Postbiotics: Modulation of the Gut Microbiota and Potential for Association with Nanotechnology

Vol.:(0123456789) Probiotics and Antimicrobial Proteins https://doi.org/10.1007/s12602-025-10675-3 REVIEW Postbiotics: Modulation oftheGut Microbiota andPotential forAssociation withNanotechnology AnaJúliaRochaCardoso1· SuzanaGonçalvesCarvalho1· VitóriaRibeiroMantovanelli1· LeonardodeFreitasMarinho2· AmandaLetíciaPolliSilvestre1· TâniaForster‑Carneiro2· MariaPalmiraDaflonGremião1· MarlusChorilli1 Accepted: 9 July 2025 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025 Abstract Postbiotics are preparations containing inanimate microorganisms or their components that have a direct or indirect beneficial effect on the host and can include many different components, such as short-chain fatty acids, bacterial lysates, cell-free culture supernatants, cell wall fragments, enzymes, and exopolysaccharides. Despite the numerous advantages of postbiotics for the body, their use is limited due to unfavorable pharmacokinetics, low bioavailability, non-selective pharmacological action, poor palatability, and unpleasant odor. The development of nanotechnology-based delivery systems could be an important industrial tool to enhance the selective action of these agents and improve their therapeutic efficacy, particularly in the pharmaceutical and food sectors. In the pharmaceutical industry, several nanotechnology-based delivery systems have already been approved by the FDA and successfully marketed, demonstrating their clinical and industrial viability, such as Abraxane®, Doxil® (or Caelyx®), Onivyde®, Marqibo®, and Vyxeos®. In the food industry, products such as Driphorm® (nanostructured lipid emulsion for the efficient delivery of vitamin D in food) illustrate how nanotechnology has been applied in concrete ways to the development of functional foods and nutraceuticals, contributing to technological innovation, added value, and advances in health promotion. However, although nanotechnology in the delivery of postbiotics is an emerging and innovative field with promising preclinical studies, the lack of consolidated clinical or commercial data means that this topic needs to be expanded in order to achieve standardization and clinical validation. This review aims to highlight the importance of postbiotics in the modulation of gut microbiota and in the prevention/treatment of disease, as well as the potential of using nanotechnology to facilitate the targeting of these compounds and the limitations of using these systems for such applications. Keywords Microbiota· Intestinal diseases· Drug delivery· Dysbiosis· Health benefits· Bacteria-derived factors Introduction The large intestine is home to trillions of microorganisms, including fungi, viruses, and over a thousand different species of bacteria, known as the microbiota [123, 133]. The microbiota has been called the “eighth organ” of the human body because it communicates with the host through metabolites and molecules and also performs several physiological functions in the body, such as modulating the immune system, establishing a defense against pathogen invasion, and maintaining the integrity of the intestinal barrier [84, 128]. When the gut flora is altered (dysbiosis), the likelihood of developing diseases of the immune, nervous, endocrine, and cardiovascular systems, such as colorectal cancer, depressive Ana Júlia Rocha Cardoso and Suzana Gonçalves Carvalho contributed equally to this work. Highlights • Postbiotics have several biological properties, mainly modulating the gut microbiota and the immune system. • Postbiotics are effective in the prevention of a variety of intestinal diseases. • Nanoparticle-based drug delivery systems can reduce toxicity, increase bioavailability and biocompatibility of postbiotics, and allow localized targeting of these compounds in the gut. Extended author information available on the last page of the article Probiotics and Antimicrobial Proteins disorders, obesity, diabetes, and inflammatory bowel disease (IBD), increases [5, 18, 35, 72, 78, 118]. The prebiotics, probiotics, and postbiotics are used to modulate the microbiota and prevent the onset of dysbiosis or the disease progression [38, 70]. Prebiotics are substrates selectively used by host microorganisms that have beneficial effects on the human body and can be used in the form of food ingredients such as sweeteners (inulin, oligofructose) [12, 37]. Probiotics were defined by the World Health Organization (WHO) in 2002 as “live microorganisms that, when ingested in sufficient quantities, exert beneficial effects in the host organism, the most commonly used are bacteria of the genera Lactobacillus and Bifidobacterium.” Postbiotics, on the other hand, are gaining increasing attention and interest due to their potential (Fig.1). Tsilingiri and Rescigno [108] defined a postbiotic as any substance released or produced by the metabolic activity of a microorganism