The esophagus and stomach are host to their own population of bacteria, which differs in health and disease. Helicobacter pylori uniquely colonizes only gastric mucosa, but an increasing number of bacteria is now isolated from the gastric juice and gastric mucosa, including Lactobacillus . The presence of H pylori alters populations of other gastric bacteria with a marked reduction in diversity. Alterations in intragastric acidity may be the cause or the consequence of changes in the microbial populations of the stomach. Esophageal inflammation is associated with an altered microbiota in gastroesophageal reflux disease, Barrett’s esophagus, eosinophilic esophagitis, and cancer.
Key points
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The esophagus and stomach are host to their own population of bacteria, which differs in health and disease.
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Helicobacter pylori uniquely colonizes only gastric mucosa, but an increasing number of bacteria is now isolated from the gastric juice and gastric mucosa, including Lactobacillus , which also colonizes gastric mucosa.
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The presence of H pylori alters the populations of other gastric bacteria with a marked reduction in diversity.
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Alterations in intragastric acidity may be the cause or the consequence of changes in the microbial populations of the stomach.
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Esophageal inflammation is associated with an altered microbiota in gastroesophageal reflux disease, Barrett’s esophagus, eosinophilic esophagitis, and cancer.
Introduction
The microbiota of the esophagus and stomach have been the least systematically studied in the organs of the gastrointestinal tract and, until recently, most publications have reported phenomenological observations and associations rather than underlying physiologic or pathophysiologic mechanisms. The discovery of Helicobacter pylori by Marshall and Warren in 1982 has focused attention over the last 30 years on the unique characteristics of this bacterium to colonize and alter the immunologic and physiologic functions of the host.
The widely held view was that the gastric secretions of hydrochloric acid and the proteolytic enzyme pepsin ensured a sterile stomach despite numerous observations by scientists from the late nineteenth century describing bacteria in the acidity of the stomach. This may have influenced the commonly held view that Helicobacter species are the only organisms capable of colonizing the human stomach. H pylori research has increased the understanding of how it can modify its own microclimate, and it is now clear that other organisms also occupy the gastric mucosa and lumen.
Indeed, further investigations with modern techniques have shown that the microbiota of the stomach involves hundreds of phylotypes with a microbial density of between 10 1 and 10 3 colony-forming units (CFU)/g. There are unique anatomic and physiologic features of the stomach that differentiate the microbiota here from that elsewhere in the gastrointestinal tract and especially the esophagus.
It is important to appreciate that the definitions and basic concepts and methodology for identifying bacteria and other microorganisms that constitute the microbiome and their interactions with the immune response, are covered earlier in this issue and also apply to the upper gastrointestinal microbiota. The terms microbiome and microbiota comprise the bacterial, fungal, viral, and potentially prion populations. However, this review addresses the bacterial components of the esophagus and stomach and the inherent differences that require consideration.
The esophageal microbiome in health
Esophageal Microbial Flora
Under normal physiologic conditions, the esophagus acts as a conduit and does not retain food contents, which is in contrast to the oral cavity or the stomach and colon. Culture studies based on washings from the esophagus suggested that bacteria that were obtained from the esophagus were either swallowed from the oral cavity or reached the distal esophagus during reflux from the stomach. A study of the bacterial flora of the oral cavity and the upper and lower esophagus, obtained by esophageal brushings and biopsy samples, revealed that Streptococcus viridans is the most common bacterium. Methods of bacterial detection, which are independent of culture, are increasingly reported and characterize the diversity of the esophageal microbiota. In a group of healthy individuals, using broad-range 16S rDNA polymerase chain reaction (PCR) applied to esophageal biopsies, Pei and colleagues found a range of microbial diversity with the most prevalent organisms being Streptococcus , Prevotella , and Veillonella . Fillon and colleagues studied the esophageal microbiome by sampling with a new technique, the Enterotest capsule, an esophageal string test and an oral string and nasal swab. They found that the diversity at the phylum level was similar, and the most common genera were also Streptococcus , Prevotella , and Veillonella , similar to those found by Pei and colleagues. In a study using PCR of biopsies from the distal esophagus in healthy volunteers, patients with either esophagitis or Barrett’s esophagus (BE), Yang and colleagues found that Streptococcus dominated in the healthy esophagus, whereas gram-negative anaerobes dominated in both esophagitis and BE. They further designated this division into 2 distinct types: type I and type II, respectively, for the 2 conditions.
