Court (https:// www. ibanet. org/ Artic le/ NewDe tail. aspx? Artic leUid = 71b81 7c7802648de874450d22 7954e04; Greene 2019; Solntsev 2019) to prosecute/adjudicate such laws’. 7 | Microbial Technology Barriers to Intoxication 7.1 | The Disease Burden of Intoxication Intoxication—the poisoning of the body—takes many forms with many outcomes, ranging from mild discomfort to death, and from acute to chronic disease. Particularly concerning is longterm (chronic), lowlevel exposure to environmental chemicals (micropollutants), including diverse agrochemicals used Microbial technologies to increase the acreage of healthy, fertile soils • Biofertilisers • Biopesticides • Plant:microbe partnerships to improve and maintain soil fertility and structure • Plant:microbe partnerships to regenerate lowfertility and desertified soils • Microbial inoculants to increase plant resistance to stressors and range of cultivation • Microbial inoculants to increase plant resilience and resistance to increasing stressors of global warming • Microbiota transfers from disease suppressive to disease conducive soils 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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18 of 61 Microbial Biotechnology, 2025 on crop plants, with slowly developing symptoms that are recognised late in disease progression, and emerging pollutants (Wang, Xiang, etal.2024; Wang, Li, etal. 2024) and contaminants of emerging concern (CECs; https:// planb leu. org/ wpconte nt/ uploa ds/ 2021/ 05/ Pollu tionemerg entes - EN. pdf). An extension of intoxication is the exposure to allergens, which can also have a range of health outcomes. According to Fuller et al. (2022), 9 million premature deaths were attributable to environmental pollution in 2019, with air pollution responsible for 6.7 million and water pollution for 1.4 million. But the authors remark that these are underestimates because of the lack of comprehensive health data. The WHO estimates that 24% of global deaths are linked to the environment (https : // www. who. int / d a ta/ gho/ da ta/ t he me s / topics/ sd g - targ e t3_ 9morta lityfromenvir onmen talpollu tion). 7.2 | Chemical Toxins Chemical toxins are highly diverse and have many sources, such as industrial manufacturing processes, mining, including the extraction, processing and use of fossil fuels, accidents of transportation and storage of chemicals, handling and disposal of wastes, agricultural practices, domestic use of fossil fuels, and mobility. Many pollutants are channelled into municipal wastewater treatment plants, whereas industrial pollutants are usually treated onsite at the point of production. In both cases, the treatment processes may or may not remove all of the pollutants and, if not, they enter the environment where they may negatively impact the health of life forms in the biosphere, including that of humans. Nondegradable pollutants and heavy metals like mercury that reach the sea can bioaccumulate in the food web and reach dangerous levels in top predators, like tuna, which may become part of our diet (e.g., see https:// www. bloom assoc iation. org/ en/ mercu ryc onta minat ionbloom - expos esahealt hscand alonanunpre ceden tedscale/ ). Delayed cognitive development has been observed in children suffering from mercury intake resulting from fishrich diets (Freire etal.2010). Whereas the primary action needed to reduce chemical intoxication is the reduction in production and release of pollutants, this is difficult to achieve in many cases and will take considerable time in others. In addition to ongoing production of pollutants and their contamination of air, water and soils, there are many ‘legacy sites’, sometimes containing massive amounts of toxic chemicals that can leak into and disperse in surrounding soils, watersheds and, through volatilisation, into aboveground air. Microbes are the great transformers—the catalysts of biogeochemical processes—and are key agents of processes that transform many toxic pollutants into harmless or less harmful products. Microbes are the basis of wastewater treatment and bioremediation technologies that reduce pollutant levels and hence human exposure to and suffering from chemical intoxication (e.g., Timmis, Steffan, and Unterman1994; Young and Cerniglia 1995; DuranteRodríguez et al. 2024). Even emerging pollutants and nondegradable metal pollutants, such as the example of mercury above, can be transformed by microbes from toxic species into less toxic or less bioavailable species, activities that have been developed into bioremediation technologies (WagnerDöbler etal.2000; Ding etal.2024; Kariyawasam etal.2024). Microbial technologies for pollutant mitigation raise barriers to morbidity and mortality and improve quality of life. However, some communities still lack these basic technologies so there is an urgent need to deploy them where needed. 7.3 | Air Pollution According to the WHO, ‘Almost all of the global population (99%) are exposed to air pollution levels that exceed the safe WHO guideline level…’ (https:// www. who. int/ teams/ envir onmen tclima techang eandhealth/ airquali t yenerg yandhea lt h/ healt himpac ts/ expos ureairpollu tion#: ~: text= Ambie nt % 20(O utdo or)% 2 0 Ai r % 20Pol lution% 2 0Exp osu re ,the% 2 0h ig hest% 20lev els% 20of% 20exp osure ). Exposure in utero can have lifelong health impacts (https:// www. state ofglo balair. org/ sites/ defau lt/ files/ docum ents/ 20 2406/ how_ does_ air_ pollu tion_ impact_ child rens_ health_ facts heet. pdf). Further: ‘An estimated 4.2 million deaths globally are linked to ambient air pollution, mainly from heart disease, stroke, chronic obstructive pulmonary disease, lung cancer and acute respiratory infections. The health consequences of air pollution have a significant economic impact’ (https:// www. oecdilibr ary. org/ docse rver/ 56119 490en. pdf? expir es= 17 256 07601 & id= id& accn a me= guest & check sum= 52AFE 630E9 AF166 C7CD3 3F792 651BFA3). Air pollution is often coupled with odour pollution, because the responsible gasesvolatile organic chemicals (VOCs) are often malodorous, which also lowers the quality of life in affected localities (Rotton1983; Shusterman1999; GuadalupeFernandez etal.2021). Global warming has diverse impacts on air pollution, including levels of ozone, particulates, organic aerosols and persistent organic pollutants, which in turn influence the composition of the aerobiome, the air microbiota (Robinson etal.2024), all of which are taken into the lungs in the average 6 L of air that humans inhale per minute (Pleil etal.2021). While air pollution comes in many forms and from many different types of sources, industrial offand processgases are an important source and many can be captured and rendered harmless by microbial filters (Devinny, Deshusses, and Webster1998; Komang RalebitsoSenior etal. 2012; Lan etal.2020) in processes called biofiltration, biotrickling filtration and bioscrubbing, in some instances also generating electrical energy in the process (Liu, Lin, and Lin2023). Atsource treatment of industrial off gases by microbial systems not only removes polluting gases, lowering emissions and thereby reducing health impacts, but also captures carbon and reduces carbon emissions, thereby reducing their contribution to global warming and its health impacts. 7.4 | Noninfectious Food Poisoning Food can be contaminated in various ways by a variety of toxins. A major class is microbial toxins that can be introduced at 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
19 of 61 different stages in the food supply chain. These include mycotoxins (https:// www. who. int/ newsroom/ factsheets/ detail/ mycot oxi ns #: ~: tex t= Key % 2 0 fa c t s,under% 2 0wa r m% 20 and% 20 hum id% 20con ditions) produced in planta or during postharvest fungal growth, like aflatoxins, toxins found in shellfish and finfish harvested from waters experiencing harmful algal blooms, and toxincontaining meals, the preparation of which allowed growth of toxinproducing microbes, like Staphylococcus aureus, Clostridium spp., Bacillus cereus and so forth in a component of the meal. Unlike most foodborne pathogens which can be killed by cooking, many toxins are heat stable, and are not inactivated by cooking. Allergens can also be delivered by food, either as inherent components, or extrinsic substances acquired along the farmtofork chain. While much of the strategy to avoid food poisoning revolves around hygiene practices, an important microbiological technology is that of toxin and allergen detection/monitoring which enables the removal of contaminated materials from the food supply chain and identification and elimination of operational practices that allow toxin contamination of food. While there are a number of different ways of detecting and measuring toxins and allergens in food, biosensors and lateral flow tests have the advantages of portability—they can be used essentially anywhere, so onsite at any point in the food supply chain, are usually simple to use, so do not need highly trained personnel, and many are or can be made frugal, so can be used worldwide. Many such tests are based on immunological detection of the target substance and use antibodies and control antigens produced in microbial cell factories. 7.5 | Agrochemical Intoxicants and Causes of Intoxication Pollution with agrochemicals is particularly insidious because they can enter the human food supply chain (Ahmad etal.2024) but also directly affect people handling them or the products they have been used to treat (e.g., see: https:// www. bbc. com/ news/ artic les/ c4gly dv8qlgo). Moreover, chemical pesticides not only directly affect humans but, because of their low specificity, poison a range of nontarget organisms. These include beneficial insects, such as pollinators (Stuligross and Williams2021; Douglas etal.2022), and earthworm ecosystem engineers (Zeng etal. 2024, both of which are essential for food security which is a barrier to malnutrition. Contaminated worms are in turn eaten by birds (see also Carson1962). Nontarget effects of pesticides are exacerbated by climate change (SiroisDelisle and Kerr2022). Agrochemical fertilisers, primarily nitrogen (see Verstraete2024, for a comprehensive overview of nitrogen and its benefits and hazards) and phosphorus compounds, while not toxicants in of themselves, engender toxin production by causing eutrophication and harmful algal blooms in receiving water bodies. This is due to the fact that agrochemical fertilisers are highly mobile in water and, rather than being used by target plants for growth, mostly migrate in runoff into receiving water bodies. Microalgae that inhabit these water bodies are mostly nitrogenand/or phosphoruslimited for growth. Their population sizes determine the nature of prevailing aquatic food webs. An influx of agricultural fertiliser removes the growth limitation and there is a burst of growth—a bloom—of microalgae, the process of eutrophication, that exceeds the grazing capacity of available predators and hence perturbs the food web. Growth of the microalgae therefore continues until nutrients are exhausted, after which they die and are degraded by bacteria which in the process consume most or all of the available oxyge. The microalgae and cyanobacteria that bloom in response to the inflow of nutrients often produce toxins, particularly neurotoxins, many of which are lethal to aquatic animals, especially filter feeders and animals feeding on them, fish, larger aquatic species and birds feeding on fish, and humans (https:// unesd oc. unesco. org/ ark:/ 48223/ pf000 0233419; https:// www. fishe ries. noa a . gov/ featu restor y/ toxic - a lgal - bloom - suspe cteddolph inandsealiondeath ssouth erncalif ornia ; Karlson et al. 2021). Algal blooms mandate the prohibition of harvesting, sale and consumption of affected shellfish and finfish, so reduce food security and have significant economic impacts, especially on coastal populations dependent on fish. Eutrophication also creates oxygen minimum (dead) zones in aquatic systems, causing the death of oxygenrequiring species, loss of coral reef systems and local biodiversity (Altieri etal.2017), and frequently, major kills of fish that again decrease food security. Although harmful algal blooms are also naturally caused by the transportation of nutrients from nutrientrich to nutrientpoor environments, for example by upwelling events involving nutrientladen deep cold waters (Pitcher etal.2010), and wind transportation/deposition events of nutrientrich soil particles to nutrientpoor photic surface waters (https:// www. epa. gov/ habs/ clima techang eandfresh water - ha r mf ulalga l - bloom s #: ~: t ext = Coa st a l% 20 upw elli n g& tex t= A long% 2 0 the% 2 0west% 20coa st% 20of,nutri ent% 20pol lution% 20from% 20the% 20land), a major contributor to eutrophication is agrochemical fertiliser runoff from agricultural land. The only means of countering this source of eutrophication is massive reduction in the use of agrochemical fertilisers on farmland. But, because of the need Microbial technologies that raise barriers against intoxication • Municipal wastewater treatment • Drinking water treatment • Microbial filters for industrial offgas removal • Industrial pollutant wastewater degradation systems • Industrial heavy metal capture wastewater systems • Environmental bioremediation by pollutant biodegradation • Environmental bioremediation by heavy metal biocapture and/or bioimmobilisation • Plant–microbe partnerships for pollutant biodegradation and bioconcentration • Land farming • Constructed wetlands • Reporter systems for detecting toxins in water and food • Reporter systems for environmental detection, measuring and mapping of pollutants 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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20 of 61 Microbial Biotechnology, 2025 for fertiliser to achieve crop yields needed to feed the growing human population, in order to do this, alternative fertilisers are required: the agrobiologicals (Bernal2024). Plant symbiotic nitrogenfixing bacteria (rhizobia) live in symbiosis with leguminous plants, fix atmospheric nitrogen and make it available to the plant. Nfixation by bacteria associated with nonleguminous plants also exist. Other microbes, particularly mycorrhizal fungi, solubilise and make available phosphorus in soil that is otherwise unavailable to plants. Plantassociated microbes also mobilise micronutrients important for plant growth and vitality. Agrobiologicals not only include microbes that provide or facilitate acquisition of plant nutrients and plant stress tolerance promoters, but also serve as biopesticides against a variety of plant pathogens and pests (bacterial, fungal, insect, nematode: Ruffner etal. 2012; Collinge etal.2022; Bernal2024; Compant etal.2025; Erdrich etal.2024; Jiménez etal.2024). Importantly, in contrast to agrochemical pesticides, agrobiologicals tend to be highly specific, not affecting nontarget organisms like pollinators, and have a low impact on ecosystems and the services they provide. 