that has a beneficial effect on the host. However, more recently, in 2021, the International Scientific Association of Probiotics and Prebiotics (ISAPP) suggested that a postbiotic is the elaboration of a “preparation of inanimate microorganisms and/or their components that confers a health benefit to the host.” Unlike the first definition, which considers postbiotics to be any substance released by microbial activity, ISAPP is more specific and normative, focusing on standardized preparations and defining postbiotics as inanimate microorganisms and/or their components, i.e., no longer just metabolic side products, but also the dead or inactive microorganisms themselves. Recent research has demonstrated the potential of postbiotics based on their antimicrobial, antioxidant, and immunomodulatory properties [17]. In addition, although the mechanisms by which the benefits to the host are exerted are not fully understood, it is known that many of these properties alter microbiota homeostasis, metabolic and/or signaling pathways, generating positive physiological, biological, and immunological responses that act to prevent disease and help stabilize existing pathologies [2]. Despite the advantages of postbiotics, they have limitations that can alter their activity when ingested, such as biodegradability, low molecular weight, low solubility, high proteolytic activity, and low membrane permeability, resulting in a systemic and less effective effect [34, 98]. As a way to overcome these limitations, the idea of using nanotechnology has emerged [75, 98, 106, 129]. Nanotechnology is emerging as a promising way to optimize encapsulation for targeted and specific delivery, overcoming the barriers of the gastrointestinal system such as pH variation and enzymatic activity, as well as being able to improve the physicochemical properties, bypassing the limitations of the compounds [32]. In this context, the aim of this work was to discuss the importance of postbiotics for the modulation of the microbiota and the immune system and their benefits for human health and intestinal diseases, as well as the use of these compounds in nanotechnology-based delivery systems and the importance of advancing these studies. The approach to postbiotics from nanostructured systems is an unprecedented study that fills a gap in the literature. Gut Microbiota Composition andFunctions There are more than 1000 species of bacteria in the human gut, and more than 50 bacterial genera have been described. The large intestine has the highest number of bacteria in the gastrointestinal tract, approximately 1011–1012 cells per gram. Most species belong to the phyla Fig. 1 Number of articles published on postbiotics in the last 10years (data obtained using the term “postbiotics” in PubMed). Data collected in January 2025 Probiotics and Antimicrobial Proteins Firmicutes, Actinobacteria, Proteobacteria, Fusobacteria, and Bacteroidetes. The gut microbiota plays an important role in maintaining host health by providing various nutrients, regulating energy balance, and modulating immune response and defense against pathogens. Therefore, maintaining a favorable balance of gut microbiota is beneficial for host health [1]. Important physiological changes can occur in the gastrointestinal tract as a result of microbiota dysregulation. Some examples include a decrease in pH from approximately 6.0–7.2 for normal colonic function to 2.3–5.5 for dysfunctional or inflamed colonic function, as well as changes in mucus production, epithelial structure, and enzyme milieu. In addition, the decrease in Bacteroides and Bifidobacterium species may mark the progression of IBD, the accelerated colonic transit time characterized by diarrheal events [25]. As the regulation of the gut microbiota is involved in various physiological functions, several clinical trials have explored its modulation and impact on the treatment and prevention of related diseases (Fig.2). In addition to the remarkable regulatory functions associated with the microbiota, it can also influence the bioavailability of oral drugs due to its ability to secrete different types of enzymes involved in various types of biotransformation, such as reduction, hydrolysis, dehydroxylation, decarboxylation, deacetylation, and acetylation reactions. Thus, after oral drug administration, the first-pass effect and enterohepatic recirculation in the intestine/liver, the enzymatic activity of the gut microbiota can affect the bioavailability of drugs through these reactions [128]. The gut microbiota also plays an important role in the digestion of polysaccharides and the production of short-chain fatty acids. It is also a source of essential amino acids and vitamins (metabolites produced by the gut microbiota) such as biotin, vitamin K, folate, thiamine, and riboflavin [44]. There is evidence that the use of prebiotics, probiotics, and especially postbiotics can make a significant contribution to