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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: Curr Opin Physiol. 2021 Apr 24;21:57–64. doi: 10.1016/j.cophys.2021.04.003

Interactions between H. pylori and the Gastric Microbiome: Impact on Gastric Homeostasis and Disease

Carolina Serrano 1, Paul R Harris 1, Phillip D Smith 2, Diane Bimczok 3,*
PMCID: PMC8186273  NIHMSID: NIHMS1697204  PMID: 34113748

Abstract

Like many seemingly inhospitable environments on our planet, the highly acidic human stomach harbors a diverse bacterial microflora. The best-known member of the human gastric flora, Helicobacter pylori, causes a number of gastric diseases, including peptic ulcer disease and gastric adenocarcinoma. In the absence of Helicobacter pylori infection, the gastric microbiota displays some features similar to the oral cavity with Firmicutes the most common phylum, followed by Proteobacteria and Bacteroidetes. When present, H. pylori dominates the gastric microbiome and reduces diversity and composition of other taxa. The composition of the gastric microbiome also is altered in the setting of proton pump inhibitor therapy and gastric neoplasia. This review summarizes foundational and recent studies that have investigated the composition of the human gastric microbiome in a variety of patient groups, with a focus on potential mechanisms involved in regulation of gastric microbial community structure.

Keywords: Microbiome, Stomach, Helicobacter, gastric cancer

1. Introduction

Although studies from as early as the 1940s and 1950s describe bacteria in human gastric samples [1–4], the stomach has generally been considered an inhospitable environment for microbes due to its high level of acidity [5]. This concept was challenged by Marshall and Warren’s discovery of Helicobacter pylori (H. pylori) as a highly common stomach-specific pathogen in 1983 [6]. The emergence of culture-independent high throughput and next-generation sequencing methods in the mid-2000s opened the door for in depth analyses of microbiota in different environments, including the stomach [7–10]. In a hallmark study from 2006, Bik et al. were the first to use unbiased 16S ribosomal RNA (rRNA) gene sequencing to characterize bacterial diversity in the human gastric mucosa [7]. Since 2010, more than 300 primary research papers focusing on the gastric microbiome have been published. However, the role of the gastric microbiota for human health and H. pylori-associated disease processes is not fully understood. This review will highlight and summarize findings from the past three years (2018–2021) that have provided key insights into the interactions between H. pylori and the gastric microbiome in human health and disease.

2. The gastric microbiota: H. pylori and beyond

While not a sterile environment, the human stomach harbors several orders of magnitude fewer culturable bacteria than the small and large intestine, with only 102-104 colony forming units (CFUs) per mL content, compared with 1010-1012 CFUs per mL in the colon [8]. H. pylori is the most well-known and clinically relevant member of the human gastric microbiota and is associated with the development of peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma [11]. Since only a small proportion of H. pylori-infected humans, mainly adults, develop clinical disease, H. pylori is considered a pathobiont, a natural member of the microbiota that has pathogenic potential under certain conditions. A key feature of H. pylori that enables its survival in the acidic gastric lumen is the ability to convert urea to ammonia using the enzyme urease, which leads to local neutralization of the gastric acid around the bacteria [12]. When H. pylori is present, this species dominates the gastric microbiome, representing up to 72% of culturable gastric bacteria and up to 97% of transcriptionally active taxa [7,13].