7.6 | Animal Venoms and Toxins Many animals, including bees and wasps, ants, spiders, jellyfish and snakes, produce toxins (Chen etal. 2018). Snake envenoming—the injection of venom and resulting disease (Gutiérrez etal. 2017)—has been called the world's biggest hidden health crisis (Basnyat and Shilpakar 2022), with more than 5 million people bitten by snakes each year, resulting in ca. 2 m envenomings, ca. 100,000 deaths, and ca. 300,000 amputations and permanent disabilities (Kasturiratne etal. 2008; https:// www. who. i nt/ ne w s - r o om / fa c ts he et s / det a i l / snake bite - env en om i n g # : ~: text= An% 20est imate d% 2 05 . 4% 20mil lion% 2 0p eo ple, are% 20 cau sed% 20by% 20sna kebit es% 20ann ually ; https:// www. nature. com/ artic les/ s4146702233627-9# citeas). Snake bites are particularly important in rural areas of tropical and subtropical countries, and children are particularly vulnerable because of their smaller body mass. Antivenom antibodies are generally effective treatments, but their timely delivery to patients can be challenging in settings with weak health systems and infrastructure. Moreover, even under ideal clinical treatment conditions, antivenoms are not perfect (Hamza etal. 2021; BenardValle etal. 2024). However, there is considerable current activity developing new, more effective antivenom therapeutics based on oligoclonal nanobodies obtained by phage display technology, and produced in microbial cell factories (see Ledsgaard etal. 2023; BenardValle etal. 2024, and references therein). 7.7 | Ecosystem Engineering Microbial Barriers for Health and Resilience The issue of environmental pollution caused by chemical emissions from urban, agricultural and industrial activities is a welldocumented, critical challenge for the future of our planet. It has long been understood that many microorganisms can degrade pollutants into CO2 and water. The study of interactions between microorganisms and chemical pollution gained significant momentum with the advent of recombinant DNA technology in the mid/late 1980s. On one hand, molecular techniques allowed microbiologists and biochemists to explore and dissect the immense catalytic potential of environmental microorganisms in combating contaminants. On the other, these technologies anticipated the potential to genetically engineer new traits, creating supercatalysts that, once released, could address many environmental issues caused by different types of emissions (Timmis, Steffan, and Unterman1994). However, these early efforts were hampered by the limited understanding of microbial ecology at the time and opposition from environmental groups to genetic engineering. As a result, while the promise of these approaches was recognised, their immense potential remained largely unrealised (Cases and de Lorenzo2005). A few decades later, we are now facing a vastly different pollution scenario, compelling us to revisit some of the earlier ambitions and integrate them with modern tools that were unavailable back then. While the traditional response to the widespread presence of diverse chemicals and greenhouse gases has focused on prevention and monitoring, the time is now ripe for entertaining largescale bioremediation interventions that not only mitigate but reverse environmental damage (de Lorenzo, Marlière, and Solé2016). In this way, we can now consider actions aimed at counteracting pollution in both targeted and extensive ecosystems. The objective in these cases is not only to rehabilitate them, but also protect them from future aggressions and secure their longterm functionality (Hassard etal.2024). Note that successful largescale ecosystem engineering for the sake of sustainability is not a new endeavour, as evidenced by the effort along the XIX century to bring a balanced biological network to Ascension Island (Wilkinson2004). How can this be achieved in our case? First, we now possess a far greater understanding of microbial ecology and element cycling on a planetary scale. The catalytic potential of the global environmental microbiome (Paoli etal.2022) may be the most powerful actor in changing the state of the planet, as has been the case in other moments of our planet's History. The spectacular increase in Earthwide metagenomic data attests to this. Second, the nature and distribution of pollutants have also evolved. Whereas past bioremediation efforts concentrated on localised oil spills or toxic chemicals at specific sites, the current challenge lies not only in managing globally spread greenhouse gases but also in addressing ubiquitous micropollutants and microplastics (de Lorenzo2017). A new branch of microbial biotechnology, which we are calling Environmental Galenics (de Lorenzo2022), must be developed to deliver live catalytic agents on a large scale, capable of tackling these extraordinary challenges. There is also a third crucial aspect: the need to adopt advanced genetic engineering and synthetic biology to enhance the biochemical capabilities of microbial agents. While it is true that many environmental problems could be alleviated by simply reducing or stopping the sources of emissions, if stressed environments surpass tipping points, eliminating the causes alone will not be sufficient. In such cases, advanced interventions will be necessary, likely involving the release of catalysts genetically programmed to restore environmental balance. This, of course, demands a broader public debate and the expansion of societal consensus around the technology, as the 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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21 of 61 regulations governing these developments have remained stagnant for the last 30 years, despite remarkable advances in genome editing, environmental impact modelling (CondePueyo et al. 2020), and the development of entirely new enzymatic functions in the Laboratory (Arnold2015; Hossack, Hardy, and Green2023). Just as serious human diseases require advanced medical treatments, serious environmental problems require cuttingedge solutions based on the best systems and synthetic (micro) biology of our time (Timmis and Ramos2021). 8 | Microbial Technologies to Confront Global Warming 8.1 | The Health Burden of Global Warming Global warming is likely to be the most important cause of increasing suffering and mortality in the coming years. Global warminginduced climate change and extreme weather events affect wellbeing, morbidity, mental health and mortality in a variety of ways (Gasparrini et al. 2015; https:// iris. who. int/ bit st re am/ ha ndle/ 10 6 65/ 10 7552/ 9 78 92 89 010 94 8 - en g. pd f ? seque nce= 1& isAll owed= y; https:// www. ipcc. ch/ report/ ar6/ syr/ ), through a diverse range of often interacting and synergising causes (https:// www. ipcc. ch/ report/ ar6/ syr/ downl oads/ report/ IPCC_ AR6_ SYR_ SPM. pdf), with the elderly and those suffering from underlying morbidities affected the most by weather extremes, especially women (Calleja-Agius, England, and Calleja 2021; https:// www. swiss info. ch/ eng/ cl i m a techan g e/ w hyolder - women - a r eh ith ar de stbydea d l yheatw aves/ 78907 902# : ~: tex t= Older % 20a du lts% 2 C % 20esp ecial ly % 2 0ov er % 2 075,verdi ct% 2 0 aga in st% 2 0S w i tzerl and% 20 in% 20April; https:// www. swiss info. ch/ eng/ scien ce/ histo ricverdi ctcould - linkclima tecrisi sandhuman - rights/ 75321434). One study estimates that by 2050 global warming will have been responsible for 2 billion DALYs and 14.5 million premature deaths (https:// www3. wefor um. org/ docs/ WEF_ Quant ifying_ the_ Impact_ of _ Cl ima te _ Cha nge _ on _ Human_ Hea lth _ 20 2 4 . pdf). Around 3.5 billion people live in regions highly vulnerable to climate change (https:// www. ipcc. ch/ report/ ar6/ syr/ downl oads/ report/ IPCC_ AR6_ SYR_ SPM. pdf). Children, the elderly and people in lowresource settings will be disproportionately affected and existing health inequities exacerbated (https:// www. wef or um . or g/ a gend a / 2024 / 0 9/ ch i ld r encl i m a t e - ch a n g eimpac thealt h/? utm _ sourc e= sfmc& utm _ mediu m= email & utm_ campa ign= 28370 04_ Agend aWeek ly4Octo ber20 24& utm_ term= & email Type= Agenda% 20Weekly; CallejaAgius etal. 2021; https:// www. who. int/ newsroom/ factsheets/ detail/ clima techang eandhealth; see also Bressler2021). The global economic cost, and health cost in particular, will be huge. The effects of climate change on human health will become increasingly severe as the pace of climate change accelerates. Some existing health threats will increase and new health threats will emerge. There are strong indications that climate change may lead, inter alia, to an increase in respiratory and cardiovascular diseases, injuries and premature deaths related to extreme weather events, and changes in the prevalence and geographical distribution of food and waterborne diseases and other infectious diseases. This will inevitably lead to increases in hospitalisations, particularly for those with underlying illnesses, and rises in hospitalacquired infections with pathogens that are often antibiotic resistant. Weather extremes also cause desertification and erosion of fertile agricultural land, which reduces available acreage for crops and hence food supply, and thereby increases malnutrition and resulting disease. Global warming also provokes changes in the geographical distribution of organisms of the biosphere. One of many consequences is the killing of essential algal symbionts of coral, leading to the death of coral reefs and destruction of habitats of marine life and food webs that ultimately provide food for humans. Shoreline communities that are heavily dependent on fish for their nutrition are particularly affected and malnutritionrelated diseases alluded to above can result. Another consequence is the ability of insect disease vectors to populate regions at higher latitudes and introduce new pathogens into naïve populations. If (when) the human species goes extinct, global warming will probably be the cause. Humans thus have huge personal and collective selfinterests in mitigating greenhouse gas (GHG) emissions that drive global warming. Microbes are intimately and essentially involved in a number of aspects of the production and consumption of GHGs (Cavicchioli etal. 2019) and these activities can be influenced in a number of ways. There are fundamentally two actions to reduce atmospheric GHGs: (a) reduce/prevent their production, and (b) capture them after production. There are a number of microbial technologies for reducing GHG emissions and capturing carbon, both of which can positively modulate carbon fluxes. 8.2 | Carbon Capture and Carbon Burial Photosynthesis is the basis of creation of most biomass, and hence food for most organisms of the biosphere. It involves the conversion of carbon dioxide, the principal GHG, to organic carbon, so photosynthetic organisms play a central role in carbon capture. For this reason, planting trees is often promoted as a key carbon capture strategy. However, most trees have a particular average lifetime, after which they die and their carbon is recycled by microbes, much of it back to CO2, mostly by white rot fungi (the emergence of which may have ended the formation of fossil carbon deposits typical of the Palaeozoic era; Floudas etal.2012), if they are not consumed by forest fires beforehand. Carbon capture is thus distinct from carbon burial, which is the sink that removes carbon from the carbon cycle and has a longterm positive impact on global warming. However, some of the carbon captured by photosynthesis is not used for tree growth but is transferred to the roots and released into the soil as exudate, which feeds the tree root microbiota. Tree root exudatepromoted multiplication of rhizosphere microbes creates soil microbial biomass, some of which becomes soil organic matter (SOM), part of which is not recycled and becomes buried (e.g., see PettRidge etal.2021, and references therein). Thus: planting trees is an effective means of capturing carbon from the atmosphere, but it is the tree–microbe partnership that is actually responsible for carbon burial. There are opportunities to improve the fraction of carbon captured that becomes carbon buried through microbial technologies for tuning soil and rhizosphere microbiomes. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
