Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review

pathogens Review Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review Ascensión Rueda-Robles 1,† , Teresa Rubio-Tomás2,3,† , Julio Plaza-Diaz 4,5,6 and Ana I. Álvarez-Mercado 1,5,6,*   Citation: Rueda-Robles, A.; Rubio-Tomás, T.; Plaza-Diaz, J.; Álvarez-Mercado, A.I. Impact of Dietary Patterns on H. pylori Infection and the Modulation of Microbiota to Counteract Its Effect. A Narrative Review. Pathogens 2021,10, 875. https://doi.org/10.3390/ pathogens10070875 Academic Editor: Hiroyuki Marusawa Received: 24 June 2021 Accepted: 9 July 2021 Published: 10 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1Center of Biomedical Research, Institute of Nutrition and Food Technology “JoséMataix”, University of Granada, Avda. del Conocimiento s/n., Armilla, 18016 Granada, Spain; [email protected] 2Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; teresa.r[email protected] 3School of Medicine, University of Crete, 70013 Heraklion, Crete, Greece 4Children’s Hospital Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada; [email protected] 5Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain 6Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain *Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the stomach and can induce gastric disease and intra-gastric lesions, including chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This bacterium is responsible for long-term complications of gastric disease. The conjunction of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence the disease outcomes related to chronic H. pylori infection. In this regard, the consumption of unhealthy and unbalanced diets can induce microbial dysbiosis, which infection with H. pylori may contribute to. However, to date, clinical trials have reported controversial results and current knowledge in this field is inconclusive. Here, we review preclinical studies concerning the changes produced in the microbiota that may be related to H. pylori infection, as well as the involvement of diet. We summarize and discuss the last approaches based on the modulation of the microbiota to improve the negative impact of H. pylori infection and their potential translation from bench to bedside. Keywords: Helicobacter pylori; diet; gastrointestinal microbiota; experimental models; therapeutic approaches 1. Introduction Helicobacter pylori, considered the main bacterium responsible for gastric disease and long-term complications [ 1 ], is a Gram-negative bacterium that colonizes the stomach [ 2 ]. Infection with H. pylori is very prevalent around the world. It is estimated that 48.6% of the global adult population is affected [ 3 ]. All patients infected with H. pylori suffer from inflammation of the gastric mucosa (chronic gastritis), while, in some cases, the disease becomes more developed (e.g., peptic ulcer, gastric adenocarcinoma, and mucosaassociated lymphoid tissue lymphoma) [ 2 , 4 ]. In fact, H. pylori is responsible for 90–95% of duodenal ulcers and 70–85% of gastric ulcers [5]. The most important virulence factors of H. pylori are cytotoxin-associated A (CagA) and vacuolating cytotoxin (VacA). The expression of these proteins varies among H. pylori strains [ 6 ]. In the strains that carry the CagA gene, the CagA protein enters the host gastric cells upon H. pylori secretion, where it is phosphorylated and causes changes Pathogens 2021,10, 875. https://doi.org/10.3390/pathogens10070875 https://www.mdpi.com/journal/pathogens Pathogens 2021,10, 875 2 of 20 in cell morphology that lead to disturbed cell function by affecting multiple signaling pathways. CagA is related to higher rates of peptic ulcer disease and a higher probability of developing a more aggressive inflammatory disease and gastric carcinoma [ 7 ]. In the strains that express the VacA gene, H. pylori secretes the pore-forming protein VacA, which enters the host cells by endocytosis [ 6 ]. VacA accumulation in different host cell compartments can have many consequences related to gastric inflammation and, therefore, gastric carcinogenesis, such as the induction of apoptosis [ 8 ] and autophagic cell death [ 9 ], the disruption of gastric epithelial cell tight junctions [ 10 ], the suppression of host T cell proliferation and activation by yet to be discovered mechanisms [ 11 ], and the modulation of host cell metabolism [12]. H. pylori produces ammonia through urease activity, protecting itself from