In the absence of H. pylori, the microbiota of the stomach were found to be less diverse, based on the richness (number) and abundance (frequency) of the bacteria, than those in the ileum and colon [14,15]. Whether gastric bacteria represent a truly resident flora has been a matter of debate that has recently been resolved by Spiegelhauer et al. who found no significant difference between tissue-adherent and non-adherent gastric bacteria [16]. Representative taxa from five major bacterial phyla are routinely detected in H. pylori negative gastric samples, with Firmicutes being the most common, followed by Proteobacteria, Bacteroidetes, Actinobacteria and Fusobacteria [7,8,17–19]. How these gastric microbes survive in the acidic environment of the stomach is not well understood, but periplasmic chaperones that protect protein structures and specific transcriptional pathways involved in the acid tolerance response and the amino acid-dependent extreme acid resistance have been implicated as protective mechanisms [20]. Notably, Firmicute classes in the stomach are mostly composed of Bacilli and Negativicutes as opposed to Clostridia and Erysipelotrichia, which dominate in the lower gastrointestinal tract [21]. An overview of commonly detected bacterial taxa in non-H. pylori infected stomach is provided in Fig. 1A,B. At the genus level, Prevotella, Streptococcus, Neisseria, Lactobacillus, Veillonella, Gemella, Fusobacterium, Rothia and Haemophilus have been detected as dominant taxa in the healthy stomach in a majority of studies [8,13,18,21–24]. While the majority of studies have focused on antral and corpus mucosa, a study investigating the cardiac region found Halomonas, Shewanella, and Comamonasas to be the most prevalent genera [25]. In total, 57 bacterial genera from eight major phyla have been reported in >20% of the studies included in a recent systematic review and were therefore considered typical gastric bacteria [22]. Importantly, the gastric microbiota showed significant similarity with the microbiota of the duodenum, oral cavity and esophagus, but differed from the colonic microbiome [15,18,21]. Moreover, microbiota in the stomach were more dissimilar across individuals than in other parts of the gastrointestinal tract [8,18,21,22]. This high degree of inter-individual variability may partly explain the discrepant findings obtained in different studies, especially if only a limited number of subjects were included. Further differences in detected taxa appear to be associated with the geographical origin of the samples analyzed (Fig. 1A,B).

Figure 1.

Figure 1.

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Commonly reported taxa at the genus/family level according to geographical location or presence of gastric lesions. (A) Bubble plot showing frequency of detection (not abundance) for different taxa in H. pylori-free, non-inflamed stomachs according to geographical origin of the samples [15,18,21,22,25,60]. Size of the bubbles represents the number of papers that reported each taxon as present. (B) Venn diagram of the data in (A) showing the number of taxa that were represented in a specific location or were shared between locations. (C) Bubble plot showing frequency of differentially expressed taxa in stomachs with gastric cancer or with preneoplastic lesions (PNL) including atrophic gastritis and intestinal metaplasia and compared to H. pylori gastritis controls. Data were obtained from available comparison plots between PNL and H. pylori gastritis and gastric cancer and H. pylori gastritis [22,42,54–57,59]. Size of the bubbles represents the number of papers that cited each taxon as differentially expressed between lesions and gastritis. (D) Venn diagram of the data in (C) showing the number of taxa that were represented in PNL and gastric cancer or were shared between both.