22 of 61 Microbial Biotechnology, 2025 That said, the primary problem of carbon capture by trees is deforestation: the destruction of existing stands of mature trees. Agrifood systems are the single biggest driver of deforestation, biodiversity loss and water use, accounting for one third of global greenhouse gas emissions. Vast tracts of land are cleared annually on an industrial scale to satisfy the evergrowing demand for commodities from international markets (Sylvester etal.2024). In this context, therefore, it is important to note that photosynthetic microbes can carry out both carbon capture and burial on their own, both on soils, in aquatic systems, and importantly in constructed bioreactors that occupy very little space. Unlike trees, they do not need to take up any agricultural land, so do not compete with food production activities; indeed, some may actually contribute food. There are exciting developments to optimise and scale up such activities (Onyeaka and Ekwebelem2023; https:// www. bbc. com/ future/ artic le/ 20230 829thebacte riathatcancaptu recarbon). Engineered microorganisms can also efficiently transform captured carbon into valueadded products (Bae etal.2022; Turlin etal.2022), including and importantly food (Sakarika, Ganigué, and Rabaey2022). 8.3 | Reducing Greenhouse Gas Emissions and Carbon Footprints of Industrial Activities Greenhouse gas emissions that drive global warming, climate change and all of the health consequences that result from this, are still rising (https:// ourwo rldin data. org/ emiss ionsbysector; https:// www. c2es. org/ conte nt/ inter natio nalemiss ions/ ). There is an urgent need to massively reduce emissions and, where possible, to draw down some of the already released GHG. In recent years there has been an explosion in microbiology research and metabolic engineering aimed at reducing greenhouse gas (GHG) emissions, with notable successes (Wang, Nguyen, etal.2021; Wang, Harindintwali, etal.2021; Ahn etal.2023; The Role of Microbes in Mediating Methane Emissions [Internet]. Washington, DC: American Society for Microbiology; 2023 Nov 15. PMID: 38194471; Wood etal.2023; Hiis etal.2024; Tiwari etal.2024). These include the prevention of emissions at source by promotion of green practices, carbonnegative manufacturing, renewable energy production such as microbial production of hydrogen fuel, hydrocarbon biofuels, conversion of GHGs to biofuels, chemicals and materials. Electromicrobial processes show considerable promise for conversion of organic wastes and methane into electricity. Carbon capture technologies involving photosynthetic microbes are important, as are offgas biofilters that capture industrially produced GHGs. Methylotrophs are important in microbial technologies to capture methane at source and convert it into useful products. The construction industry has a very significant carbon footprint, both in terms of GHG emissions and energy used. The incorporation of biological processes and biological products into building materials including bioconcrete and biobricks (https:// www. wefor um. org/ stori es/ 2020/ 02/ resea rcher s - haveinven tedabrick - thatcanbuild - itself/ ; Smirnova etal.2023; Zuiderveen etal.2023) can significantly lower this footprint. Whereas these approaches can be highly effective in addressing point sources of carbon emissions or point origins of carbon capture, many important sources, such as sediments underlying water bodies, and sinks or potential sinks, are nonpoint or diffuse, which is considerably more challenging. Nevertheless, the urgency of the global warming crisis demands attention to nonpoint sources and sinks: largescale environmental microbial carbon capture technologies and technologies to stimulate natural carbon capture processes. For example, one major element of increasing GHG emissions is the global warmingdriven thawing of permafrost and frozen peatlands, with resulting metabolic activation of their microbial communities and production of methane. Fortunately, methane oxidising microbes that use methane as a growth substrate act as a methane biofilter (also in other settings like anaerobic sediments, gas clathrates and landfills) significantly reduce emissions (Dang etal.2022; Venetz etal.2024). Nitrous oxide (N₂O) is a potent greenhouse gas, with a global warming potential about 274 times greater than carbon dioxide (CO₂) over a 100year period. N₂O emissions are particularly concerning in agriculture, wastewater treatment and industrial processes, where microbial activities significantly contribute to its release. Recent advancements in microbial technologies offer solutions to reduce N₂O emissions in nitrogenrich environments, such as wastewater treatment. One example is the anammox (anaerobic ammonium oxidation) process, which treats nitrogen without producing N₂O and provides a more energyefficient alternative to traditional nitrification and denitrification. Anammox bacteria convert ammonia directly into nitrogen gas under anaerobic conditions, minimising N₂O emissions (Henze etal.2008). Another is the use of N₂Orespiring bacteria (Hiis etal.2024) Microbial technology approaches to raise barriers to global warming and its effects • (development and mass planting of plant:microbe partnerships with improved carbon capture and burial characteristics) • Development of microbe:plant partnerships that better tolerate global warming stresses • Development of microbe:crop plant partnerships that tolerate coastal saline soils increasingly created by global warmingpromoted extreme weather events • Microbial food production to improve food security and diminish the pressure for deforestation • (advancement of Wolbachiatype technologies to mitigate expansion of insect vector geographical range and carriage of pathogens) • (development of new prophylaxes and therapies for infections increasing as a result of global warming) • Biofilters to capture industrial offgases • (development of methanotrophs with improved methane capture characteristics and their deployment to reduce methane emissions) • Development of new bioconstruction materials with lower carbon and energy footprints 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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23 of 61 8.4 | Reducing Dependence on Fossil Fuels Biofuels are considered as a key solution to reduce GHG emissions, which peaked in 2023 with CO2 levels at 424 ppm and global temperature increase of 1.45°C over preindustrial levels (https:// www. ipcc. ch/ report/ ar6/ syr/ summa ryforpolic ymake rs/ ; Fletcher etal. 2024). Terrestrial transport and air travel contribute significantly to emissions, with air travel contributing 785 million metric tons of CO2 in 2019 (https:// theic ct. org/ wpconte nt/ uploa ds/ 2021/ 06/ CO2comme rcial - aviat ionoct20 20. pdf) equivalent to the pollution from 164 million cars. Despite global agreements like the Kyoto and Paris protocols pushing green energies (https:// unfccc. int/ sites/ defau lt/ files/ unfccc_ spm_ 2016. pdf), efforts to curb emissions have failed and the UN Climate Conference COP28 affirmed that anthropogenic pollution has an impact on global changes including severe droughts, wildfires and floods all over the planet (https:// unfccc. int/ sites/ defau lt/ files/ resou rce/ Summa ry_ GCA_ COP28. pdf). Current energy trends favour renewable sources such as solar, wind and biofuels. Countries like USA, Brazil, China and European Union have implemented biofuel programs to reduce emissions and to enhance energy security. However, biofuels currently account for a low percentage of global energy use. Ethanol, primarily produced from corn, is the most common biofuel. The US produces about 15 million gallons annually, replacing about 500 million barrels of petroleum. Brazil produces 7.5 billion gallons from sugarcane. However, this bioethanol, known as firstgeneration (1G) biofuel, is derived from food crops and raises concerns over food security, biodiversity and its impact on gasoline demand is limited. Second generation (2G) biofuels and biochemicals, made from nonedible sources like agricultural waste and municipal solid waste (MSW), offer a more sustainable alternative. It has been estimated that only the United States could produce 7.5 billion gallons bioethanol form MSW, which could replace up to 16% of the US transportation fuel, significantly reducing GHG emissions (Kalago etal.2007). Emerging biofuels like butanol, which blends better with gasoline, and advanced fuels like farnesane for aviation, are gaining attention. Additionally, microbial processes for producing chemicals and fuels, such as using methane and methanol for plastic production, offer interesting alternatives. Challenges remain, such as high cost of 2G biofuels and scaling up processes (Valdivia etal.2020), but biofuels hold significant potential to mitigate climate change. 9 | Microbial Technology Barriers to Wastage 9.1 | Wastage of Planetary Resources Geographical and special situation exceptions notwithstanding (e.g., regions of high rainfall that do not experience water shortages), wastage of essential resources in limited supply ultimately negatively impacts health and wellbeing. For example, despite widespread hunger in the world, between 20% and 30% of all food produced is wasted: the equivalent of 1 billion meals per day in a world in which 735 million people go hungry (https:// ope nk nowle d g e . fa o. org/ s erv er/ api/ cor e/ bits t r e ams/ 103 88 b165f1a45d0b690e89bb 78d33 bb/ content, https:// www. wfp. org/ stori es/ 5facts - about - foodwaste - andhunger; https:// www. un. org/ en/ obser vances/ endfoodwaste - day; Javourez etal.2024). More broadly, the linear economy of linear production—resource in, product out, waste discarded (‘takemakewaste’; see also, e.g., Conway 2023)—and linear consumption—product used, product discarded—creates unnecessary waste that needs to be treated, in the process consuming various additional resources including energy and land (e.g., land available in Melbourne for landfill may run out in 2025, and wastes are increasingly being transported to landfill sites ever more remote, with the associated carbon footprint of the additional transportation needed: https : // a c ehub. or g . au/ ne ws/ w h atist helinea re c ono m ya ndwhydoweneedtogocircular). Furthermore, waste creates toxic waste streams and greenhouse gases. Crucially, it often contains still useable limiting natural resources, such as clean water, used in production (e.g., clean water used in semiconductor manufacture: https:// www. wefor um. org/ agenda/ 2024/ 07/ thewater - chal l engeforsemic onduc t o rmanuf ac tu r ingandbigtechwhatneeds - tobedone/ ). Consumerism, fuelled by policies of perpetual economic growth, advertising, media and peer pressure (‘new trends’), etc., and price competition, which often encourages environmentally damaging processes, promotes the linear economy, wastage of natural resources and pollution of the environment. This is exemplified by the fashion industry with fashions changing each year, much nonrecyclable/degradable clothing being made cheaply from materials produced from fossil fuels and being discarded after a short time, some ending up in the Atacama Desert to sit for hundreds of years (https:// www. natio nalge ograp hic. com/ envir onment/ artic le/ chile - fashi onpollu tion), if it does not catch fire/is not burned first (https:// www. wired. com/ story/ fashi ondispo salenvir onment/ ). Consumerism may be considered to be the deliberate creation of stranded assets (Caldecott etal.2021). According to the United Nations, if the human population reaches 9.7 billion by 2050, the resources needed to support it will be three times that which planet Earth can provide (https:// www. un. org/ susta inabl edeve lopme nt/ susta inabl econsu mptio nprodu ction/ ). Both the linear economy and the policy of consumerism are unsustainable. They also negatively impact the biosphere in general, causing loss of biodiversity and reducing ecosystem resilience (according to the European Commission, 90% of biodiversity loss is caused by resource extraction and processing; https:// envir onment. ec. europa. eu/ topics/ circu larecono my_ en). This unnecessarily costs lives and causes suffering in various ways, such as polluting local soils, waters and aquifers, creating shortages of vital resources like clean water, driving up the cost of resources making them unavailable to the less affluent members of society, etc. (https :// www 3 . wef or u m . or g/ docs/ WE F_ New_ Nat u r e_ E c ono my_ Report_ 2020. pdf). The barrier to unnecessary human suffering caused by the linear economy is the circular economy, which is based on the fact that used products either continue to harbour some or all of the 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
24 of 61 Microbial Biotechnology, 2025 resources used in production, or new resources that can be exploited (https:// www. un. org/ sites/ un2. un. org/ files/ circu lar_ econo my_ 14_ march. pdf). The circular economy seeks to eliminate or at least reduce to a minimum resource wastage, by reusing and recycling production waste streams and used products. Where possible, the circular economy also seeks to regenerate, to put resources back into the system to improve its quality and resilience and support biodiversity (Timmis, Ramos, and Verstraete 2022; https:// www. ellen macar thurf ounda tion. org/ thecircu larecono myindetai ldeepdive). The strategies underpinning the circular economy are varied and range from policy through economics to recycling by individual households. Product design is key to the circular economy because up to 80% of the environmental impacts of products are determined at the design phase (https:// envir onment. ec. europa. eu/ topics/ circu larecono my_ en). Because transitioning from linear to circular economies necessitates paradigm–process–economic–behavioural changes, education is crucial for both understanding of what is needed and achieving broad acceptability. Importantly, microbial technologies play vital roles in many different components of the Circular Economy, ranging from water purification for reuse (https : // asm . o r g/ a rt ic le s / 20 20/ a pri l / howm ic r o b eshelpusrecla imourwaste water ; Metcalf and Eddy Inc. An AECOM Company et al. 2007), metal recovery from digital devices (Chauhan etal.2018; Han, Teo, and Yew2022), resource recovery from wastewaters (Pikaar etal.2022), energy generation from wastewaters (Tchobanoglous, Burton, and Stensel1991; Bazina et al. 2023), the creation of new, better recyclable materials such as microbial polymers (Zhu, Romain, and Williams2016; PereyraCamacho and Pardo2024) and cellulose (Wang, Lu, and Zhang2016), and less polluting extraction processes through biomining (Ehrlich and Newman 2008; Jerez 2017). 