restoring and maintaining intestinal homeostasis. This homeostasis refers to the dynamic balance between the commensal microbiota, the intestinal epithelial barrier, and the immune system. Intervention with these compounds can strengthen mucosal integrity, modulate inflammatory and immune responses, and inhibit pathogen colonization, thereby promoting overall host health and preventing intestinal and systemic disease [107]. Postbiotics: Concept, Key Challenges, andClasses ofPostbiotics The word “postbiotic” is of Greek origin, “post” meaning “after” and “bios” meaning “relating to life.” The term “biotic” also has Greek origins, “biotikos,” referring to “pertaining to life.” This word refers to a technique that relates to the use of nutrition to enrich intestinal microorganisms, which includes studies of living beings and their physiological environment [13, 85, 90, 92, 112, 120]. In general, postbiotics can act as cellular and molecular mechanisms and cause numerous effects on human wellbeing, such as anti-tumor [80, 83], anti-inflammatory activities [105], inhibition of pathogenic microorganisms [49, 119], antioxidant [51], glucose homeostasis [89], immunomodulation [28], improvement of the intestinal barrier, normalization of physiological functions, and modulation of microbiota composition and activity (Table1). In addition, Fig. 2 Number of clinical trials for the treatment and/or prevention of diseases caused by dysbiosis of the intestinal flora by region and study phase. Data collected in September 2024 Probiotics and Antimicrobial Proteins they can act as regulators of gene expression, as catalysts for molecular activities that cause comorbidities, provide therapeutic benefits, eliminate free radicals to reduce skin lesions, help lower blood glucose, and improve insulin activity in people with obesity [64, 124]. It should be noted that certain classes of post-biotics, such as bacterial lysates and cell-free supernatants, have proven to be particularly relevant for therapeutic applications due to their complex and functionally active composition. These classes bring together a variety of bioactive components (such as antimicrobial peptides, cell wall fragments, short-chain fatty acids, exopolysaccharides, and soluble metabolites) that act synergistically to modulate the immune response, promote intestinal barrier integrity, and reduce inflammatory processes [13]. Probiotics are live microorganisms characterized by the disadvantages of standardization and unpredictability of dosage. Postbiotics, on the other hand, do not have these problems; they require low temperatures for preservation and have a longer shelf life, making them easier and safer to store and transport. In addition, compared to probiotics, postbiotics have faster and more precise production technology and quantitative control [92, 134]. Recent studies indicate that postbiotics can reshape the landscape of pharmaceuticals and food products with ecological and revolutionary alternatives for human health [90]. In addition, research data show that postbiotics have applications in agriculture and animal husbandry and have bioactivities invitro and invivo (such as biopreservation) [13]. Despite the many benefits and applications of postbiotics, they are still considered new molecules and have been little studied compared to probiotics and prebiotics. As a result, the introduction of new postbiotics to the pharmaceutical and food markets requires new development efforts, including clinical trials, field testing, and animal studies. In addition, postbiotics must meet regulatory requirements for certain applications, such as those related to biosafety, especially if they need to be inspected by international authorities [13]. Regulatory bodies such as the European Food Safety Authority (EFSA) have established specific guidelines for the risk assessment of nanomaterials in food. These guidelines include stringent physicochemical characterization criteria as well as toxicity, bioavailability, and bioaccessibility testing, which are essential to ensure the safety and efficacy of nanoencapsulated compounds. In the context of nanoencapsulation of microbial metabolites, these requirements are particularly relevant since the physicochemical properties and reactivity of the compounds can be significantly altered after nanoencapsulation. Thus, the development of nanoencapsulated postbiotics not only represents a promising frontier for therapeutic and nutritional innovation, but also requires careful attention to European regulatory requirements for their potential commercial and clinical application. Table 1 Overview of the main biological functions of postbiotics in intestinal diseases Postbiotic class Active compound Application References Bacterial lysates OM-89 Chronic colitis [6, 61] OM-89 Inflammatory bowel disease [43] Cell-free culture supernatants CFS-Lactiplantibacillus plantarum Colorectal cancer [83] CFS-Lactobacillus casei