The esophageal microbiome in disease
Several studies have reported changes in the microbiota of the lower esophagus in a variety of diseases, including reflux disease, BE, and esophageal carcinoma, in addition to eosinophilic esophagitis in a pediatric population.
In patients with severe gastroesophageal reflux disease (GERD), Dunbar and colleagues reported histologic changes characterized by T-lymphocyte predominant inflammation with papillary and basal cell hyperplasia with no loss of surface cells. They suggest this inflammation may be cytokine mediated rather than the result of the usually attributed acid chemical injury. Another group suggests that pathogenesis might be driven by alterations of the esophageal microbiome with increasing gram-negative bacteria in esophagitis and BE. With this increase in gram-negative bacteria, their lipopolysaccharide can upregulate gene expression and, through the TLR4 and NFКB pathway, proinflammatory cytokine production can also be increased.
As mentioned earlier, the microbiota in the healthy esophagus is dominated by Streptococcus species (type I) but gram-negative anaerobes predominate in the presence of inflammation and BE (type II). In patients with BE, the dynamic nature of the bacterial composition of the upper gastrointestinal tract was emphasized with some overlap between the esophageal and gastric microbiome, particularly of the antrum. Streptococcus and Prevotella spp dominated, and the ratio of these 2 species was associated with 2 known factors for esophageal adenocarcinoma in BE: the waist-to-hip ratio and the length of hiatal hernia.
Another report of Barrett’s patients and controls found 16 genera with 46 bacterial species, where 10 species were common to both Barrett’s patients and controls. They found high levels of Campylobacter species ( Campylobacter concisus , Campylobacter rectus ) in 4 of 7 Barrett’s patients (57%). These bacteria are more commonly linked to enteritis and periodontal infections, but these were not found in any of their controls. They suggested a possible link between nitrate-reducing species in BE and the potential for progression to adenocarcinoma. This group also reported differences in the esophageal biofilm in disease, revealing C concisus dominance in reflux disease, with an increased expression of cytokines associated with carcinogenesis.
Esophageal Cancer
The rate of adenocarcinomas of the gastroesophageal junction and distal esophagus has been increasing over the past 3 decades, especially in white men in the developing world and is attributed to GERD, smoking, and alcohol consumption. Conversely, H pylori infection has been proposed as protecting from distal esophageal cancer, likely through gastric atrophy leading to loss of acid secretion, cytokine or hormonal deregulation, and microbiome alteration.
One study in healthy Chinese volunteers and patients using the Human Oral Microbe Identification Microarray, after adjusting for gender, smoking, age, antibiotic use, and a balloon sampling device, showed a significant positive association between microbial richness and pepsinogen I/II ratio and an inverse association with esophageal squamous dysplasia. These findings suggested that individuals with lower microbial diversity were more likely to have chronic atrophic gastritis and squamous dysplasia in the esophagus. They also found a correlation between esophageal squamous dysplasia with the odds ratio (OR) being significantly decreased with increasing microbial richness.
Another study in Northern Iran, which is considered part of the “esophageal cancer belt,” evaluated the gastric microbiota from the gastric fundic mucosa in patients with esophageal squamous cell carcinoma as compared with healthy controls. They found higher numbers of Clostridiales and Erysipelotrichales species, belonging to the phylum Firmicutes, which were significantly associated with early squamous dysplasia and esophageal squamous cell cancer.
Gastric microbiome in health
Gastric Microbial Flora
Microbes in the human body interact not only with their host but also with each other, which can lead to a significant microbial imbalance or dysbiosis. When considering bacteria, dysbiosis usually refers to increased levels of potentially harmful or harmful bacteria. Conversely, reduced levels of bacteria are considered to be beneficial. Historically, the stomach has been considered a germ-free environment due to the acidic milieu. However, observations reported by several scientists over the years, including Bottcher and Letulle (1875), Klebs (1881), Bizzozero (1893), Salomon (1896), Krienitz (1906), Edkins (1921), Doenges (1938), Freedberg and Barron (1940), Gorham (1940), and Steer and Colin-Jones (1975) all described finding bacteria in the stomach. One of the most important contributions came from the Polish scientist, Walery Jaworski, in 1899, who was studying gastric juice from the human stomach. He reported spiral-shaped bacteria and, importantly, rod-shaped bacilli, which he isolated and cultured and demonstrated that they produced lactic acid. Thus, he confirmed that more than one bacterial species could colonize the stomach simultaneously, and he speculated that spiral-shaped bacteria might be involved in the pathogenesis of stomach ulcer, stomach cancer, and achylia.