gastric acidity and other enzymes, such as phospholipase A2 and C, and glucosulphatase, which handle gastric mucosal damage [ 13 ] and chronic superficial gastritis, leading to atrophy of the gastric glands and resulting in reduced gastric acid secretion. Infection with H. pylori is also associated with anemia, as it impairs iron absorption as a result of chronic gastritis and gastric hypochlorhydria [ 3 ]. Infection during early childhood is associated with an augmented risk of coeliac disease [ 14 ]. Findings from epidemiologic studies point to H. pylori as an initiator of gastric cancer [ 2 , 15 ]. Moreover, this bacterium has been included as a class I carcinogen of gastric cancer development in the World Health Organization’s International Agency for Research on Cancer since 1994 [ 16 ]. The effect of H. pylori on oncogenesis is described by two mechanisms: (1) an indirect inflammatory reaction to H. pylori infection on the gastric mucosa, and (2) a direct epigenetic outcome of H. pylori on gastric epithelial cells development [ 17 ]. Consequently, H. pylori infection impairs the gastric tissue microenvironment, and promotes epithelial-mesenchymal transition and further gastric cancer progression [ 17 ]. In this line, dietary habits such as a high intake of green tea, fruits, or vegetables showed benefits against gastric cancer risk. Moreover, carotenoids, folate, vitamin C, and phytochemicals from fruits and vegetables seem to exert a protective role in carcinogenesis. On the contrary, salt and the availability of some transition metals can alter H. pylori virulence and accelerate carcinogenesis [ 18 ]. In addition, in the context of chronic H. pylori infection, the intersection of host genetics, immune response, bacterial virulence expression, diet, micronutrient availability, and microbiome structure influence disease outcomes [18] (Figure 1). With the aforementioned in mind, one might suggest that changes in diet patterns, aimed to modulate microbiota in H. pylori carriers, might be exploited to improve disease risk and promote gastric health. However, the relationship of these variables remains poorly understood. In the present review, we aimed to shed light on current knowledge about the changes in microbiota induced by H. pylori infection and the impact of diet, as well as to summarize the recent approaches aimed at modulating the microbiota to avoid and reduce the negative effects caused by H. pylori. Pathogens 2021,10, 875 3 of 20 Pathogens 2021, 10, 875 3 of 20 Figure 1. H. pylori invades the human stomach, negatively impacting host health, which is promoted or aggravated by specific dietary patterns. The main effects are gastritis, which can lead to peptic ulcers and eventually gastric cancer, alterations in the gut microbiota, and inflammation. Animal and in vitro models are routinely used to test the efficacy of emerging treatments for the eradication of H. pylori. These approaches mainly focus on the inhibition or reversal of adverse effects by avoiding the attachment and colonization of host intestinal epithelial cells and the attenuation of the consequences of the host´s pro-inflammatory state after H. pylori infection. Abbreviations: LPS, lipopolysaccharide, TLR4, toll-like receptor 4, and TNF-α, tumor necrosis factor-alpha. Figure 1. H. pylori invades the human stomach, negatively impacting host health, which is promoted or aggravated by specific dietary patterns. The main effects are gastritis, which can lead to peptic ulcers and eventually gastric cancer, alterations in the gut microbiota, and inflammation. Animal and in vitro models are routinely used to test the efficacy of emerging treatments for the eradication of H. pylori. These approaches mainly focus on the inhibition or reversal of adverse effects by avoiding the attachment and colonization of host intestinal epithelial cells and the attenuation of the consequences of the host ´ s pro-inflammatory state after H. pylori infection. Abbreviations: LPS, lipopolysaccharide, TLR4, toll-like receptor 4, and TNF-α, tumor necrosis factor-alpha. Pathogens 2021,10, 875 4 of 20 2. The Impact of Diet Patterns in Helicobacter pylori Infection After infection, H. pylori can induce malabsorption of several nutrients [ 19 ] and affect the physiological regulation of the intestinal metabolic hormones, such as ghrelin and leptin, which are involved in food intake, energy expenditure, and body mass [ 20 ]. Low circulating ghrelin levels were