10 | The Potential of Microbial Activities to Counter Disease, Injury and Mortality Caused by Aggression: Warfare, Violence, Discrimination and Abuse In humans, aggression is expressed in different forms—physical and psychological—at different levels, in different circumstances, including abuse of the vulnerable, discrimination, demonisation of groups and nations, conflicts and warfare. It is often expressed in the context of political polarisation, in and out grouping and ‘othering’ (https:// ethic sunwr apped. utexas. edu/ gloss ary/ ingroup - outgroup ; Hitlin, Kwon, and Firat2021), which are often exploited by individuals to gain and maintain personal power, influence and wealth. Comprehensive data on harm and suffering visited by humans on humans are lacking because of extremely low reporting. Data on warfareviolence lethality indicate that the number of premature deaths per 100,000 range between 50 and 500 (htt ps: // ou rwo rldi n dat a . org / g r aph er/ g loba ldeat h - rate - inviole ntpolit icalconfl ictsoverthelongrun; https:// ourwo rldin data. org/ warandpeace ; https:// ourwo rldin data. org/ graph er/ death sinarmed - confl icts; https:// www. dw. com/ en/ glob a lc onfl ic t sde ath - tol lath ighe stin21stcent u ry/ a66047287; Rutar 2024). However, these numbers are those easily measured and just the tip of the iceberg because, as is the case for current conflicts in 2024, a large number of people not killed directly during the conflict experience all manner of injuries and deprivation, including the stressanxiety of experiencing traumatic events (AlburezGutierrez etal.2024), displacement and forced migration, poor access to food, hygiene, healthcare and medicines, education, etc., and human suffering, including grieving for lost family–friends and fragmentation of social groupings, that can translate into massive human suffering, initiation of new and exacerbation of existing health conditions including stressanxietyneuropsychiatric disorders, and poorer quality of life, all of which can result in premature death. The longterm effects on the young are not known but are significant. These, coupled with longterm interruptions in education, have lifechanging consequences, analogous in some ways to those of ‘long Covid’. The global health impact of violence and aggression has not been quantified but it can be assumed that it is huge. While warfare is all about killing and maiming personnel of the ‘other side’, prevention of loss of life and suffering, and healing of personnel of the ‘own side’ are also central elements of warfare. This latter includes vaccination of personnel against infections anticipated in theatres of war, and measures to reduce infections resulting from conditions of poor hygiene that are typically experienced, but also treating physical and mental injuries of affected military and civilian personnel (see also https:// www. nato. int/ cps/ en/ natohq/ offic ial_ texts_ 224669. htm). Available microbial technologies relevant to treatment of physical injuries include antibiotics, microbially produced biocompatible wound dressings, and microbially derived promoters of wound healing (RiveroBuceta etal.2020; Canchy etal.2023; Yin etal.2024). Since it is known that anxietystress are influenced by the gut microbiota, there may be opportunities for microbiota interventions that lessen the effects of, and accelerate recovery from, traumainduced mental problems. Posttraumatic stress disorder (PTSD) in both combatants and civilians, especially the young, is a common outcome of war, developing in 15% of people exposed to trauma (https:// www. who. int/ newsroom/ factsheet s/ det ail/ posttraum at icstres s - disor der#: ~: text= A n% 20 e st imate d% 203.9% 25% 2 0 of % 2 0t he% 20wor ld% 2 0 p op ulat i on% 2 0ha s% 20 ex p erien ce d% 2 0P T S D,c on f l ict% 2 0 or % 20war% 20(3). However, almost 4% of the global population Microbial technologies to reduce wastage and enable the circular economy • Design and production of recyclable, microbially generated materials • Use of wastes to produce microbial biomass • Use of wastes to produce bioenergy • Use of wastes to produce useful materials • Use of wastes to produce food • Use of microbial technologies to recover resources, like metals from electronic devices • Use of microbial technologies to upcycle lower value materials • Recycling used water into clean water 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
25 of 61 experience PTSD during their lifetimes, with rates particularly high following sexual violence. A recent study found that adolescents with PTSD had a distinct gut microbiome profile and lower microbial diversity compared to resilient individuals. Lower microbiome diversity was associated with more posttraumatic symptoms in early childhood, increased emotional and behavioural problems in adolescence, and poor maternal caregiving. The study also revealed less mother–child microbial synchrony in youth with PTSD, suggesting that reduced microbial concordance between mother and child may indicate susceptibility to posttraumatic illness. Importantly, when germfree mice were transplanted with microbiomes from individuals with PTSD, they displayed increased anxiety behaviour, suggesting that the traumaassociated microbiome profile contributes to the anxiety component of PTSD. This important study highlights the potential role of the microbiome as a biological marker for PTSD risk and resilience, and suggests new avenues for microbiomerelated diagnosis and treatment following trauma (Yirmiya etal.2024). Another relevant aspect of microbes in the context of warfare is the potential use of pathogens as weapons (Casadevall and Pirofski2004; Oliveira etal.2020; Gani Mir etal.2022). While most countries have long abandoned microbial weapon research because of the lack of predictability and the logistics of handling and delivery, the relatively low cost of microbial weapons keep them as options for less technically advanced groups, especially terrorist groups. The anthrax attack of 2001 is one such example (Bush and Perez2012). The COVID19 pandemic was a timely reminder that the issue of biological warfare needs to remain in focus (Gostin and Nuzzo2021). Microbial warfare research and development in most countries focuses on developing barriers—defensive strategies—which include early detection systems (Gani Mir etal.2022) and response strategies that include new vaccines (Croucher 2024), phages, antibiotics, as well as handling strategies for delivery media: air, water, food, fomites. The production and use of munitions is associated with environmental pollution which is harmful to health. Mapping and remediation of contaminated sites is thus essential and microbial biosensors for pollutant detection and bioremediation processes involving microbes and microbe–plant partnerships that degrade the pollutants is a promising option (Lewis, Newcombe, and Crawford2004; van Dillewijn etal.2007; Kalsi etal.2020). Violence and aggression may be characteristic of wars but are also generally prevalent in society and impact health (e.g., see Wang, Fu, et al. 2022). A report by the Organisation for Economic Cooperation and Development (OECD; https:// www. oecd - ili br ary. org/ docs e rver/ health_ glanc e20178en. pdf? expir es= 17269 00577 & id= id& accna me= g uest & check sum= 5451A CDC42 48008 64A17 5A53E F79BF20) identifies diet, smoking and alcohol consumption as playing important roles in global deaths, with violence, accidents and selfharm being important in ‘external’ causes of death. Alcohol consumption is sometimes linked to violence and abuse, which in turn are linked to physical and mental injuries. Alcohol consumption and substance abuse may also be linked to risktaking, like dangerous driving, unsafe sex, etc., associated with higher probabilities of injury and suffering. Thus, violence and aggression are influenced by a range of factors that are networked and partly reinforcing and downward spiralling. Since these are in part behavioural in nature, their roots often lie in mental makeup/state, tendency to risktaking, aggressivity, upbringing and other influences, some of which have been associated with the human microbiome. One fascinating study has shown that the microbiome is implicated in aggressive behaviour in fruit flies (Grinberg etal.2022) and a recent study from the same group demonstrated the microbiome also played a role in aggressive behaviour in a mouse model (UzanYulzari etal. 2024). In both cases, germfree or antibiotictreated animals were more aggressive than their wildtype control. Surprisingly in both models, recolonization with bacteria (monocolonisation in flies or faecal microbiota transplantation (FMT) in mice) caused aggression levels to return to normal. Changes in aggression levels were accompanied with changes in pheromone and metabolite levels and also changes in gene expression levels. The researchers also conducted an FMT experiment in mice with faecal material from 1 monthold human babies who had received antibiotics during the neonatal period, or not, and demonstrated again that antibiotic treatment in the infants increased aggression in the transplanted mice. Given that aggressive behaviour is responsible for a considerable amount of human suffering at all levels of society, from personal relationships, to road rage, to wars, the possibility of modulating it through targeted microbiota interventions should be considered. It is also worth noting that the gut microbiota is also implicated in substance abuse, so there may be opportunities for microbiota interventions to ameliorate its practice and effects (Kazemian and Pakpour2024) (Table1). 11 | Everyday Problems in Everyday Life: Stress, Neuropsychiatric Disorders and the Microbiome While everyday life experience varies enormously among individuals and communities, in general most of it is occupied by work or education and sleep, with the rest usually filled with household chores, meals and leisurehobbiessport (lifestyle), including and especially electronic and social media activities. In many settings, each of these three daily activities roughly take up about 8 h or an equal third of the day. While everyday life can be stimulating, fulfilling and enjoyable for many, it can be a battleground for others and, for some, home or workschool may represent confined spaces harbouring chronic stressors. This can create new or exacerbate existing neuropsychiatric Microbial technology barriers to injury and disease resulting from warfare, aggression and accidents • Vaccines • Antibiotics • Immunotherapies • Biocompatible materials for wound dressings • Field POCTs • Microbiome early diagnosis of PTSD • (microbiome intervention to treat PTSD) • (microbiome intervention to treat aggressive behaviour) • Biosensors for detection of munitionscontaminated sites • Bioremediation of postcombat contaminated sites 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
32 of 61 Microbial Biotechnology, 2025 Agricultural expansion to feed a growing global population— invasion of new ecosystems—is predicted to drive the spread of infective agents (Rohr etal.2019; Waage etal.2022). Moreover, large scale, centrally prepared and distributed food will tend to transmit similar foodborne microbes to everyone (also pathogens, as a result of centralised contamination, and thus has the potential to initiate largescale foodborne infections, both accidental and deliberate/terrorist) and to support and select gut microbiomes that are more similar/less diverse among people. Even fresh foods, like fruit, vegetables, milk products and meat, will tend to be sourced from a few major suppliers able to supply the large quantities required, and hence have a limited microbial diversity, rather than a large number of small outlets collectively supplying products with greater diversity. This and other constraints on ambient microbial diversity, such as ventilation systems in large buildings, circulating the same air to everyone, and urban pollution, which reduces microbial diversity and selects pollutanttolerant microbes, and the widespread application of antimicrobial cleaning products, tend to reduce ambient microbial diversity and hence microbiome diversity in the population. The progressive reduction in microbiome diversity is currently considered to be associated with a reduction in microbiome services provided and reduced health resilience (Blaser2018; Finlay etal.2021; https:// asm. org/ artic les/ 2019/ nov em b er/ d i sa p peara nceofthegutmic ro biota - howwemaybe). Moreover, as noted above, air pollution is the leading environmental disease risk factor globally. Although indoor air pollution, often associated with cooking and heating, can be a serious health risk in rural communities, outdoor air of urban environments in general, and megacities in particular, can be highly polluted in many cases and a major cause of ill health (Grimm et al. 2008; https:// www. bbc. com/ news/ artic les/ c1wj4 3vqdlpo; https:// www. bbc. com/ news/ artic les/ c0k8d xpr8x5o). Young children are particularly vulnerable to air pollution and it is estimated that around 2 billion live in areas burdened with air pollution levels that exceed WHO limits https:// www. unicef. org/ sites/ defau lt/ files/ 201902/ Clear_ the_ Air_ for_ Child ren_ Execu tive_ summa ry_ ENG. pdf. Urban life is also characterised by increased time spent indoors. This often means breathing air that is loaded with the microbiomes, especially airway microbiota, of others in the same building, including their respiratory pathogens, and of volatile pollutants inherent to most built environments (e.g., see Bruinen de Bruin etal.2008), instead of fresh air outside blowing from the fields/sea, and being illuminated by lamps and having vitamin D deficiencies, instead of by sunlight that both kills airborne viruses and stimulates vitamin D production in skin. In conclusion, urban life is increasingly being associated with lower quality nutrition, exposure to pollutants, particularly air pollution, low microbiome diversity and its protective and barrier functions that contribute to resilience, high pathogen densities, higher anxiety and stress levels, and increases in disorders such as autoimmune diseases (Zuo etal.2018). How can the many virtues of urban settlements be enjoyed without being counteracted by their evils? Microbial technology solutions for ‘urban evils’ While the examples of problems of urban life listed above are incomplete, they are indicative. Measures to counteract these ‘urban evils’ will involve synergistic integration of microbial and nonmicrobial technologies. Microbial technologies will revolve around reducing exposure to noxious agents, reducing susceptibility to respiratory infections, and increasing microbiome diversity and resilience to urban evils. These involve technologies outlined above for reducing transmission of infectious agents (monitoring, especially wastewater monitoring and the food supply chain; wastewater treatment; drinking water treatment; vaccination; etc.) and exposure to environmental pollutants (monitoring; mitigation at source; bioremediation of legacy sites, etc.), improving food supply by microbial agrobiologicals and food quality by fermentation and supplementation with specific amino acids and vitamins. But, in addition, there is an urgent need to diversify human microbiomes (Finlay etal.2021). This can be achieved in various ways including • Urban space design to provide islands of biodiversity— green spaces with diverse soil types and vegetation (diverse soil and plant microbiomes) • Inducements to spend time outside (beauty spots, walks and family/friend recreational areas, children's play areas, refreshment facilities that encourage socialising (relaxing, but also sharing microbiomes) and social activities) • Urban space design to enable and encourage outdoor activities, including varied sports and gardening • Having pets, and petspecific outside areas to avoid fouling of humanused outdoor spaces • Having house and office plants • Incentivising excursions into the countryside, to farms, that involve walking and activities that expose people to new microbial diversity • Incentivising the availability of diverse foods, especially fresh foods from small local producers • Encouraging the consumption of food that promotes a healthy gut microbiome, including raw vegetables and fruit, grains and nuts, fermented foods and probiotics • Supplementation of microbiomes with ‘lost microbes’ through probiotics Because of the high densities of pathogens and their facile transmission, targeted efforts to reduce pathogen loads and transmission are needed. These will focus especially on ventilation and air conditioning systems in buildings housing large numbers of peoples, including schools, through the incorporation of filtration and sterilisation systems. Keeping windows open where possible to dilute ambient air pathogen loads with fresh air will be encouraged. During periods of high aerosol pathogen loads, the wearing of masks may be necessary. Hightouch surfaces may be treated with probiotics to reduce pathogen transmission by fomites. Other locations requiring pathogen reduction measures include health facilities, care homes and institutions. However, there exists the conundrum of needing to maximise microbial exposure to promote microbial diversity while minimising exposure to pathogens: the problem of underclean and overclean, so such measures need to be calibrated to achieve an optimal balance. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