Marshall and Warren described Campylobacter pyloridis in 1982 (renamed H pylori in 1989), and this dramatically refocused the concepts of bacteria and the stomach. Studies to define the unique mechanisms by which H pylori successfully survives and replicates within the hostile, acidic milieu of the stomach suggest that this is likely to be a unique attribute. However, although pH values <4 largely prevent bacterial overgrowth, the acidic milieu is not capable of sterilizing the stomach. Although H pylori is the best known and studied of the gastric bacteria, it is not the only microbial inhabitant of the gastric mucosa. As mentioned earlier, Lactobacillus species convert lactose to lactic acid acidifying the surface of the gastric mucous layer, which explains its adaptation to the acidic environment and colonization of the stomach. There are also other species that survive gastric acidity, including Yersinia enterocolitica, with an acid-activated urease mechanism, and Vibrio cholera , which expresses an acid tolerance mechanism that maintains the cytoplasm at pH of 4 to 5, although growth does not occur.
The microbial density of the stomach is considered to be between 10 2 and 10 4 CFU/g. However, like the rest of the intestinal microbiome, this is a dynamic situation with considerable fluctuations in microbial density changing with pH, whereby both the quantity and the proportion of genera also fluctuate. Gastric juice is mainly composed of proteolytic enzymes and hydrochloric acid, which restricts the quantity of microorganisms entering the small intestine and reduces the risk of infection by pathogens. Human gastric juice has an interprandial pH of between pH 1 and 2 in the gastric lumen, and this is also influenced by food ingestion and fluctuates to ≥pH 5. The pH within the stomach varies between the most acidic, parietal cell containing fundus, and the antrum. There is also a pH gradient from the gastric juice in the lumen to the surface of the cells of the gastric epithelium. The mucus layer consists of an inner mucus layer that is firmly attached to the epithelium and a variable mucus layer interfacing with the lumen. Thus, across the relatively stable mucus layer overlying the gastric epithelium, the pH ranges from about 5.5 to 6.8 or even 7 at the surface of the gastric epithelial cells.
To understand the dynamics of the gastric microbiota, it is necessary to consider the site of their isolation. Bacteria, and bacterial DNA, which are isolated from gastric juice, differ from bacterial isolates adhering to the mucosa, which is a more hospitable environment for colonization. During abnormal conditions, this balance may be different. Reduction of gastric acid secretion increases the risk of bacterial overgrowth and also influences the composition of intestinal or oral microorganisms, including pathogenic organisms and those which can nitrosate dietary nitrate and nitrite, which are not normally cultured from a healthy stomach. In this section, we review current knowledge concerning the gastric microbiota with a brief introduction on the role of H pylori and its relationship with other microorganisms associated with the gastric mucosa.
Helicobacter pylori
H pylori infection is the most common worldwide human infection and is associated with several important upper gastrointestinal conditions, including chronic gastritis, peptic ulcer disease, and gastric malignancy. It is the dominant gastric organism in H pylori– positive individuals when detected by conventional methods. H pylori has specific characteristics allowing it to survive in low pH environment in the stomach by producing urease and ammonia. Alkalinization enables the bacteria to survive through the variable acidity of the gastric juice and reach the higher pH of the mucous layer in close apposition to the surface epithelial cells. The acute inflammatory response to H pylori infection initiates the release of interleukin-8 and the recruitment of inflammatory cells, leading to a chronic active gastritis. The production of catalase and superoxide by H pylori protect it from reactive oxygen and nitrogen species. The immunology of the stomach and host response involved in the persistence of H pylori infection and the role of other organisms are an important new focus for current research into the gastric microbiome.
Gastric Microbiota in Healthy Individuals
Soon after the discovery of H pylori , other bacteria such as Veillonella , Lactobacillus , and Clostridium were identified in the stomach. The gastric microbiota differs from the oral cavity or pharynx, which argues for the stomach comprising resident microbes rather than those that have relocated from the oropharynx or esophagus.
The presence of non– H pylori microorganisms in human gastric tissue has been documented by conventional methods, including histology and the culture of gastric juice and mucosal biopsies. Clostridium spp, Lactobacillus spp, and Veillonella sp are the most reported bacteria of the healthy human stomach based on culture studies. Most of the bacteria are not easily cultured, but the development of culture-independent molecular techniques based on 16S rRNA has revealed several other genera in the stomach, including Neisseria , Haemophilus , Prevotella , Streptococcus , and Porphyromonas . In healthy individuals, the predominant bacteria are Actinobacteria ( Rothia , Actinomyces , and Micrococcus ), Bacteroidetes ( Prevotella species), Firmicutes ( Streptococcus and Bacillus ), and Proteobacteria (which include H pylori as well as Haemophilus , Actinobacillus , and Neisseria ), and the predominant genus is Streptococcus , which may originate from the oral or nasal cavities. Interestingly, the presence of Streptococci was recently associated with peptic ulcer disease in one study from Malaysia.