found in H. pylori-positive patients and in those with the more virulent H. pylori strain [ 21 , 22 ]. Infected individuals can also suffer irreversible inactivation of vitamin C through the effect of hypochlorhydria due to gastric atrophy, as intragastric pH levels increase, turning vitamin C into its less active form [23]. Many substances routinely taken in via diet have potent antibacterial activity against H. pylori and may reduce its potential for colonization [ 24 ]. By contrast, diet could affect the development and progression of H. pylori infection, because it alters the gastric environment through the host’s nutrient intake. For instance, animal studies indicated that diets with high salt intake promoted H. pylori colonization by disturbing the integrity and viscosity of the gastric mucosa, causing an inflammatory state that led to increased epithelial damage, hypochlorhydria, and gastric cancer [18,25]. Animal studies showed not only an increase in colonization capable of producing losses of parietal cells, atrophy, and intestinal metaplasia [ 26 , 27 ], but also high levels of gastric inflammation and oxidative stress [ 28 ]. A high-salt diet could influence gastric cancer risk by modulating H. pylori gene expression due to transcriptional alterations. In an in vitro study conducted by Loh et al., 65 genes were upregulated and 53 genes were downregulated in response to high salinity conditions [ 29 ]. The in vitro study of Voss et al. also showed that the bacterial membrane proteome was altered in response to salinity conditions [30]. By contrast, the results of sulforaphane consumption (present in broccoli sprouts) in female C57BL/6 mice infected with H. pylori Sydney Strain 1 subjected to a high-salt diet produced a reduction in gastric bacterial colonization, attenuated mucosal expression of tumor necrosis factor-alpha and interleukin (IL)-1beta, mitigated corpus inflammation, and prevented the expression of high-salt-induced gastric corpus atrophy [ 31 ]. More recently, an in vitro study showed that the concentration of salt in the environment influenced the composition of the H. pylori exoproteome and led to increased levels of a secreted VacA toxin, which would increase the risk of gastric cancer associated with the consumption of a high-salt diet [ 32 ]. In a Mongolian gerbil model, infected animals fed with diets rich in salt developed gastric ulcers significantly more frequently than those consuming a normal salt diet, and lower hemoglobin levels were found in infected gerbils consuming a high-salt and low-iron diet [33] compared to controls. In this animal study, dietary consumption of walnuts rich in n-3 polyunsaturated fatty acids were proposed as a nutritional intervention to prevent H. pylori associated with gastric cancer. The results of walnut consumption, using a model of H. pylori-initiated gastric carcinogenesis promoted by a high-salt diet in mice, showed a significant improvement in chronic atrophic gastritis and a significant decrease in tumorigenesis compared to the control group [ 34 ]. Similarly, a mouse model of chronic atrophic gastritis and gastric tumorigenesis initiated by H. pylori and promoted by high salt content was used by Jeong et al. to evaluate the efficacy of long-term dietary administration of artemisia and green tea extracts, resulting in improvements in both gastritis and tumorigenesis. These authors found decreased expression of cyclooxygenase-2 (COX-2), tumor necrosis factorα (TNFα ), IL-6, lipid peroxide, and activated signal of both the transducer and the activator of transcription 3 (STAT3) (relevant to H. pylori infection), as well as serum activations of TNF-αand nuclear factor kappa B [35]. Iron is an essential growth factor for H. pylori [ 36 ]. Several studies have associated H. pylori infection and iron deficiency anemia in human and animal studies [ 37 , 38 ]. This may be due to the fact that H. pylori-related gastritis leads to a defect in its absorption, or increases gastric pH and alters the reduction of the ferric to ferrous form (essential for the absorption of non-heme iron) [ 39 , 40 ]. Animals fed with low iron diets displayed increased infiltration of immune cells at the site of infection, more rapid onset of gastritis, and a Pathogens 2021,10, 875 5 of 20 higher rate of cancer development [ 41 ]. Results from a meta-analysis by Kin et al., indicated that red and processed meats rich in heme iron led to endogenous production of N-nitro