Colorectal cancer [30] CFS-Lactobacillus rhamnosus Colorectal cancer [30, 83] CFS-Lactobacillus rhamnosus Immunomodulation [7] CFS-Lactobacillus strain Antibacterial and antibiofilm [26] Cell wall fragments LTA Immunostimulation [57, 113] LPS Immunostimulation [66, 67] Enzymes Catalase-Lactococcus lactis Colorectal cancer [20] Superoxide dismutase and catalase-Lactobacillus plantarum and Lactobacillus acidophilus Inflammatory bowel disease [105] Superoxide dismutase and catalase-Lactobacillus casei Crohn’s disease [62] Exopolysaccharides EPS-Lactiplantibacillus plantarum Intestinal activity [45, 131, 132] EPS-Lactobacillus acidophilus Immunomodulation [28] EPS-Lactobacillus rhamnosus Salmonella typhimurium-induced intestinal inflammation [66] Short-chain fatty acids Acetate, propionate, and butyrate Inflammatory bowel disease [104] Butyrate Ulcerative colitis [63] Butyrate Diabetes mellitus [77, 89, 116] Acetate Ulcerative colitis [21] Probiotics and Antimicrobial Proteins Bacterial Lysates Bacterial lysates (BLs) present themselves as particles obtained by chemical or mechanical disruption of individual strains or a range of pathogenic gram-positive or gram-negative bacteria that are readily found in the environment [88, 134]. The European Medicines Agency defines these lysates as drugs made from bacterial cells that are broken down and used to stimulate the immune system to recognize and fight infections. The process of bacterial lysis can be achieved by chemical (alkaline) or mechanical treatment, including the use of heat and detergents. The main commercially available bacterial lysates are Broncho-Vaxom (OM-85), Liuvac LW50020, Lantigen B, Ismigen PBML, and Ribomunyl D53. The rationale for using bacterial lysates for disease prevention is related to their ability to mimic natural exposure to microorganisms and to promote an innate, adaptive, and antigen-specific immune response against the administered antigens [24]. The same class has been used as a therapeutic for respiratory infections for the last 100years, with the argument of stimulating more specific humoral responses at the mucosal surface. Currently, BLs are still widely used to treat respiratory infections by activating mucosal dendritic cells and promoting their binding to toll-like receptors (TLRs) [55]. For example, the immunomodulator OM-85 consists of eight different strains commonly found in respiratory tract infections (Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, Klebsiella ozaenae, Staphylococcus aureus (S. aureus), Streptococcus pyogenes, Streptococcus viridans, and Moraxella catarrhalis) and helps prevent such infections [59, 88]. Studies using OM-85 were conducted by Koatz etal. [59], where patients with allergic rhinitis, asthma, or chronic obstructive pulmonary disease were evaluated, and the effectiveness in reducing the incidence of respiratory tract infections was analyzed. The results showed a significant reduction before and after the use of BLs. Similarly, in Kearney etal. [55], different systematic reviews were discussed, and it was observed that BLs induced a synergistic innate immunity dependent on TLRs and reduced the relapse in children and adults with respiratory diseases. However, BLs have also been applied to other treatments, such as rheumatoid arthritis [15], asthma [69, 74], chronic colitis [6, 61], and IBD [43]. In a study carried out by Hoentjen etal. [43], colitis was reduced in transgenic rats modified to develop spontaneous colitis under specific conditions, with decreased tissue pro-inflammatory cytokines and increased immunomodulatory molecules controlling the inflammatory state of the patients, showing potential for use as an adjunctive therapy for IBD. Cell‑Free Supernatants Postbiotics are fundamental metabolites for intestinal health and contribute positively to the management of intestinal diseases. However, certain ethical issues debate the safety of administering live microorganisms to patients in poor health. Therefore, cell-free culture supernatants (CFS) have become an alternative strategy to these debates. They provide patients with the beneficial effects of metabolites without microorganisms [100]. Cell-free culture supernatants belong to the class of postbiotic drugs and are defined as fluids or liquids remaining after the removal of living cells from a biological system. It is composed of metabolites that have been secreted by living cells that were part of the system during their cellular activities. These fluids are obtained from the incubation of cell cultures and are obtained by centrifuging the system after an incubation period and subsequent removal of the microorganisms. The final mixture is filtered to ensure complete sterility to obtain the cell-free supernatant [134]. A study by Pahumunto and Teanpaisan [83] sought to evaluate the postbiotic potential of seven strains of Lactiplantibacillus plantarum, which are currently recognized as efficient