3. Crosstalk between H. pylori and other gastric microbes alters microbial colonization of the stomach and other sites

Since chronic H. pylori is known to change gastric physiology, including luminal pH and mucin structure [26,27], it has been proposed that H. pylori infection impacts other gastric microbes. Mathematical modeling has demonstrated that a minority of bacterial species are dominant drivers of the overall bacterial community structure [28]. However, to what extent H. pylori infection alters the composition of the gastric microbiome is still a matter of debate. The majority of studies has shown that H. pylori colonization in the absence of gastric atrophy or cancer was associated with a decreased diversity of other taxa [8,13,21,23,24,29,30]. This observation can be partly explained by the dominant abundance of H. pylori in the H. pylori-infected stomach [13]. Other reports failed to demonstrate significant changes in the gastric community structure associated with H. pylori infection or showed an inverse relationship [7,31,32], and one study found significant changes only in subjects infected with CagA-positive H. pylori [33]. In H. pylori-infected subjects, the flora was dominated by H. pylori, but, non-Helicobacter-Proteobacteria [32], Lactobacillus sp., Acinetobacter ursingii, and Streptococcus agalactiae [25] also were increased. Specific taxa found to be decreased in H. pylori-infected samples include Streptococcaceae [24,29] and other Firmicutes [32,33], Actynomicetaceae [29], and Roseburia [33]. The composition of the gastric microbiota in H. pylori-infected subjects may additionally be influenced by disease stage. Thus, different microbial taxa dominated the gastric microbiota in dyspeptic vs. non-dyspeptic patients [34] and in patients with different degrees of inflammation and pathology [23,25]. Certain bacterial strains in the stomach can also interfere with H. pylori infection. Thus, both certain Lactobacilli and Streptococcus mitis were associated with decreased H. pylori growth [5]. Notably, in a recent systematic review that included 65 papers, no overarching gastric microbiome signatures of health or disease were determined beyond the detrimental effects of H. pylori itself [20]. However, longitudinal studies on gastric microbiota acquisition across the human lifespan are not available at this point. Late adult acquisition of H. pylori, characteristic of the developed countries from which most of the studies originate, may represent more rigid ecosystems in terms of its modification. On the other hand, acquisition of the bacterium in early childhood may lead to a more beneficial interaction with the founder microbiota in terms of later clinical outcomes.

Interestingly, H. pylori infection of the stomach may impact microbiota in other segments of the gastrointestinal tract including the oral cavity, esophagus, duodenum and colon [35–40]. These alterations in microbiome structure can be transmitted vertically, since fecal microbiota from vaginally-delivered babies differed based on maternal H. pylori status [39]. α-Diversity, which measures the diversity of bacterial taxa within each sample, was significantly decreased in the oral cavity of H. pylori-positive individuals [37]. In contrast, H. pylori infection correlated with an increase in both α-diversity and β-diversity, which compares between sample diversity, in the duodenum in a study from South America [35]. Likewise, fecal microbiota were generally found to be more diverse in subjects with H. pylori infection compared to uninfected controls [36,41]. Investigators in Japan found that H. pylori infection was associated with an increase in fecal Lactobacillus salivarius abundance, but a decrease in Lactobacillus acidophilus [40]. A large-scale study with >300 participants from China detected 58 microbial species in the feces that correlated with active H. pylori infection [42], whereas other studies found no significant impact of H. pylori in microbial communities in the lower gastrointestinal tract [21,23].

4. Mechanisms of H. pylori-dependent regulation of gut microbiome structure

Microbial communities are shaped by competition for nutrients and host receptors, bacterial metabolites, and host immune mechanisms including antibacterial peptides [19]. Within the stomach, H. pylori occupies specific microniches in the gastric glands, and founder bacteria prevent colonization of these niches by new H. pylori and possibly other microbes [43]. Environmental conditions such as oxygen levels and pH also influence bacterial community structure. Chronic H. pylori infection generally causes hypochlorhydria, i.e., an elevated gastric pH due to H. pylori-induced suppression of the gastric proton pump or gastric atrophy, although hyperchlorhydria is observed in a subset of patients with antral-predominant gastritis and elevated gastrin levels [44]. Atrophic H. pylori gastritis led to increased bacterial diversity and abundance compared to H. pylori gastritis without atrophy, although the degree to which pH sensitive taxa contribute to these alterations is unclear [12].

Several reports indicate that the host immune response also likely impacts the gastric microbiota. β-Defensin 2, a type of innate antimicrobial factor produced by host epithelia, is upregulated by H. pylori and likely affects growth of other gastric microbes [45]. A recent study in mice focusing on gastric innate lymphoid cells (ILCs) revealed that non-H. pylori microbiota from the order Bacteroidales were essential for maintaining ILC2 populations through IL-7 and IL-33 signaling and that the ILC2s promoted gastric IgA secretion, which in turn restricted H. pylori infection [46]. In an in vitro study with human cells, Lactobacillus rhamnosus increased the H. pylori-induced production of IFN-γ and IL-12 in DC-T cell co-cultures indicating that gastric colonizers such as Lactobacilli can modulate the immune response to H. pylori [47]. H. pylori infection in children causes different disease phenotypes and immune responses than in adults, with a more potent gastric regulatory T-cell response, a reduced Th17 response and more diverse microbiota found in children [32,48,49]. Together, these changes promote reduced gastric inflammation in H. pylori-infected children compared with infected adults. Interestingly, H. pylori infection and gastritis in children also were associated with a significant reduction in the fecal Firmicutes-to-Bacteroidetes ratio, a change typically associated with obesity and metabolic syndrome that has not been reported in H. pylori-infected adults [50]. Therefore, health effects of H. pylori-induced gastric dysbiosis also may differ between children and adults.