compounds and increased progression of H. pylori infection by causing DNA damage and oxidative stress (a significant risk factor for gastric cancer) [ 42 , 43 ]. This increase in oxidative stress can be further aggravated in the stomach of individuals affected by H. pylori [ 44 ]. Thus, including sulfur-rich food, such as broccoli sprouts, in the diet can not only protect cells from oxidative stress damage, but also inhibit the viability of H. pylori and mitigate gastritis, as indicated in this study conducted in mice and humans [ 31 ]. Similarly, it was shown that, in a mouse model of infection by H. pylori, resveratrol exerted a beneficial effect against H. pylori-associated gastritis by combating oxidative stress [ 45 ], thus the consumption of resveratrol-rich foods may also have a positive effect. As far as the consumption of cured, pickled, and smoked foods is concerned, nitrosamines (which are often present in this type of food) exert a synergistic effect with H. pylori by inducing intestinal metaplasia and intraepithelial neoplasia in a model of non-human primates through changes in multiple genes associated with cancer [46]. It is well known that high-fat diets (HFD), high-ultra-processed foods and low intake of fruits and vegetables are key factors for the development of obesity. The risk of H. pylori infection is not increased in young overweight individuals [ 47 ], but high-carbohydrate and sweetened diets were positively associated with an increased prevalence [ 48 ], whereas whole-grains, roots and tubers, vegetables, mushrooms, miscellaneous beans, vegetable oils, nuts, and seeds consumed in abundance were linked to a reduced risk of infection in humans [49]. The rejuvenation of atrophic gastritis and prevention of tumorigenesis in mice, via cancer-preventive kimchi made from a changed recipe from the Research Institute at Pusan National University [ 50 ], was also promoted by the same authors. In sum, many promising results show the importance of the impact of diet on H. pylori infection, although there are many controversies in this respect that need to be elucidated. Diet, Helicobacter pylori, and the Gut Microbiota Gut microbiota (defined as the community of microorganisms that subsists within the digestive tract) plays both local and remote roles in important physiological processes, particularly inflammation and immune response [ 51 ]. Diet has a considerable effect on the composition of gastrointestinal microbiota and an unhealthy diet, among other factors, alters its composition and induces gastric microbial dysbiosis [ 52 ]. The gut microbiome is the genetic material of all the microbes that live on and inside the human body [ 53 – 55 ]. H. pylori colonization results in the alteration of gastric microbiota and a reduction in bacterial diversity [ 56 , 57 ], thus modifying the host’s gut microbiome [ 58 ]. A growing number of studies reported greater ecosystem diversity in the gastrointestinal tract and associated H. pylori presence with variations within the structure of the microbiome [ 59 ]. Gut microbiome changes triggered by the first H. pylori acquisition could also corroborate the host immunological status and, as a result, the manifestation of several diseases. This is important due to the fact that gut microbiota is modified by antibiotic treatment, which also decreases H. pylori-induced inflammation [60]. Some studies have evaluated changes in the microbial profile related to H. pylori in humans [ 61 – 63 ]. For instance, individuals infected by H. pylori present higher levels of Succinivibrio,Coriobacteriaceae,Enterococcaceae, and Rikenellaceae, and an increased abundance of Candida glabrata and other unclassified fungi [ 62 ]. In children, gastric commensal bacteria are altered during H. pylori infection [ 61 ]. Indeed, H. pylori dominated the microbial community in infected children, while H. pylori-negative individuals showed a relative abundance of Gammaproteobacteria,Betaproteobacteria,Bacteroidia and Clostridia classes and a higher bacterial richness and diversity [ 63 ]. However, the relationship and underlying mechanisms involved need to be elucidated. Concerning animal studies, a cocoa-supplemented diet was shown to modify the intestinal microbiota and health-promoting microbiota in diabetic rats [ 64 ], whereas the Pathogens 2021,10, 875 6 of 20 consumption of diets high in sugar induced gut dysbiosis [ 65 ]. Along the same line, the dietary pattern known as the