probiotics. The CFS of the strains studied showed responsive activity against pro-inflammatory signals, modulating cytokine patterns in macrophages. In another study conducted to compare the immunomodulatory effects of live strains of Lactobacillus rhamnosus (L. rhamnosus) and their cell-free supernatants against Escherichia coli, the authors reported that the supernatants were more effective in reducing pro-inflammatory cytokines than the bacteria themselves [7]. These effects may be achieved by competition for activation of the same inflammatory pathways between bacteria and CFS but through the interaction of different receptors [53, 71]. Numerous studies have also focused on investigating the anti-cancer properties of CFS. A study by Escamilla etal. [30] analyzed the ability of Lactobacillus casei and L. rhamnosus GG to inhibit colorectal cancer cells invitro through the expression of metalloproteinases and proteins. The authors compared the two strains with a gut bacterium and observed that the two strains studied exerted a diminished effect on the invasion of cancer cells, unlike the bacterium. After analyzing the samples, the size of the particles that showed inhibitory activity suggested that it could be a macromolecule, which could be a polysaccharide, nucleic acid, or protein. Another study also conducted with Lactobacillus strains for the analysis of anticancer, anti-inflammatory, and antimicrobial activity presented similar results, suggesting that L. rhamnosus GG and its supernatants showed stronger inhibition of pathogenic cells, better activity against bacteria associated with colorectal cancer, and reduced pro-inflammatory activity [83]. Probiotics and Antimicrobial Proteins The ability to form biofilm is an important feature when analyzing CFS-producing microorganisms, as this factor may indicate long-term gut colonization [110]. However, CFS is expected to have antibacterial activity against enteric pathogens. Drumond etal. [26] should investigate the antibacterial and antibiofilm effects of supernatants from 4 lactic acid bacteria of the Lactobacillus strain against Pseudomonas aeruginosa. In this study, all CFS showed bactericidal or bacteriostatic activity in addition to antibiofilm activity. Cell Wall Fragments The microbiota consists of approximately 1500 species of bacteria, including gram-negative and gram-positive bacteria. Gram-negative bacteria have two membranes, an inner and an outer, which contain lipopolysaccharides (LPS). Gram-positive bacteria have a dense cell wall rich in peptidoglycans containing lipoteichoic acid (LTA) [57, 82]. LTA is a naturally occurring acid that has the potential to enhance non-specific protective mechanisms by inducing the release of anti-infective peptides such as cathelicidin and β-defensin. Some bacteria of the genus Bifidobacterium and Lactobacillus, responsible for the production of LTA, promote the activity of cutaneous mast cell activity against bacterial and viral infections. In addition, LTA has immunostimulatory, anti-inflammatory, anticancer, and anti-infectious properties [57, 113]. Like LTA, LPS is an amphiphilic formed by the association of a hydrophilic polyphosphate polymer with a glycolipid. LPS is the most important immunostimulant, and just as in the period of bacterial development, during the lysis of bacterial cells, LPS is released (as in the case of antibiotic activity). The activity of LPS is still considered controversial, as in the work of [66, 67]) and Kuc-Ciepluch etal. [60], who demonstrate that LPS can be a pro-inflammatory mediator of various gram-negative bacteria, altering the integrity of the intestinal barrier and leading to its damage. It is, therefore, clear that further studies are needed to prove the effects of this group. Enzymes Enzymes are biological catalysts that speed up biochemical processes in living things. They aid in nutrient absorption and digestion, regulate the microbiota in the gut, and provide a host of other health benefits. In 1878, German scientist Wilhelm Kühne first used the word “enzyme” to describe the ability of yeast to convert alcohol from sugar [97]. Bacillus subtilis and Bacillus licheniformis, along with certain fungal strains such as Aspergillus niger and Aspergillus oryzae, are the primary sources of enzymes used as postbiotics [134]. Based on their mode of action or function, enzymes are classified into six general groups: ligases, isomerases, hydrolases, oxidoreductases, transferases, and hydrolases [103]. Examples include lactases, which break down lactose into glucose and galactose, and proteases, which hydrolyze proteins into peptides and amino acids. Amylases catalyze the breakdown of starch into sugars, facilitating carbohydrate digestion. Lipase breaks down fats into fatty acids and glycerol, while glucosidase hydrolyzes glycosidic bonds into carbohydrates. Bile salt hydrolase (BSH) breaks down bile salts, improving the digestion and absorption of lipids. Glutathione