H. pylori virulence mechanisms also may impact the composition of other microbes in the stomach. Zhao et al. showed that the presence of the H. pylori CagA gene was associated with to an increased proportion of other Gram-negative bacteria in the stomach, possibly contributing to elevated lipopolysaccharide (LPS) biosynthesis and increased inflammation [33]. Others have linked alterations in the gastric microbiota with H. pylori expression of the CagA virulence factors both in humans and mouse models [33,51]. The mechanisms for this relationship are unclear but could relate to the strong inflammatory response induced by CagA signaling in epithelial cells. Additional studies that include analyses of mucus structure, antimicrobial mediators and bacteriocins are needed to better understand why, how and in which circumstances H. pylori infection causes changes to other gastric microbes.

5. Altered gastric microbiota are associated with gastric carcinogenesis

Changes to the gastric microbiome associated with H. pylori infection have been proposed to contribute to gastric carcinogenesis, based on early animal experiments that demonstrated that lack of a commensal flora prevents H. pylori-induced carcinogenesis in transgenic insulin-gastrin (INS-GAS) mice [52]. H. pylori virulence factors, particularly CagA [53], directly trigger oncogenic pathways, and additional carcinogens likely accelerate gastric tumorigenesis. In a large prospective study that compared gastric biopsies from subjects before and after development of gastric cancer, significant associations between lesion progression and the abundance of Bacillus, Prevotella and Capnocytophaga were found [54]. Overall, multiple studies suggest that the gastric microbiome of cancer patients differs from that of healthy controls and is influenced by disease stage (Fig. 1C,D). In comparison with the microbiota found in patients with chronic H. pylori gastritis, gastric cancer and preneoplastic lesions are significantly associated with decreased species diversity [23,55–57]. Gastric cancer also is associated with an over-representation of specific taxa, including Streptococcus, Peptostreptococcus, Prevotella, and Fusobacterium [19,22,56,58,59]. While the abundance of H. pylori is significantly decreased in cancer compared to chronic H. pylori gastritis, the abundance of non-Helicobacter Proteobacteria may increase [55,59]. Interestingly, dysbiosis associated with gastric malignancy may persist even after H. pylori has been cleared by antibiotic therapy [60]. An intriguing hypothesis for the involvement of non-Helicobacter bacteria such as Lactobacillus, Escherichia coli and Staphylococcus in gastric carcinogenesis is through production of carcinogenic N-nitroso compounds [16,61]. In support of this hypothesis, Ferreira et al. confirmed that taxa with nitrosating functions were overrepresented in gastric cancer compared to chronic gastritis microbiomes [55]. However, other functional metagenome studies have failed to confirm these associations [56,57,62].

As with non-cancerous H. pylori gastritis, altered microbiota associated with stomach cancer were detected in other sections of the gut and in stool samples [63–65]. While the contributions of gut microbes other than H. pylori to gastric cancer progression remain unclear and warrant further investigations, specific changes in the microbiome associated with stomach cancer may have diagnostic potential as disease biomarkers.