Mediterranean diet is characterized by the high consumption of vegetables, fruits, whole grains, legumes, nuts, fish, lean meats, and virgin olive oil. This diet is associated with a health-promoting microbiota able to prevent the appearance of noncommunicable diseases or cancer [ 66 ]. In contrast, an HFD produces an increase in bacteria expressing lipopolysaccharides in the gut microbiota, resulting in a pro-inflammatory state, weight gain, and increased intestinal permeability [ 67 ]. It is not clear whether the diet, by modifying the intestinal microbiota, creates helpful conditions for colonization by H. pylori, as many factors are involved. However, it is known that H. pylori-induced alterations in the composition of the intestinal microbiota are due to changes in the lifestyle and diet patterns of H. pylori-infected individuals [ 20 ]. In addition, as discussed below, H. pylori infection leads to a reduction in Lactobacillus,Lachnospiraceae, and Blautia, bacteria that have also been found to be reduced in metabolic diseases such as obesity, metabolic syndrome, and diabetes [68–70]. Thus, altered intestinal microbiota may lead to disease. Animal studies showed an interaction between H. pylori and normal intestinal microbiota that is associated with intestinal metabolism and inflammation [ 71 ]. A study on C57BL/6 mice showed that H. pylori infection not only aggravated metabolic disorders induced by an HFD, but also altered the intestinal microbiota. The reported results highlighted that H. pylori-infected mice fed with high-fat diets had a different microbiota community, with a significantly higher proportion of Firmicutes and Proteobacteria and a reduction in the population of Bacteroidetes and Verrucomicrobia at the phylum level. In addition, metagenomics analysis showed that Desulfovibrionaceae and Mucispirillum spp., Helicobacter,Lachnospiraceae and Ruminococcaceae sequences were significantly increased in the H. pylori-infected group fed with an HFD [ 72 ]. Sex may have a greater impact on gut microbiota composition than diet, as shown by Peng et al. They found that microbiota composition was markedly different between male and female mice independent of diet [73]. Trimethylamine N-oxide is a diet-related microbial metabolite present in seafood and synthesized by hepatic oxidation of trimethylamine, which is produced by enzymatic bacteria in the colon via carnitine and choline. The major source of these compounds in the diet comes from meat, fish, eggs (rich in choline), and dairy products (rich in carnitine) [ 74 , 75 ]. These two compounds are associated with several metabolic and inflammatory disorders [ 76 ]. The effect of the presence of trimethylamine N-oxide on inflammation and intestinal microbiota was reported in a study on mice carried out by Wu et al. These authors reported an increase in the expression of growthand metabolism-associated genes and the urease activity of H. pylori, and an increase in the production of virulence factors. The VacA concentration was not increased in the group co-treated with H. pylori and trimethylamine N-oxide when compared to the H. pylori-treated group, but CagA concentration was significantly higher by treatment with trimethylamine N-oxide when H. pylori was co-cultured with GES-1 cells. Thus, trimethylamine N-oxide enhanced H. pylori virulence by upregulating the expression of the virulence gene encoding CagA. The authors also confirmed that the intake of trimethylamine enhanced the production of inflammatory markers and reduced the richness and diversity of the intestinal microbiota [ 77 ]. Similar results suggested that the treatment of infected mice with choline aggravated both the inflammation produced by the bacteria itself and the alteration of the intestinal microbiota [78]. Despite infection by the bacteria altering the profile of the gastric and intestinal microbiota in animals [ 79 , 80 ], it affects the human diurnal oral microbiota [ 81 ], causes intestinal dysbiosis in bacterial-induced gastritis [ 82 ], and can influence the composition of the gastric microbiota at lower taxonomic levels ( in vitro study) [ 83 ]. To date, the relationship between microbiota, H. pylori infection, and the effect of diet patterns is not fully understood and the number of studies involving the role of diet and its impact on H. pylori infection in gastric and intestinal microbiota remains limited (Table 1). Thus, future research will need to decipher the