peroxidase is a postbiotic enzyme that responds to oxidative stress [11, 97]. The overproduction of reactive oxygen species (ROS) impairs intestinal function, causing severe tissue damage and inflammation that leads to the onset or progression of several diseases, particularly intestinal diseases. Posbiotic enzymes act as antioxidant proteins and thus can significantly influence the physiopathology of intestinal diseases [79]. According to studies, Lactococcus lactis (L. lactis) can produce an effective catalase against colon cancer induced by the carcinogen DMH (1,2-dimethylhydrazine) in mice. The results showed that mice supplemented with the catalase-producing strain (L. lactis CAT) significantly reduced colon damage and inflammation compared to the control groups. No tumors were observed in the mice receiving the catalase-producing strain, while tumors were present in the other groups from week 14 after DMH injection. The higher catalase activity in the L. lactis CAT-supplemented mice resulted in lower levels of hydrogen peroxide in the colon, which reduced histopathological damage and inflammation [62]. Other studies have also evaluated two strains of Lactobacillus for use in animal studies, Lactobacillus plantarum 30B (L. plantarum) (which has greater catalase activity) and L. acidophilus 900 (which has greater dismutase-like activity). These strains have enzymes similar to superoxide dismutase and catalase that help neutralize and reduce oxidative stress. They help reduce pro-inflammatory cytokines and restore intestinal mucosal integrity. Mice treated with these lactobacilli showed significantly improved gut health compared to untreated or lactobacilli-free mice. The study concluded that postbiotic enzymes with dismutase-like activities are more effective at alleviating inflammation than catalysis, potentially providing a more targeted and effective approach to treating gut inflammation [105]. The BL23 strain of Lactobacillus casei–producing catalase (CAT) or superoxide dismutase (SOD) was studied in mice with trinitrobenzene sulfonic acid–induced Crohn’s disease. Mice treated with SODand CAT-producing bacteria showed significant initial recovery from Crohn’s disease–induced weight loss. The treatment resulted in a remarkable reduction in intestinal inflammation. The treated Probiotics and Antimicrobial Proteins mice had lower levels of pro-inflammatory cytokines and reduced infiltration of inflammatory cells into the intestinal tissue. There was an increase in the activities of antioxidant enzymes in the intestines of the treated mice, suggesting an improved ability to neutralize ROS and reduce oxidative stress. The authors suggest that the use of genetically engineered Lactobacillus-producing antioxidant enzymes may be beneficial in preventing or reducing the severity of certain intestinal diseases [62]. In summary, postbiotic enzymes with antioxidant properties, such as superoxide dismutase (SOD), are essential in combating ROS, which are a major contributor to impaired intestinal function. Glutathione peroxidase can be extracted in large quantities by Lactobacillus fermentum and L. plantarum in vitro [92]. In addition, Bifidobacterium adolescentis, B. longum, B. infantis, and B. breve can degrade hydrogen peroxide through the release of NADH peroxidase [10]. The properties and activities of postbiotic enzymes provide an interesting platform for the development of therapies targeting oxidative stress and inflammation, major causes of intestinal diseases [42]. Exopolysaccharides Many microorganisms have biopolymers present on the outer surface of the cell wall, called exopolysaccharides (EPS). EPSs are long-chain polysaccharides, and the monosaccharide units that make up EPS are produced by the microorganism itself and secreted into the environment during the growth process, forming another category of cellfree supernatants [22, 126, 127, 134]. Their composition may contain the same monomers or a mixture of different monomers, which classifies EPSs as homopolysaccharides or heteropolysaccharides [117]. These biopolymers perform important activities and are applied in various contexts, including biotechnology, agriculture, and water waste treatment. Regarding their biological application, EPS have already shown anti-inflammatory, antioxidant, antimicrobial, and anticancer activity [117]. Among the bacteriturbot, those producing lactic acid are the most studied as they are a safer strain [4, 96]. A study by Li etal. [67] aimed to understand how Lactobacillus rhamnosus GG protects the gut from the harmful effects of Salmonella typhimurium infection. Based on their findings using invivo models, the authors concluded that high doses of this EPS can ameliorate lesions in the ileum and significantly reduce the oxidative damage generated by the infection more efficiently than the drug used as a standard of comparison. These effects are achieved mainly due to the ability of this