33 of 61 13 | Microbial Technology Barrier Enabler: Exploration of Microbial Diversity to Mine New/ Improved Drugs, Products, Activities and Services The development of a new or improved technology to combat disease will often result from the targeted or untargeted discovery of a new or better biological product, activity or process. The microbial world, with its 3.8 billion year evolutionary history during which it biochemically and ecophysiologically explored a vast range of environments/substrates/ energy sources, its huge phylogenetic diversity (one estimate suggests that there are one trillion species of microbes: Locey and Lennon2016) and range of habitats colonised that are too hostile for most visible organisms, possesses an exceptional spectrum of activities and creates a vast range of chemicals and materials that greatly exceeds those of larger organisms. Prospecting the microbial world for new chemicals traditionally required their cultivation. Since only a tiny fraction could thus far be cultivated, there is a huge reservoir of functions remaining to be discovered. However, with genomics and metagenomics revealing potential functions of interest without cultivation, and recombinant DNA techniques permitting expression of such functions in culturable microbes (the cell factories; see below), the exploration, discovery and mining of new microbial products and functions is proceeding at an accelerating pace (Rodríguez et al. 2024; Van Goethem etal.2024; Wang, Xiang, etal.2024; Wang, Li, etal.2024). Key to the discovery of useful new products is the existence or development of selection systems and screens that access and identify what is sought. A simple screen deployed in early antibiotic discovery involved the ability of products secreted by potential producer organisms to inhibit test microbes. Microbes can now be engineered in a variety of ways to respond to a vast range of external signals that that identify sought products. Screens that target specific metabolic reactions/processes are particularly useful, especially combined with genomics/ metagenomics to identify relevant protein:protein and protein:ligand interactions. This approach has been enormously simplified by the availability of the artificial intelligencebased AlphaFold protein structure prediction software (https:// deepm ind. google/ techn ologi es/ alpha fold/ ) and the ability to model the interacting interfaces (https:// blog. goog le/ te c h n ology/ ai/ g o ogl e - de epm in dis omo rph ic - alph a fold3aimodel/ # lifemolec ules). Predicting interacting surface structures enables the identification of potential sites of action for the design of agonists and antagonists—drug candidates— that promote or prevent such interactions (see Timmis2018; Abramson etal.2024). 14 | Microbial Technology Barrier Enabler: The Microbial Cell Factory There are many microbial technologies that save lives but one of the most powerful and pervasive is the cell factory technology (Timmis and Hallsworth2024). This is because it is highly versatile, can be deployed for so many applications, and is in constant evolution through the development of new genetic tools and the application of metabolic design and synthetic biology tools and strategies. A few examples are listed here for illustration. 14.1 | Reagents Cell factories are used to make reagents used in diagnostic procedures, such as DNA polymerases for PCR and LAMP. 14.2 | Antibodies Monoclonal antibodies, nanobodies, etc., used for diagnostics, prophylaxis and therapy, are mostly made in cell factories. 14.3 | Antigens Both natural and recombinant antigens used for diagnostics and vaccines, such as the HBV surface antigen produced in yeast for the HBV vaccine, are made in cell factories. The immune response stimulatory potency of antigens may be enhanced by diverse microbial technologies, including glycoengineering (Lehri etal. 2024). 14.4 | Microbially Inspired Drugs Perhaps the most important sector of cell factory application is in drug production. Most new antibiotics are discovered in microbes which use them as weaponry in their own ecological battles (e.g., Rodríguez etal.2024; Van Goethem etal.2024; Wang, Xiang, etal.2024; Wang, Li, etal.2024). Once discovered, an antibiotic is tested for application potential: activity spectrum, selective toxicitysafety, stability, pharmacokinetics, and so forth. Materials for testing are usually produced from the organism in which the activity was first detected—which thereby acts as a cell factory—either a natural isolate from the environment or a recombinant organism into which a suite of new genes have been transferred. As the most promising candidates advance through the pipeline, their therapeutic properties are improved by chemical modification, often removal/addition/substitution of groups. Sometimes this modification is achieved by chemical reactions but, given the complexity of many natural products that serve as starting points for clinical drugs, chemistry can often be difficult, and biochemistry is necessary. Cell factories are used extensively for the production of enzymes that modify the structure of drugs and drug precursors, some of which are made by synthetic chemistry, and endow upon them properties desired for clinical use. They are also used to produce precursors and building blocks of drugs (e.g., HernándezFernández etal.2024). Using microbes as chemists leads to green and/or ecofriendly manufacturing reducing the pollution burden to the planet. 14.5 | Enzymes Although enzymes used in the production of drugs are vital for preventing and reducing suffering and loss of life, they only represent a small fraction of enzyme production in cell factories. For example, coldactive enzymes—proteases and lipases that remove food and other stains from clothing—are used extensively in detergent powders and liquids employed in automatic washing machines, enabling them to be run at much lower 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
34 of 61 Microbial Biotechnology, 2025 temperatures than is the case for detergents lacking the enzymes (Kuddus etal.2024; Oliva etal.2024). As a result, there is a significant saving in energy used by washing machines, which translates into a lower carbon footprint, a lower contribution to global warming and climate change, and hence a reduction in suffering and lives lost due to climate change. Another important example of enzyme production in cell factories is phytase, used in animal feed, especially feed for monogastric animals. Phytate is the major form of phosphorus in plants but is largely unavailable to the animal. Phytate also binds other nutrients in the gut and hence is an antinutritional factor. Phytase hydrolyses phytate and thereby makes available not only phosphorous but also other nutrients and increases significantly the nutritional value of animal feed, which in turn reduces the amount of feed needed. The production of animal feed comes with high carbon, environmental and agricultural resource footprints, which translate into contributions to global warmingclimate change, environmental deterioration and competition for human plant food production and hence food security, all of which impact health. Microbial production of phytase is therefore another example of microbial technologies that contribute to human wellbeing. Indeed, enzymes from cell factories are exploited in many, very diverse ways, some of which have positive direct or indirect impacts on health. 14.6 | Metabolites Microbial cell factories are also extensively used to produce simple metabolites, such as amino acids and vitamins essential to healthy nutrition, sunscreen compounds like melanin, microsporine and microsporinelike amino acids, and scytonemin (Cordero, Vij, and Casadevall 2017; https://enviromicrojournals.onlinelibrary.wiley.com/doi/10.1111/j.17517915.2010.00241.x/), which reduce skin damage by ultraviolet light and hence skin cancer. Other compounds, including some that serve as basic scaffolds for organic synthesis of drugs and other compounds of value, can be also obtained by cell factories. A striking example is the production of the anticancer drug vinblastine in engineered yeast cells (Zhang, Hansen, etal.2022), which includes 30 enzymatic steps encoded by 34 heterologous genes from plants. Another example relevant for health applications is the production of fluorinated precursors in engineered bacteria (Pardo etal.2022), which is relevant when considering that one quarter of all pharmaceuticaldrugs in the market contain fluorine decorations to enhance bioavailability (Haas and Nikel2023), among other advantages. 14.7 | Advanced Materials Microbial biotechnology is revolutionising the field of materials science, with bacteria emerging as powerful producers of biopolymers that hold significant potential for biomedical applications (Moradali and Rehm 2020; Blanco et al. 2021; HernándezArriaga et al. 2022; PereyraCamacho and Pardo2024). Through advancements in microbial biotechnology, synthetic biology and metabolic engineering, bacterial biopolymers are being transformed into customizable, highperformance materials for a range of applications, particularly in medicine and sustainable industries. Three primary bacterial biopolymers—bacterial cellulose, polyhydroxyalkanoates and γpolyglutamic acid exemplify distinct classes of polysaccharides, polyesters and polyamides, respectively, each offering unique properties that make them ideal for critical applications such as drug delivery, tissue engineering and regenerative medicine. These biopolymers present sustainable and biocompatible alternatives to traditional synthetic materials, addressing both medical and environmental needs. Bacterial cellulose, produced by species like Komagataeibacter, stands out for its exceptional mechanical strength, biocompatibility and high waterholding capacity. Its nanoscale fibrous structure closely mimics the extracellular matrix, making it particularly suitable for tissue scaffolds, wound healing and vascular grafts. Moreover, its ability to support host cell growth and tissue regeneration, alongside its efficient drugcarrying capacity, positions bacterial cellulose as a valuable material for controlled drug delivery systems. Polyhydroxyalkanoates are biodegradable polyesters synthesised by bacteria such as Cupriavidus necator and Pseudomonas putida. These biopolymers are widely used in drug delivery systems due to their ability to encapsulate drugs and ensure sustained release, thus enhancing therapeutic effects and reducing toxicity. Furthermore, polyhydroxyalkanoatebased scaffolds show immense promise in tissue regeneration, with applications in bone and cardiac tissue engineering. Genetic engineering has further enhanced the production of polyhydroxyalkanoates, broadening their suitability for various medical uses, including sutures and regenerative medicine. γPolyglutamic acid, synthesised by bacteria such as Bacillus subtilis, is a watersoluble, biodegradable polymer with excellent potential in drug delivery and tissue engineering. Its ability to form hydrogels makes it particularly useful for developing scaffolds in tissue regeneration and controlled drug delivery systems, especially in challenging environments like the gastrointestinal tract. To maximise the utility of these biopolymers, advanced technologies are employed to optimise bacterial production. Metabolic engineering plays a key role in enhancing biopolymer production by finetuning bacterial biosynthetic pathways, transforming bacteria into highly efficient biofactories capable of producing large quantities of tailored biopolymers for both medical and industrial applications. Synthetic biology enables precise control over bacterial production processes, facilitating the creation of engineered living materials that possess smart functionalities such as selfrepair and responsiveness to environmental stimuli. These innovations are paving the way for the development of materials that can dynamically respond to biological signals, thereby opening up new possibilities for smart drug delivery systems and tissue regeneration. Further customisation of bacterial biopolymers is achieved through chemical modification and diversification, using techniques like crosslinking, grafting, and blending with other polymers. These methods enhance the flexibility, biocompatibility and antimicrobial activity of the materials, making them particularly effective in wound healing, tissue engineering and drug delivery applications. An emerging and promising approach involves the development of hybrid 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