6. Impact of H. pylori therapy on gastric microbiota

Standard H. pylori therapies utilize combination antibiotics and proton pump inhibitors (PPIs). As expected, antibiotic treatment for H. pylori infection will initially lead to reduced microbial colonization of the stomach and other sites including the esophagus and small intestine [5,19]. Several studies have shown near complete normalization of the gastric microbiota two months after antibiotic eradication of H. pylori in both children and adults [30,66,67], although two independent studies reported an increase in gastric Acinetobacter after treatment in a subset of patients [62,68]. Overall, microbes other than H. pylori appear to readily re-colonize the stomach following their elimination [23]. Similarly, the intestinal flora fully recovered after antibiotic treatment following an initial decline in α-diversity [19,67,69,70].

Acid-blocking agents, particularly PPIs, appear to have more lasting effects on the gastric microbiome, possibly because they commonly are used long term. Along with H. pylori-infection, PPI therapy is considered one of the two key microbiome-perturbing mechanism in the stomach [71,72]. In general, PPI treatment promotes bacterial growth, with a higher number of culturable bacterial strains in the stomach [73]. 16S rRNA gene sequencing revealed that PPI induces a higher diversity of bacterial species in the stomach with an increased abundance of Firmicutes and Fusobacteria and a decrease in Bacteroidetes [13,14,22]. At the genus level, Streptococcae were most significantly increased in number following PPI application [13,14,73]. Notably, several of the changes observed in PPI-treated subjects were also found in subjects with atrophic gastritis, implicating luminal pH as a major regulator of gastric microbial community structure.

7. Technical considerations of gastric microbiome studies

The majority of recent studies focusing on gastric microbiota have utilized 16S rRNA gene sequencing. Factors that impact the bacterial community structure of the stomach include the geographical origin, ethnicity, diet and age of the subjects, the sampling method, the type of sample used, and the sequencing and data analysis approach [5,22,24,74,75]. Preventing contamination of the sample with throat oral and esophageal bacteria is a challenge that can be overcome with specialized endoscopes or careful technique [73]. Both biopsy samples and gastric fluids have been used in gastric microbiome studies, with fluids harboring a more diverse flora with increased Actinobacteria, Bacteroidetes and Firmicutes, and tissue samples harboring increased Proteobacteria including H. pylori [17].

One drawback of 16S rRNA gene sequencing is that actively growing bacteria cannot be differentiated from inactive or dead bacteria or gene fragments. To address this issue, several recent studies have used a 16S rRNA transcriptomics approach to identify active taxa and have identified a similar distribution of genera as previously described using 16s rRNA gene [13,21]. Alternatively, culture-based analyses, proteomics, or a combination of the two have been successfully applied to characterize gastric microbes including “culturomics”, a combination of high throughput bacterial culture with nine different growth media, followed by identification of bacterial taxa using MALDI-TOF-MS and the bacterial database Biotyper [8,14,34]. Going forward, multi-omics approaches will provide a more accurate assessment of the gastric microbiome.

8. Summary and outlook

A large number of studies from the past decade have provided detailed insights into the gastric microbiome beyond H. pylori. Overall, the stomach appears to harbor a low density, but complex resident flora and that is disrupted in the presence of H. pylori infection, H. pylori-induced gastric pathology and cancer. However, impacts of altered gastric microbiota other than H. pylori on human health are unclear, and the majority of studies have been correlative and descriptive. Future studies of the functional interactions between different microbial taxa and their complex relationships with the host should provide more mechanistic insights into the role of gastric microbiota in gastric homeostasis and disease.

Acknowledgements

Funding: This work was supported by the National Institutes of Health [R01GM131408 and U01EB029242; to D.B. and HD088954 to P.D.S.], the Montana Agricultural Experiment Station USDA/NIFA Hatch project [#1026146 to D.B.], a UAB School of Medicine Award, UAB Microbiome Research Center Award and a DiGregorio Family Foundation Award to P.D.S., a Montana INBRE pilot award [P20GM103474; to D.B.] and CONICYT-PIA ANILLO [ACT172097 to P.R.H.].

Footnotes

Declarations of interest: none

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