EPS to activate or inhibit the TLR4/NF-κB and B/MAPK pathways, modulating the inflammatory process. Another study investigated the activities of Lactobacillus acidophilus, and the results showed that EPSs exhibited immunomodulatory activities through the action of IL-2, IL-8, and tumor necrotic factor (TNF) [28]. Many studies have focused on exploring the various therapeutic effects of L. plantarum NCU116, an exopolysaccharide originally isolated from traditional Chinese sauerkraut and now widely used for its probiotic properties [3]. A study by Hu etal. [45] sought to observe the effects of Lactiplantibacillus plantarum EPSs on the gut microbiota in turbot models. The authors reported that the group treated with EPSs showed an improvement in the activities of digestive enzymes and an increase in enzymes associated with the immune system, suggesting that supplementation with these substances may contribute to better intestinal activity. Another study by Zhou etal. [131] investigated the effects of this same strain on the maintenance of the intestinal barrier in rats with intestinal inflammation. The main results obtained were an alleviation of the animals’ weight loss, an increase in the level of proteins that maintain the epithelial barrier, and a decrease in the concentration of pro-inflammatory cytokines, characteristics that led to the inhibition of the development of ulcerative colitis in the animals. The regulatory functions of the intestinal barrier by this EPS were achieved by increasing the number of intestinal stem cells in the crypts of the colonic tissue. In addition to the aforementioned applications, the search for hypocholesterolemic activity has also gained momentum over the years. Bhat and Bajaj [8] attempted to understand how EPSs from Lactobacillus paracasei, an isolate from breast milk, would act against elevated cholesterol, and the results suggested optimal hypocholesterolemic activity, in addition to the antioxidant effects observed through the elimination of different types of free radicals and antibiofilm activity against a number of human pathogens. Metabolites Produced byGut Microbiota Bacterial metabolites are naturally produced by the gut microbiota, depending on genetic factors and the specific consumption of certain foods. Their presence provides benefits to the body, including immunomodulatory, antioxidant, and antimicrobial effects [2, 86]. Vitamin K (a term used to refer to a group of fat-soluble vitamins) has beneficial effects on the body, helping to activate blood clotting factors and the functioning of the pancreas, bones, lungs, brain, and kidneys. A review carried out by Pereira and Monteiro [87] demonstrated, through planning in serum and feces, that the administration of vitamin K in patients with rheumatoid arthritis generates slower progress and a delay in its initial appearance. In a planned study carried out by Karl etal. [52], the plasma and fecal concentrations of inflammatory cytokines of patients undergoing a diet were measured over 8weeks. As a final result of the distribution, it was shown that the concentration of vitamin K Probiotics and Antimicrobial Proteins varied due to the different composition of the microbiota, but despite this, the biomarkers of non-significant peculiarities showed significant changes (IL-6 and TNF-,both p > 0.05). Folate, another example of a metabolite produced by the gut microbiota, is a coenzyme that aids in purine synthesis and other methylation reactions. When present, it has been implicated in the control and development of chronic diseases such as cancer, cardiovascular disease, and cognitive dysfunction, as well as the development of neural tube defects in fetuses [27]. Studies report that the likelihood of developing colorectal cancer may be reduced by 40% in people who consume more folate [58]. Short‑Chain Fatty Acids Short-chain fatty acids (SCFAs) are microbial metabolites produced through the process of carbohydrate fermentation by bacteria present in the colon, with acetate, propionate, and butyrate being the major representatives of this class [22]. Acetate and propionate are mainly produced by Bacteroidetes strains (Bacteroides spp., Bifidobacterium spp., Lactobacillus spp.). In contrast, butyrate is produced by bacteria of the phylum Firmicutes (Enterococcus spp., Eubacterium spp., Roseburia spp.) [73, 109, 126, 127]. Despite being in the same classification, these three fatty acids act through opposite pathways. In a study designed to evaluate the effects of the three major SCFAs on the expression of P-glycoprotein and breast cancer resistance protein in the intestine of rats, the authors reported opposite behaviors. Acetate showed no significant effects, while propionate and butyrate showed positive effects that were better in the butyrate-treated group [121]. Another study by Tedelind etal. [104] also showed positive results against IBD. However, in this study, the authors evaluated the