35 of 61 living materials, which combine living bacteria with synthetic components to produce materials with adaptive properties. These materials can selfassemble, selfheal and adapt to their environment, rendering them especially suitable for biomedical applications. Additionally, innovative techniques such as bioprinting and cell encapsulation have enabled the creation of complex, threedimensional materials that support cell growth and maintain biological activity, thereby further expanding the potential uses of bacterial biomaterials in therapeutic applications. Microbial cell factories are also used to produce nanomaterials of various types for agricultural, environmental, nutritional and medical applications (Li etal.2011; Yang etal.2022; Carmona etal.2023). In medicine, they are used inter alia in diagnostic procedures and biosensors, imaging, as biomaterials for tissue regeneration and in drug delivery systems. Some nanomaterials have antimicrobial, antifungal, insecticidal or anticancer activities (Arora, Lashani, and Turner2024). Nanomicrobiology is also being used to develop new materials for electronics, chemical catalysis and separation science. Nanomaterials have been traditionally produced by physical methods which are inefficient, have high energy needs and require the use of toxic chemicals. Nanomicrobiology, which is based on the metabolic transformation of input materials to nanomaterials like metal, oxide, sulfite and other nanoparticles, is characterised by high efficiencies and low energy and toxic chemical inputs, so is more environmentally friendly. 14.8 | The Factory Itself (or Parts of It) as the Barrier Agent Cell factories are also used to design cells or cell components with novel features, such as surface decoration (surface display) with foreign antigens, nanobodies or ligands that provide important functionalities that can be exploited in various ways, especially for medical interventions, including the engineering of microbiomes (e.g., Timmis etal.2019; Timmis, Soffritti, Mazzacane, etal.2019; Shen etal.2022; Srivastava and Lesser 2024). Extracellular vesicles (EVs) are subcellular membranebound structures released from cells that contain all types of cellular materials (nucleic acids, proteins, metabolites, sugars, fatty acids, etc.): their socalled ‘payloads’ (György etal.2015). They readily fuse with other cells, delivering their payloads, and are thought to be important means of intercellular communication. Importantly, they tend to have low toxicity and good permeability. EVs are produced by cells of both prokaryotes and eukaryotes and in principle those from one branch of the tree of life can fuse with cells of other branches. As a consequence, EVs are currently perceived as offering many possibilities for efficient delivery of specific payloads to diverse types of target cell for a range of applications. Cells producing EVs can be engineered so that EV surfaces are decorated with functional structures that serve as immunising antigens, lipopolysaccharides to trigger good immune responses (Gerritzen etal.2017; Jiang etal.2021), and ligands that bind to specific structures, for example cancer cellspecific antigens, and hence constitute ‘homing devices’. Applications include diagnosis (e.g., of cancer: Chronopoulos and Kalluri2020), active and passive prophylaxis with vaccines (Micoli, Adamo, and Nakakana2024), therapy, especially of infectious diseases and cancer (Gao, Yujie, and Wang2022; Long etal.2022), and tissue repair and regeneration (Liu etal.2022; Liang etal.2022). Bacterial minicells are anucleate cells budded off parental cells that have a defect in cell division (https:// pubmed. ncbi. nlm. nih. gov/ 34516 078/ ). Although analogous to EVs, they are quasi normal cells, with a similar structure and complement of cellular functions except that they lack a genome. As a consequence, they are more robust than EVs, are easy to isolate, are relatively homogeneous, and can also be engineered/treated to carry specific payloads. In addition, as indicated above, their surfaces can be decorated with ligands, for example ligands to tumourspecific antigens, which endows them with the ability to home in on specific targets (Brahmbhatt and MacDiarmid2021). Recent clinical trials with antitumour minicells show promising results (Ganju etal.2024). A further development of this is the surface display of cytokines on tumourhoming bacteria which boosts the activity of local immune effector cells that destroy hardtotreat tumours (Fidelle and Zitvogel2024). Living microbes are also an attractive platform for detecting and treating disease invivo (see Vargason and Anselmo 2018; Srivastava and Lesser 2024). Microbial cell factories can produce a wide array of therapeutic agents, including singlechain antibodies, enzymes or cytokines. Engineered bacterial therapeutics have shown efficacy in animal models for various pathologies, including infectious diseases, cancer (Kalia et al. 2022), inflammatory bowel disease and cystic fibrosis (PiñeroLambea, RuanoGallego, and Fernández 2015; Riglar and Silver 2018; Mazzolini etal.2023). The possibility for realtime monitoring and insitu production of therapeutic agents offers tremendous possibilities for targeting diseases that are currently difficult to manage. 14.9 | Cell Factories and Nutrition As mentioned above, cell factories are used to create foods and fermented foods. Metabolically designed cell factories are also used to produce food supplements, like amino acids and vitamins, but also neutraceuticals like curcumin, which has antiinflammatory, antioxidant and anticancer properties, in addition to being an important food colourant (Beganovic and Wittmann 2024), natural food colourants (Thomsen, Nielsen, and Borodina2024) and flavours (Guo, Luo, etal.2024; Guo, Ding, etal.2024). Probiotics have been mentioned multiple times in this discourse: classically they are cell factories that operate inside our bodies and belong to the class of agents that also include prebiotics, synbiotics, postbiotics and neutraceuticals. Probiotics are live microorganisms used to confer health benefits on an individual when administered in adequate amounts. Prebiotics are ingredients nondigestible by hosts that selectively stimulate the growth and activity of probiotic bacteria in the digestive tract. Synbiotics are a combination of proand prebiotics. Postbiotics are dead microbes and/or their components that offer health benefits to the host. Neutraceuticals are biological products incorporated into diets that have health properties. All of these 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
36 of 61 Microbial Biotechnology, 2025 can act as regulators of gut microbiota and are viewed as having considerable potential for preventing and treating infectious and metabolic diseases such as obesity, type2 diabetes, and fatty liver disease (see also Alessandri etal.2024), as well as neuropsychiatric disorders, all of which are associated with an imbalance of gut microbiota. Recently, it has been suggested that gut microbiota manipulation by preor probiotics may become a potential therapy for polycystic ovary syndrome (Babu etal.2024). In order to protect the viability of probiotics during transit through the gut, carrier materials and prebiotics may be required. New technological improvements will help to develop functional foods and neutraceuticals that increase the viability and effectiveness of probiotics (Li etal.2021). Interesting examples include a riboflavinproducing probiotic (Dricot etal.2024), Lactobacillus helveticus probiotic attenuation of alcoholic liver injury (Lv et al. 2024), and grape seed extract prebiotic that modulates the gut microbiota to prevent oestrogen deficiencyinduced bone density reduction (Lu et al. 2024). Of course breastfeeding provides infants with a multitude of probiotics and prebiotics, in addition to antibodies and nutrients (Masi and Stewart2024). On the other hand, the term probiotics has more recently been extended to include applications that modify microbiota outside of the body, be it on surfaces of humans (e.g., in wound healing: Nakatsuji etal.2017; Canchy etal.2023; Yin etal.2024) or, for example, on the surfaces of inanimate objects, such as the hightouch surfaces of hospitals and subways, in agriculture, and in the protection and preservation of cultural artifacts. 14.10 | Cell Factories Saving Clean Water Many industrial processes consume clean water, sometimes huge amounts as is the case in the semiconductor industry (htt p s :// www. wef or u m . or g / ag end a/ 20 24/ 0 7/ the - wat er - cha l l en ge - f ors em ic onduc to rm a nu f a ct u r i n gandbi gt e chw hatneeds - tobedone/ ). Given that fresh water and especially clean drinking water are limiting in parts of the world, which directly contributes to ill health through dehydration or use of contaminated water for drinking, or indirectly through lower crop yields or crop failures because of inadequate irrigation, processes to save fresh water are vitally important (https:// turni ngthe tide. water commi ssion. org). Seawater is not limiting in coastal regions and near salt lakes, so cell factory processes based on salttolerant microbes, and using salt water for production, are of considerable relevance for sustainability. One example of such a salttolerant microbe being developed as a cell factory is the fungus Aureobasidium (Xiao etal.2024) which can produce a range of products, including melanin and polymalate (e.g., for delivery of anticancer drugs) (Table2). 15 | Microbial Technology Barrier Enabler: Diagnostics and Sensors 15.1 | The Prompt Diagnosis Barrier In general, the earlier disease is accurately diagnosed, the earlier appropriate treatment can be initiated and the better the outcome. Diagnostic methods, reagents, instruments and trained personnel are thus pivotal to reducing human suffering and avoidable premature death. Microbial technology contributes massively to the diagnostic effort, either by providing microbialoriginating reagents, such as antigens and enzymes, or producing these and other reagents in microbial cell factories, or engineering microbes as biosensors to detect biomarkers of disease, invitro or invivo (Turjeman and Koren2021; Capin etal. 2024). 15.2 | Programmable Microbes for Diagnostics and Therapy Living cells can process a myriad of signals in parallel and compute an adapted output via their signalling networks. Microbes are attractive candidates to engineer nextgeneration diagnostic tests, as they are inexpensive, easy to manipulate and store, while capable of sophisticated sensing and signal processing. Researchers have built microbial biosensors equipped with engineered receptors that detect molecules of interest, such as environmental pollutants or biomarkers of disease (see, e.g., Capin etal. 2024; Zhong etal.2024). Proofs of concept have been made towards application to the clinics, detecting biomarkers such as glucose, bile acids, and zinc in serum or in faeces (Courbet etal.2015; McNerney etal.2019; Voyvodic and Bonnet2020; Chang etal.2021). Genetic circuits can also improve the robustness and sensitivity of such ‘bactosensors’ (Courbet etal.2015). Microbial cell extracts can also be used to engineer biosensors (Voyvodic and Bonnet2020). While barriers to deployment remain, microbial biosensors have an immense potential for providing highly versatile platform for affordable, sophisticated and decentralised diagnostics devices. 15.3 | The Surveillance Barrier As the military well know, intel (intelligence; knowledge of the enemy: known strategies and expertise, behaviour, predictability, numbers, battlefield, weaponry, etc.) is vitally important and can mean the difference between success and failure. The battles of humans against disease are also greatly influenced by knowledge of what infectious agents (the enemy) are doing and how they are evolving, particularly in the context of the microbiome (and its noncombatant microbes). Pathogen surveillance by regional and national public health authorities, and transnational and international organisations like the WHO, is fundamental to understanding the ecology/epidemiology and predicting the behaviour of infectious diseases, in order to mount the best possible defences and erect appropriate barriers. Pathogen detection and diagnostic tools and methods lie at the heart of surveillance and epidemiology, and most are based on microbial technologies. Polymerase chain reaction (PCR) and loopmediated isothermal amplification (LAMP) detection systems are based on microbial DNA polymerases and primers designed from the pathogen genome, whereas antigen detection systems are usually based on pathogen antigens, and sometimes also monoclonal antibodies/nanobodies, made in microbial cell factories. Other methods include genomic technologies, particularly proteomics and metabolomics, for rapid identification and quantification of key biomarkers of disease, and assessment of pathogens, AMR microbes and microbiota dysbiosis. The 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
37 of 61 development of new CRISPRCas systems hold much promise, not only for precision but also for low cost and ability to form the basis of easytouse POCTs (Pandya, Jagani, and Singh2024). The efficacy of deployment of these technologies was demonstrated in the recent COVID19 pandemic. They included centrally organised PCR detection of SARSCoV2 virus nucleic acids, lateral flow antigen detection kits for personal use, and community surveillance through PCR analysis of wastewater in treatment plants. All of these were vital for surveillance and reducing persontoperson transmission, as was genome sequencing to monitor the evolution of pathogen variants. Pathogen surveillance of wastewater has now become routine to provide early warning and monitoring of community infections (e.g., GirónGuzmán, Sánchez, and PérezCataluña 2024). LAMP tests have been used in some airports and LAMPbased lateral flow tests are being developed. 16 | Overarching Issues That Provide Important Context 16.1 | Leaving NoOne Behind The rallying cry of the United Nations—leaving noone behind (https:// unsceb. org/ sites/ defau lt/ files/ impor ted_ files/ CEB% 20equ ality% 20fra mewor kA4 - webrev3. pdf )—is not only hugely inspirational and the encapsulation of the TABLE 2 | Microbial cell factories for raising barriers against preventable human suffering, morbidity and mortality. Barrier need Examples of cell factory products that respond to need Diagnosis: diagnostic reagents • DNA polymerases for nucleic acid amplification (PCR, LAMP) • Antigens • Monoclonal antibodies, nanobodies Sensing • Whole cell biosensors for detection of disease biomarkers (also in food animals and plants), toxins, pollutants, emerging contaminants Prophylaxis • Vaccine antigens, recombinant vaccines • Prophylactic monoclonal antibodies Therapies: microbiallyinspired pharmaceuticals • New pharmaceuticals/pharmaceutical scaffolds • Weaponised microbes/microbial components (minicells, membrane vesicles) carrying surface display ligands for precise targeting and delivery of payloads • Cas for CRISPRCas applications • Production of hormones (including growth hormone, insulin) Nutrition • Microbial biomass as food/single cell protein • Amino acids, vitamins for nutritional supplementation • Probiotics Catalysis: microbes as chemists • Enzymaticallyproduced reagents, medicaments, micronutrients, etc. • Low footprint enzyme catalysts for medicinal chemistry • Enzymes that save energy (e.g. coldactive enzymes for washing powders) • Enzymes that upgrade food value (e.g. phytases) • Enzymes that capture CO2 and other greenhouse gases • Salttolerant biocatalysts for bioreactors using seawater as the solvent/ aquatic phase • Active agents for bioremediation of environmental pollution Metabolites • Pharmaceuticals, pharmaceutical precursors/scaffolds • Anticancer agents • Sunscreen compounds Advanced materials • Bacterial cellulose for wound healing, tissue scaffolding and vascular grafts • Polyhydroxyalkanoates and γpolyglutamic acid as biocompatible plastics and drug delivery systems, and tissue regeneration scaffolds in regenerative medicine • Selfassembling, environmental adapting polymers for biomedical applications • Microbiallyproduced nanomaterials, inter alia for biosensors and as antimicrobial, insecticidal and anticancer materials, and especially as imaging materials 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