exact mechanisms of H. pylori pathogenesis on the H. pylori-microbiota axis and extend our understanding of H. pylori colonization. Pathogens 2021,10, 875 7 of 20 Table 1. Summary of recent studies linking the effect of diet on H. pylori and microbiota. Dietary Pattern Animal Model (n)Effects Main Effects in Microbiota Reference (1) Excessive salt intake (2) High-salt and low-iron diet (1) Mongolian gerbil n=108 (2) Mongolian gerbil model n= 96 ↑Colonization by H. pylori (1) ↑Risk of gastric cancer, hypochlorhydria and epithelial damage, Loss of parietal cells, and intestinal metaplasia (2) ↓Hemoglobin levels NA [18,27,33] Cured, pickled, and smoked foods Rhesus monkey n= 23 Induction of intestinal metaplasia and intraepithelial neoplasia ↑Expression of oncogenes NA [46] Diet poor in iron Mongolian gerbil n= 10 ↑Infiltration of immune cells at the site of infection ↑Onset of gastritis ↑Rate of cancer development NA [41] High-fat diet C57BL/6 mice n= 10 Intestinal microbiota alteration ↑Firmicutes and Proteobacteria ↓Bacteroidetes and Verrucomicrobia [72] High-fat diet Specific-pathogen-free C57BL/6 mice n= 10 H. pylori infection and high-fat diet promote dysbiosis intestinal microbiota ↑Firmicutes/Bacteroidetes (F/B) ratio ↑Prevotellaceae-UCG-001, Helicobacter, and Rikenella ↓Blautia,Lactobacillus, and Lachnoclostridium [84] Meat, fish, eggs, and dairy products BALB/c female mice n= 40 TMA and TMAO taken by diet induced: ↑H. pylori development ↓Intestinal microbiota richness and diversity ↓Anaerovorax,Rikenellaceae RC9 gut group, Lachnospraceae UCG 008 and Parabacteroides ↑Escherichia/Shigella [77] Abbreviations: n, number of animals; NA, not analyzed; TMA, trimethylamine; and TMAO, Trimethylamine N-oxide. 3. Management of Helicobacter pylori Infection 3.1. Current Standard Treatments There are some guidelines regarding the management of H. pylori infection, such as the Maastricht V/Florence Consensus Report [ 85 ] and the Taipei global consensus [ 86 ]. The latter is specially focused on elucidating the populations that should be screened, and it identified the best treatment (“screen and treat” strategy) to prevent gastric cancer. Although there is no universally accepted regimen for the eradication of H. pylori, the current first-line treatment is a triple therapy that combines one proton pump inhibitor and two antibiotics (clarithromycin and amoxicillin) and the quadruple therapy, which includes tetracycline, metronidazole, bismuth salts, and proton-pump inhibitors. However, resistance to clarithromycin has become very prevalent in some geographical areas. In such cases, it can be substituted by metronidazole, although resistance to this antibiotic has already developed in specific areas as well. Aside from drug resistance, antibiotics can also be problematic because they can cause side effects, in part because of the undesired killing of healthy microbiota [ 87 – 89 ]. Therefore, owing to a decrease in the therapeutic efficacy of these antibiotic-based therapies, further research is needed in this field. Pathogens 2021,10, 875 8 of 20 3.2. New Antibiotics Some studies have tested new antibiotics or new antibiotic regimes. On one hand, Shi et al. evaluated the efficacy of linezolid and novel oxazolidinone analogs in vitro , by culturing clinical multidrug-resistant H. pylori isolates, and in vivo , by orally inoculating mice with these isolates and then administrating the drugs intragastrically. The authors concluded that both, but especially oxazolidinone analogs, were suitable candidates to treat drug-resistant H. pylori infections [ 90 ]. Linezolid was observed to exhibit in vitro activity, with minimum inhibitory concentrations (MICs) ranging from ≤ 0.25 mg/L to 32 mg/L against clinical H. pylori isolates (MIC 50 , 2 mg/L; MIC 90 , 8 mg/L). The oxazolidinone analogue sy142 inhibited all of the clinical isolates, with MICs of ≤ 16 mg/L (MIC range, ≤ 0.25–16 mg/L; MIC 50 , 1 mg/L; MIC 90 , 4 mg/L), even for the multidrug-resistant isolates [90]. On the other hand, Jeong et al. subjected H. pylori-infected mice to a gentamicinintercalated smectite hybrid-based treatment and observed reduced H. pylori burden and cytokine secretion, and less atrophy of gastric mucosa, compared to the group treated with standard triple therapy. Importantly, they also analyzed changes in fecal microbiota and concluded that microbiota composition was more similar to uninfected and infectednon-treated groups than microbiota