decrease in TNF release and expression of colorectal cancer genes, and propionate and butyrate were more efficient in inhibiting the expression of the cytokines and genes studied compared to acetate. Although they have different mechanisms of action, both have been shown to be beneficial in obesity. Studies suggest that SCFAs may regulate the inflammatory response, lipid metabolism, and eating behavior, thereby helping to reduce the health risks associated with obesity [76]. Butyrate has been shown to positively affect intestinal epithelial renewal and the transcriptional regulation process, as well as regulate receptors and pro-inflammatory cytokines [134]. In an evaluation of the effects of butyrate against IBD, this metabolite was able to inhibit pro-inflammatory cytokines and stimulate the production of pro-inflammatory cytokines. The authors administered oral supplementation to rats with colitis, and the results suggested a reversal of histone acetylation [63]. Butyrate also has diabetes-related effects [89]. Some studies have linked reduced levels of butyrate-producing bacteria in children predisposed to type 1 diabetes mellitus [19]. Another study found that sodium butyrate indirectly induced insulin secretion in the pancreatic islets of rats fed these SCFAs [116]. As for acetate, studies have increasingly elucidated its antimicrobial, appetite-regulating, and intestinal barrierprotective effects [134]. Deleu etal. [21] sought to evaluate the anti-inflammatory and protective effects of acetate on the intestinal epithelium by administering high doses to patients with ulcerative colitis. The results indicated that the group treated with acetate showed a reduction in pro-inflammatory cytokines and an increase in epithelial resistance, suggesting that supplementation of IBD patients with acetate may contribute to better pharmacotherapy. Acetate also has the important function of being a mediator of fat formation in the body, as fructose is first converted to acetate before acetyl-CoA. In other words, the depletion of the microbiota that produces this metabolite may interfere with the lipogenic process (Fig.3) [130]. SCFAs contribute positively to colonic health and are mainly sourced from a diet rich in fruits and vegetables [125]. Propionate is an SCFA derived primarily from gluconeogenesis in the liver and is associated with inhibitory and anti-inflammatory activities [134]. Haghikia etal. [40] conducted a randomized human study to evaluate the effects of propionic acid on cholesterol metabolism, in which patients received doses of 500mg twice daily for 8weeks, and by the results, controlled HDL levels and a significant reduction in LDL levels were observed. Modulation ofGut Microbiota andImmune System byPostbiotics The composition of the microbiota varies among different hosts, and the versatility of its mechanisms of action is altered not only by diversity, but also by the health and dietary intake of the individual [2]. Postbiotics, in turn, intervene through molecular and cellular mechanisms in the control of the immune and nervous systems, producing beneficial effects that are consistent with the environment to which they have been exposed [85]. In general, they can increase innate immunity, reduce inflammation caused by pathogens by inhibiting their actions and growth, and promote the emergence of beneficial bacteria, contributing to eubiosis and gut improvement (Fig.4) [16, 68]. Despite the variability of the gut microbiota and the different mechanisms, functions may converge to produce a common effect. For example, metabolites of vitamins B, A, and K can result from synthesis by different bacteria such as Acetobacter pomorum and Bifidobacterium, where they neutralize toxins from luminal bacteria and provide an antiinflammatory environment by regulating cellular activities such as B cells [65, 93]. Bile acids, on the other hand, have Probiotics and Antimicrobial Proteins Fig. 3 Short-chain fatty acid biosynthetic pathways. Adapted from Portincasa etal. 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Authors and Affiliations AnaJúliaRochaCardoso1· SuzanaGonçalvesCarvalho1· VitóriaRibeiroMantovanelli1· LeonardodeFreitasMarinho2· AmandaLetíciaPolliSilvestre1· TâniaForster‑Carneiro2· MariaPalmiraDaflonGremião1· MarlusChorilli1 * Suzana Gonçalves Carvalho suzana.g.carv[email protected] * Marlus Chorilli marlus.chor[email protected] Ana Júlia Rocha Cardoso [email protected] Vitória Ribeiro Mantovanelli vitoriarmantov[email protected] Leonardo de Freitas Marinho [email protected] Amanda Letícia Polli Silvestre amanda.silves[email protected] Tânia Forster-Carneiro [email protected] Maria Palmira Daflon Gremião [email protected] 1 Department ofDrugs andPharmaceutics, School ofPharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, SP14800-903, Brazil 2 Department ofFood Engineering, School ofFood Engineering (FEA), University ofCampinas (UNICAMP), Campinas, SP13083-862, Brazil