38 of 61 Microbial Biotechnology, 2025 humanitarian spirit, but also captures the range, diversity and interconnectedness and interdependency of relevant issues. It encourages the view of health through the lens of social and environmental ills. For example, poverty is frequently associated inter alia with poor nutrition, lack of clean water, poor hygiene, poor access to healthcare, especially preventive medicine, mental stress, all of which promote physical and mental illhealth. Microbial technologies are a major component of the broader and growing bioeconomy which has the potential to create employment in regions where it is most needed (Timmis etal.2014; Timmis, de Lorenzo, etal.2017; Timmis, de Vos, etal.2017) and thereby reduce poverty and associated health ills and, in some instances, also help realise the demographic dividends (Timmis, de Lorenzo, etal.2017; Timmis, de Vos etal.2017, and see below). However, creating employment must go handinhand with improved education and training in skills essential to employment. Forced human migrations resulting inter alia from poverty, hunger and conflicts also creates situations of polydeprivations that favour illhealth, often in the context of refugee camps and informal settlements that sometimes also resemble war zones. Although such underlying causes of ill health are not the subject to this discourse (but see Anand etal.2023), access to public health and healthcare services for monitoring, diagnosis, prophylaxis and therapy are even more essential than in highresource settings (although inadequacies are pervasive in most healthcare systems: Caldwell etal.2024). 16.2 | Challenge 5: Poor Resource Settings—The Issue of Health Inequity Despite the power of existing, and the development of new and more powerful, microbial and other technologies for disease monitoring, prevention and therapy, their exploitation is highly unequal among peoples, with those in resourcepoor settings suffering major deficits and disadvantages (Hojat2022; https:// www. wefor um. org/ agenda/ 2024/ 0 6/ inves tingina f r ic anhealt htechcantrans formhealt hsyste ms/ ). Levelling up requires political and economic commitment which are often hindered by shortterm and constituency considerations and priorities. However, access to quality healthcare is one of the conditions of maximising the demographic dividends (Fried 2016), the substantive potential socioeconomic benefits of demographic changes in the world. One of the barriers to healthcare equity is biased perceptions of priorities based on needs of highincome countries rather than needs of larger populations in lowincome countries (Kruk et al. 2018), biases that can be countered to some extent by education, especially of the young (Timmis etal.2024). Moreover, research that leads to medical advances is often HIC populationcentric, so may not always be applicable to LMIC populations and settings, as is the case for some current microbiome studies (Gulliver et al. 2024). Another, currently perceived as almost insurmountable, barrier is the absolute cost of levelling up, both in terms of materials and experienced personnel, so ways and means of reducing costs and personnel will lower this barrier (and ultimately also the bias barrier). However, in this case, there is currently considerable progress in the development of more affordablefrugalmicrobial technologies and products, that include diagnostics and sensors, POCTs, probiotics for hightouch surfaces in for example healthcare facilities that transmit pathogens, and 'smart microbes' - bacterial probiotics and therapeutics for example to be deployed against gastrointestinal infections like cholera and childhood rotavirus infections prevalent in LMICs, and that promote wound healing (see Srivastava and Lesser 2024, and citations therein). Prioritising development of quality and effective frugal technologies and products will undoubtedly accelerate the process of dismantling health inequalities in all countries. 16.3 | The Key Issue of Disease Burden Granularity While it is normal and proper to focus on the numerically most important global health burdens, it is equally important to be aware of, and address, health burdens whose significance may not be high globally but important locally, regionally or in certain contexts. A classic example before the deployment of ivermectin was river blindness caused by Oncocerca volvulus. Communities along rivers in which O. volvuluscarrying black fly (Simulium spp.) bred had high, almost universal levels of onchocerciasis which created a situation in which adults were blind with only children having sight and needing to be caregivers of the adults (https:// www. who. int/ newsroom/ factsheets/ detail/ oncho cerci asis). River blindness was catastrophic for affected communities. Onchocerciasis is a neglected tropical disease—NTD—defined by the WHO as “almost absent from the global health agenda…. NTDs have very limited resources and are almost ignored by global health agencies…. NTDs are diseases of neglected populations that perpetuate a cycle of poor educational outcomes and limited professional opportunities;… in addition, are associated with stigma and social exclusion.” (htt p s:// www. who. int / new s - ro om / que st ion sa nda n s we r s/ item/ negle ctedtropi caldiseases). NTDs include Chagas disease, dengue and chikungunya, leishmaniasis, schistosomiasis, leprosy, and others, and can be regionally important disease burdens. Invasive fungal infections are prevalent in some The vital importance of frugal technologies To achieve maximal health technology benefits in lowresource settings (but also in HICs) the technologies considered above and below, as well as other relevant nonmicrobiological technologies, need to become less costly, more frugal (Brown, Bhatti, and Harris 2023; Brown, Harris, and Bhatti 2024; Hindocha et al. 2021), and for pointofcare testing (POCT) and personal use. In fact, some of the technologies identified above, such as lateral flow and LAMP POCT tests,are already relatively inexpensive and can undoubtedly be developed further to become even more so, especially when produced at scale. However, other technologies can certainly be made more frugal if appropriate effort is invested and effectively incentivised (Skopec, Issa, and Harris2019). We consider it vital to establish a broad alliance of policymakers, microbial technologists from academia and enterprise, financiers from government, industry and philanthropy, and regional stakeholders, to spearhead the rapid development of frugal, especially microbial, technologies for monitoring, preventing and treating disease, in order to achieve health equity and enable realisation of the demographic dividends. Ultimately, this could save huge numbers of lives globally and prevent/reduce the suffering of a much larger number of humans. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
39 of 61 regions. Snake bites are major health issues in tropical regions. The dominant burden of physical and mental health in some regions is extended conflicts and warfare. The problem of NTDs is intertwined with and compounded by other inequalities, such as poverty, inadequate access to clean drinking water, food, healthcare, housing and education, and unsustainable practices and policies, and are a significant challenge to the UN ideal of “leaving noone behind” and the NHS slogan of “every mind counts” (George etal. 2023; Sun and Amon 2018). Granularity of disease burdens matters and NTDs and other causes of disease and suffering specific to certain regions and situations need to be given attention equal to that accorded the top global causes of morbidity and mortality. NTDs must become an increased focus of effort for development of microbial technologies. 16.4 | Towards a WellbeingCentric Economy One of the most dramatic changes over the last century has been the increase in the human lifespan coupled with a decreasing working life, which has resulted in a longer pensionable life. This, and the facts that many societies have also experienced a lowering of fertility and increased engagement of women in the workforce, has resulted in significant demographic change, and the societal and economic consequences of this: changing patterns of consumption and recreation, the numbers of children in school, a reducing workforce, changes in input versus disbursement of tax revenues, increasing burdens of healthcare, pensions, caregiving and so forth. A great deal has been written about the economic consequences of demographic change and about demographic dividends (https:// www. imf. org/ exter nal/ pubs/ ft/ fandd/ 2006/ 09/ basics. htm; Bloom, Canning, and Sevilla 2003; Bloom, Canning, and Fink 2010; https:// www. ncbi. nlm. nih. gov/ books/ NBK14 8831/ ; Ogawa et al. 2021): the potential for economic growth as a consequence of • Labour supply in societies with young populations and workforces • Wealth accumulation in societies with ageing workforces that is invested to some extent in national economies • The social capital represented by retirees (the silver dividend: wisdom and generativity) • The female gender capital represented by the higher proportion of women not yet in the workforce. In all cases, realisation of the demographic dividends is not automatic and requires substantive investment inter alia in health and education (https:// www. unfpa. org/ demog raphi cdivid end# readm oreexpand; https:// www. un. org/ devel opment/ desa/ dpa d / publ i c ation/ front iertechn ology - is s ue s - har ne s s i n g - the - econo micdivid endsfromdemog raphi cchange/ ; https:// 4divi dends. prb. org) and a conducive and responsive policy environment (Bloom, Canning, and Sevilla2003). In most discussions of demographic dividends, health and education are viewed through the lens of economic performance and measures of it—gross domestic product, GDP—as necessary means of achieving economic benefits, of increasing human capital (but see also analysis on healthy lifetime income by Zhang etal.2023). However, although healthcare and education are often viewed in terms of populations, their purpose fundamentally concerns the wellbeing, nurture of talents and fulfilment of aspirations of the individual. In societies where individuals matter, economic benefits should have their purpose in improving the wellbeing of individuals and society, rather than health and education having their purpose in driving economic performance. The development and application of microbial technologies can bring economic benefits not only to the commercial enterprises that exploit them, but also more widely through enabling a healthier, better educated and more productive population. Improvements in education and health, which are mutually reenforcing, can offer substantial return on investment for individuals and society as a whole (https:// www. unfpa. org/ demog raphi cdivid end# readm oreexpand; https:// www. un. org/ devel opment/ desa/ dpad/ publi cation/ front iertechn ology - i ssue sh arne ssin g - theecono micdivid end sfr omdemog ra phi cchange/ ; https:// 4divi dends. prb. org). This editorial provides a multitude of examples of microbial technologies that contribute to good health and there is good evidence that improvements in health can lead to stronger economies. https:// www. scien cedir ect. com/ scien ce/ artic le/ pii/ S0277 95362 40064 39? via% 3Dihub. An increasing healthy life expectancy (https:// www. gov. uk/ gover nment/ publi catio ns/ under stand ingthedrive rsofhealt hylifeexpec tancy/ under stand ingthedrive rsofhealt hylifeexpec tancy - report) can also bring a ‘silver dividend’ (https:// www. adb. org/ sites/ defau lt/ files/ publi cation/ 864241/ ewp678popul ation - aging - silve rdivid endecono micgrowth. pdf; Kotschy, Bloom, and Scott2024) from the economic and social capital of older adults living longer lives (https:// iris. who. int/ bitst ream/ handle/ 10665/ 356910/ Polic ybrief - 1997807320221eng. pdf? seque nce= 1; https:// cdn. who. int/ media/ docs/ defau ltsource/ decad eofhealt hyageing/ decad epropo salfinal - apr20 20en. pdf) and the desire of many to continue contributing to society (Erickson 1963; McAdams and Guo 2015). However, while the average participation in voluntary and charitable activities in Europe of individuals aged 65+ is 14%, there exists substantial variation with a distinct concentration among NorthernWestern European countries (range: 33% in Denmark visàvis 3% in Romania) (Lee2022). This clearly indicates that some regions of Europe are utilising and benefitting substantially more from the silver dividend than others. While various individual benefits of voluntary and charitable activities have been reported (for the age bracket 50+), such as ‘greater wellbeing, encompassing life satisfaction, sense of purpose and meaning in life […], happiness, optimism, selfconfidence and feeling in control’ (HaskiLeventhal2009; Kim etal.2020; Owen, Berry, and Brown2022; as cited by WeziakBialowolska, Skiba, and Bialowolski2024), the personal decision to participate in voluntary and charity activities may reflect an underlying humanitarian conviction/motivation, desire to pay society back for benefits realised over the working life, loneliness (https:// www. hhs. gov/ sites/ defau lt/ files/ surge ongener alsocia lconne ction - advis ory. pdf), or simply an intention to continue working after retirement age, (Park and Shin2023). 