diversity of the standard triple therapy-treated group. These results suggested that this regime may restore gut dysbiosis [ 91 , 92 ]. On the contrary, treatment with antibiotics of H. pylori-infected mice fed with a diet high in folate but low in vitamin K caused dysbiosis and hypovitaminosis K, which were likely related to the anemia, gastric hemorrhage, and mortality observed in these animals [93]. It is important to remark that there is active research in nanoparticles for targeted antibiotic delivery against H. pylori infection [ 94 ]. Other therapeutic options, such as nutraceuticals, have also been considered. Finally, there is also an exceptional effort being made on the generation of a prophylactic vaccine against H. pylori. 3.3. Nutraceutical Approaches In contrast to antibiotics and pharmacological drugs, nutraceuticals, especially substances found in our daily diet and traditional herbs or plants, have a low probability of toxicity, as they have been consumed for generations in some areas. Consequently, they might be agents for H. pylori elimination. Recent literature concerning this subject is summarized in Table 2. Pathogens 2021,10, 875 9 of 20 Table 2. Nutraceutical approaches to treat H. pylori infection reported in animal models (2016–2020). Nutraceutical Tested Type and Nature of Strain Analyzed Sensitivity Profile Animal Model (n)Effects Main Effects in Microbiota References Extracts and compounds isolated from food Ellagic acid Sydney Strain 1 isolated from gastroduodenal patients In vitro minimum inhibitory concentration 15 mg/L ellagic acid, 0.015 mg/L clarithromycin, 0.5 mg/L amoxicillin, 0.25 mg/L metronidazole (resistant) C57BL/6 mice n= 6 Elimination of H. pylori in cultures and mice Reversion on H. pylori-induced gastric mucosa injury in mice NA [95] Linoleic acid The nature of the strain: Not indicated. Sydney Strain 1 and TN2GF4 strains Not indicated C57BL/6NCrl mice n= 6 Inhibition of H. pylori growth NA [96] Snakehead fish extract The nature of the strain: Gastric biopsy specimens of duodenal ulcer patients. Strain: unknown Not indicated Albino rats n= 7 Elimination of H. pylori NA [97] Channa striata fish extract The nature of the strain: Gastric biopsy specimens of duodenal ulcer patients. Strain: unknown Not indicated Albino rats n= 7 In combination with standard triple therapy, reversion of gastritis NA [98] Astaxanthin from shrimp cephalothorax The nature of the strain: Gastric biopsy specimens of duodenal ulcer patients. J99 strain Not indicated BALB/c mice n= 40 ↑synthesis of IFN-γ, IL-2 and IL-10 in splenocytes in infected mice NA [99] Traditional plants or herbs Hwanglyeonhaedok-tang The nature of the strain: Not indicated. Sydney Strain 1 In vitro minimum inhibitory concentration: 400 to 1600 µg/mL Hwanglyeonhaedok-tang; 0.00396 ~ 0.125 µg/mL amoxicillin; 0.001953 ~ 32 µg/mL clarithromycin C57BL/6 mice n= 7 Elimination of H. pylori cultures and mice ↓H. pylori-induced inflammation in cultures and mice NA [100] Yugeunpi The nature of the strain: Not indicated. 51 and 43,504 strains In vitro minimum inhibitory concentration: 25 and 50 µM bioactive compounds of Yugeunpi: (2R,3S)-2-ethoxychroman-3,5,7-triol7-O-β-d-apiofuranoside, fraxetin, 4-O-β-d-glucopyranosyl vanillic acid, syringic acid In vitro Murine microglia BV-2 cell line Elimination of H. pylori in cultures ↓H. pylori-induced inflammation in cultures NA [101] Palmatine The nature of the strain: (1): not indicated; (2): Chronic atrophic gastritis. (1): Sydney Strain 1; (2): SCYA201401 and Sydney Strain 1 strains (2) In vitro minimum inhibitory concentration: strain SCYA201401 6.25 µg /mL Palmitine; Strain Sydney Strain 1, 3.12 µg/mL Palmitine (1) Male Sprague-Dawley rats n= 6, (2) C57BL/6 mice n= 8 ↓H. pylori-induced chronic atrophic gastritis in rats Elimination of H. pylori in cultures and mice NA [102,103] Pathogens 2021,10, 875 16 of 20 19. Annibale, B.; Capurso, G.; Delle Fave, G. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Dig. Liver Dis. 2002,34 (Suppl. 2), S72–S77. [CrossRef] 20. Mohammadi, S.O.; Yadegar, A.; Kargar, M.; Mirjalali, H.; Kafilzadeh, F. The impact of Helicobacter pylori infection on gut microbiota-endocrine system axis; modulation of metabolic hormone levels and energy homeostasis. J. Diabetes Metab. Disord. 2020, 1855–1861. [CrossRef] [PubMed] 21. Isomoto, H.; Nishi, Y.; Ohnita, K.; Mizuta, Y.; Kohno, S.; Ueno, H.; Nakazato, M. 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