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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40 of 61 Microbial Biotechnology, 2025 The silver dividend is expressed in various ways, including remaining in the labour force, education and caregiving within and beyond the family, volunteer charitable work and the creation of philanthropic charities. While this effect is significant, it could undoubtedly be increased substantially by appropriate supportive organisational policies and actions (https:// ntacc ounts. org/ doc/ repos itory/ NTA14. Lao. pdf; https:// india. unfpa. org/ en / ne ws/ india sa gein gp op ul a tion - whyitm a tte rsmor eever), including efforts to improve health (Fried2016) and education of the older members of society, which is part of lifelong learning (Rocha de Jesus Fernandes and Lanza Queiroz2024; Timmis etal.2024). Moreover, it is also possible that the microbiome plays a role in the desire to participate, since it is known that microbiome structure and function are associated with mood and loneliness (e.g., see Cryan et al. 2019; Donovan etal.2020; Finlay etal.2021; Lopizzo etal.2021; Kim etal.2022; Falkenstein etal.2024). Therefore, potential microbiome modulation to treat loneliness and associated neuropsychological disorders may have a collateral benefit in some of increasing the desire to become more involved in social activities, including those related to the silver dividend. Similarly, there are economic and societal benefits to gain from reducing gender inequalities and enabling greater participation of women in the workforce (https:// www3. wefor um. org/ docs/ WEF_ GGGR_ 2022. pdf). According to the International Labour Organisation, 72% of men but only 47% of women are in the global labour force (https:// webap ps. i lo. or g/ inf o s t ories / enGB/ Stori es/ Emplo yment/ ba rr i er swomen# globa lgap). There is thus a huge potential to increase the workforce and its economic benefits, calculated by one source to be $ 1 trillion (https://www3.weforum.org/docs/ WEF_Closing_the_Women's_Health_Gap_2024.pdf; but see also https:// www. unwom en. org/ sites/ defau lt/ files/ 202309/ pro g r e s s - onthes us t a i n a bl e - dev el opmen tgoa l s - t hegende rsnaps hot2023en. pdf). Unequal participation in the digital workforce—the digital gender divide—is particularly notable (https:// www. wefor u m . org / agenda/ 2024/ 09/ south - asiadigit algende rdivid e/? utm_ sourc e= sfmc& utm_ mediu m= email & utm _ ca mpa ign= 2 8365 67_ A gend aWeek ly27S ep tembe r2 02 4 & utm_ term= & email Type= Agenda% 20Weekly; according to UNICEF, ‘The gender digital divide has cost developing countries 1 trillion USD over the past decade’: https:// www. unicef. org/ rosa/ media/ 27721/ file/ Agenda). There are many reasons for the lower participation of women in the workforce, which vary from country to country and culture to culture, including personal choice, cultural constraints including ‘gender roles’, child marriage (https:// docum ents1. world ban k. org / curat ed/ en/ 53089 14985 11398 503/ pdf/ 11682 9 - WPP1518 42PUBLI CEICM - Globa lConfe re nce - Edit i on - Ju ne27. pdf), childbearing/−rearing, homemaking, caregiving, inadequate education and training (https:// gende rdata. world bank. org / en/ datastor i es/ at aleofolda ndnewgende rgaps; https://sciendo.com/article/10.2478/izajodm20210001), insufficient employment opportunities, poor working conditions, poor health (women spend 25% more of their lives than men in debilitating health: https://www3.weforum.org/docs/ WEF_Closing_the_Women's_Health_Gap_2024.pdf), unequal (or zero) remuneration (https:// www. oecd. org/ en/ topics/ polic yissues/ gende requal ity. html) and other forms of discrimination (ht t p s: // iri s . w ho. i nt / b it st r e a m / h a ndle/ 106 6 5/ 311 314/ WHOHISHWFGende rWP12019. 1eng. pdf? sequ; see also https:// www. u nwom en . org/ s ite s/ def au lt/ file s/ 20 2 3 - 09/ progr e s s - on - t hes usta ina bl edevel opmen tgoals - thege nde rsna ps hot20 23en. pdf). More specifically, women disproportionately undertake unpaid, but socially essential, roles like caring for children or older people. A major challenge therefore is to ensure that unpaid caring and domestic labour is more equally shared between men and women, and appropriately valued. Crucially, there needs to be massive investment in women and girls, particularly in education (https:// www. unicef. org/ rosa/ media/ 27721/ file/ Agenda; https:// www. un. org/ devel opment/ desa/ dpad/ publi c at ion / f r ont iert e ch n ology - is sue s - h a rne ssi n g - theec ono m ic - divid endsfromdemog raphi cchange/ ) and health (Onarheim, Iversen, and Bloom2016; Remme etal.2020). Microbial technologies, in particular those concerned with health, nutrition, hygiene and provision of clean drinking water, reducing pollution, frugal technologies and global warming (‘Girls are also disproportionately affected by natural disasters and economic shocks’; https:// www. unicef. org/ rosa/ media/ 27721/ file/ Agenda) have an important role to play in reducing the burden of ill health in women. Measuring economic benefits only in terms of GDP undervalues many of the roles currently taken by women and overvalues commercial activities that are damaging to health like producing and selling healthharming products https:// wellb einge c onomy. or g / wpcont e nt/ uploa d s/ We Al l - BRI E F ING SMeasu ringtheWellb eingecono myv6. pdf. It is therefore vital that society shifts the current focus of measuring GDP as an end in itself to developing a ‘wellbeing economy’ which is in service of human and planetary wellbeing, rather than the other way round (Friel etal.2023; https:// www. weall scotl and. org/ whatisawellb eingeconomy). To ensure that the economic gains from microbial technologies support health and wellbeing means ensuring that benefits are shared fairly and that adverse externalities are avoided. The next section of this editorial considers the use of Health in All Policies as a way to maximise benefits and minimise risks from any development, and strategies to avoid cost externalities. 16.5 | Health in All Policies The many examples in this paper show the potential for microbial technologies to contribute to better health in many ways. Yet there are also risks to population health if they are misused, or if access to these benefits is inequitable. Health in all policies (HiAP) is an approach that aims to gain maximum health benefit, and avoid health risks, from policies and interventions in any sector. The WHO defines HiAP as ‘an approach to public policies across sectors that systematically takes into account the health and health systems implications of decisions, seeks synergies and avoids detrimental health impacts, in order to improve population health and health equity’. (https:// www. who. int/ publi catio ns/i/ item/ 97892 41506908). HiAP often involves using processes like Health Impact Assessment (HIA) to assess the likely impacts on health and the population groups likely to be affected by these, to inform changes that maximise benefits and mitigate any risks. 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. 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41 of 61 The HiAP approach is built on collaboration and partnership between public health and other sectors (Green etal.2021; https :// i ris. w ho. i nt/ bit s t r e a m / h a n d le/ 10 6 6 5/ 112 6 3 6/ 9 7 8 9 2 41506 908_ eng. pdf). Equity and participation are key values underpinning HiAP and HIA practice. (Green et al. 2021; Kemm 2013; https:// iris. who. int/ bitst ream/ handle/ 10665/ 112636/ 97892 41506 908_ eng. pdf; Winkler et al. 2021). This means that the interests of the most vulnerable and highest need populations should be prioritised, and their views taken into account. It involves considering a comprehensive range of ways in which any policy or intervention might affect health, rather than addressing individual health issues at a time. (Green etal.2021) Sustainability is also a key value for HiAP and HIA (Green etal.2021; Winkler etal.2021; https:// iris. who. i nt / bit st r e a m / h a nd le/ 106 65/ 11 2 63 6/ 9 7 89 2 415 0 6 9 08_ eng. pdf). While SDG 3 is specifically about health, the other SDGs are all determinants impacting population health outcomes. Some HIAs explicitly use the SDGs as a framework to identify relevant impacts for assessment (Green, Gray, and Ashton 2020; Winkler etal.2020). It has even been argued that HIA practitioners were implementing the SDG framework before the UN even created it (Gulis2019). HIAs are applied to policies and plans related to many of the issues described here, especially those affecting social and environmental determinants of health such as urban planning, agriculture and industry. An understanding of microbial technologies may help HIA practitioners to identify opportunities to mitigate some of the adverse impacts identified. Similarly, HiAP has been little used to date to understand and influence the development and implementation of microbial technologies, but it has great potential to help ensure their benefits are realised and shared more equally. A future paper in this special issue will explore this potential in more detail. 16.6 | Cost Externalisation ‘Externalised costs are costs of production that someone else pays’. (https:// reali tysan dwich. com/ sacred_ econo mics_ chapt er_ 10/ ). The concept of cost externalisation usually refers to financial costs, for example environmental pollution associated with a commercial operation that engenders a societal cost through taxpayerfunded remediation, commercial loss of revenue from tourism or fishing through oil spills on beaches that affect coastal businesses, increased healthcare costs due to increased disease from intoxication, etc. In all cases, these financial costs are not borne by the polluting producer (and hence not passed on to the customer who buys the products, or result in reduced dividends to shareholders) because they are externalised—transferred to others (https:// www. imf. org/ en/ Publi catio ns/ fandd/ issues/ Series/ BacktoBasics/ Exter nalities). It is, however, apparent from this example there can also be nonfinancial currencies of externalisation, in this case, the preventable human suffering and increase in morbidity and mortality caused by the externalisation. Policies that embody acceptance, however reluctant or justified by cost considerations, of preventable morbidity and mortality engender major collateral costs that include unnecessary suffering, loss of days worked and corresponding revenue, time lost in education and its longterm consequences for the individual and the family, a need for caring and the time and economic burden of this, emotional and mental strain on the individual and family and any mental disease consequences. Cost externalisation is therefore not just about money, but very much about health and wellbeing—physical and mental—the transfer of health burdens to individuals and families, and the personal and collective responsibilities of those wittingly or unwittingly mediating the externalisation. Cost externalisation issues relating to health range over multiple spheres which include: • Vaccine hesitancy, which prejudices attainment of herd immunity and disease erradication, and increases risk of infection, and thereby transforms a personal preference/ ideology (often acquired via societal trends and influences) into health burden costs of disease risk to individuals who are either unable to tolerate vaccination or for which vaccination is ineffective (example measles: Hotez, Nuzhath, and Colwell2020; Opel etal.2023), and of the associated unnecessary increased burdens on caregivers (Dhaliwal etal.2022) and health systems that have to cope with these diseases • Antibiotic use for viral diseases, which unnecessarily promotes the development and spread of AMR, and thereby transforms a perception of an improved individual health outcome into a collective health burden risk of increased morbidity and mortality to persons succumbing to infections untreatable with antibiotics • Food supply and security, though as indicated above are essential to health, also engender health problems themselves on several fronts through associated carbon footprints and contribution to global warming, use of and pollution by agrochemicalseutrophicationpromotion of oxygen minimum zones and associated loss of biodiversity and ecosystem services (also caused by deforestation), water and agricultural resource use footprints, the health consequences of which are largely or entirely externalised • Unnecessary bureaucracy and unbalanced/disproportionate restrictions inter alia take up valuable time of frontline health professionals (https:// www. gov. uk/ gover n me nt / cal l s - forevide nc e/ r educ ing - bu r ea uc ra c yi n - t hehe a lt hand - so c ia lcaresy st e m - c a l lf ore vide nc e/ out c o me/ bu sti ngbu rea ucr ac yempo w eri ng - f ront l ine - st a f f - byreduc ingexces sburea ucrac yinthehealt ha ndcaresyste minengland) which reduces their availability for timely diagnosis and treatment of patient issues, some of which are based on microbial technologies, and can lead to poorer health outcomes. This externalisation of bureaucratic tasks to healthcare professionals is directly paid for by the healthcare professionals, who cannot fulfil their full potential to heal and, as a consequence, by patients who suffer poorer health outcomes, and their families and friends. • Unnecessarily slow approval of new medicaments, medical processes, etc., that save lives. That this is in need of intense scrutiny and improvement is illustrated by the fast tracking of COVID19 vaccines which saved millions of lives and 17517915, 2025, 1, Downloaded from https://enviromicro-journals.onlinelibrary.wiley.com/doi/10.1111/1751-7915.70068 by Readcube (Labtiva Inc.), Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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