The reported variability in the gastric microbiota is in part due to geographic and cultural variations, but also due to the different methods of investigation used. Moreover, several studies show that the gastric microbiota in patients infected with H pylori is different from uninfected individuals. For example, a Swedish study showed the gastric microbiota from H pylori –negative subjects displays a greater diversity than the microbiota of H pylori– positive patients. However, in contrast, a study in 215 healthy Malaysians showed that the microbial diversity was not influenced by the presence of H pylori . Thus, there might be geographic differences in the diversity of the human gastric microbiota, which result in variations in the interactions between H pylori and other gastric bacteria residing in the gastric mucosa. The human gastric microbiota was surveyed in 8 studies using 4 molecular methods: next-generation sequencing technologies, Sanger sequencing of 16S rDNA, a community fingerprinting method to define a library for Sanger sequencing, and the PhyloChip. Although there is considerable variation in the gastric microbiome between individuals at the genus level, the most frequently detected phyla detected in the stomach were Proteobacteria , Firmicutes , Bacteroidetes , Actinobacteria , and Fusobacteria . The most abundant phyla in the stomachs of H pylori– infected subjects were Proteobacteria , Firmicutes , and Actinobacteria . In the absence of H pylori infection, the most abundant phyla were the Firmicutes , Bacteroidetes , and Actinobacteria . Overall, H pylori is the most dominant species in the human stomach, comprising 72% to 99% of sequencing readouts with Proteobacteria the dominant phylum in those infected with H pylori . In the absence of H pylori infection , analysis consistently reports the presence of Streptococcus spp.
These findings have been further tested in several in vitro and animal studies. The prolonged exposure to H pylori infection alters the composition of the microbiota in rodent stomachs. In an animal model of H pylori infection, Lactobacillus johnsonii , Lactobacillus murinus , and Lactobacillus reuteri inhibited the growth of H pylori organisms in vitro. In the same model, some Lactobacillus , Bifidobacteria , and Saccharomyces also prevented adhesion and colonization of H pylori. Streptococcus mitis , which is a commensal microorganism of the human stomach, also inhibited the growth of H pylori and its conversion from a spiral to a coccoid form. In another study, 2 L reuteri strains, isolated from gastric juice and biopsies, showed resistance to acid and a strong antimicrobial effect against H pylori . The mechanism of altering the gastric microbiota by H pylori is unclear; however, one theory is direct killing of bacteria by the induction of host antimicrobial peptides, such as β-defensin 2 or cecropinlike peptide. H pylori infection also induces an inflammatory cascade that may end in reduced gastric secretion from parietal cells and elevation of intragastric pH. The higher pH will eventually result in colonization by other microorganisms in the stomach, and existing evidence also suggests that alteration of the gastric microbiota may predispose to the development of gastric cancer.
Interaction Between H pylori and Other Microbiota
In the absence of H pylori infection, the structure and composition of the gastric microbiota most resemble that reported for the distal esophagus with unique differences due to Proteobacteria. However, the effects of H pylori infection on the gastric microbiota are not fully understood. H pylori density increases with the onset of gastritis, which may allow H pylori to outcompete other bacteria. In one study, H pylori accounted for 93% to 97% of all reads in the infected stomach and also substantially decreased diversity because only 33 phylotypes were observed in H pylori –positive individuals compared with 262 phylotypes observed in H pylori –negative subjects. However, several studies have reported the ability to detect H pylori sequences at extremely low levels in subjects who were H pylori negative by other diagnostic methods. These results may reflect the host response, leading to reduction of H pylori or the presence of non– H pylori Helicobacters . Regarding the uniformity of the microbiota within the stomach, several studies have found no differences in the microbiota of the antrum and corpus in their populations, with the exception of decreased Prevotella reported in the antrum of patients with gastritis. In contrast, others have noted bacterial differences between subjects and between the antrum and corpus. Thus, H pylori infection and the associated changes in the stomach alter the ecological niche of the gastric microbiota. However, the gastric microbiota also competes with H pylori for a gastric niche and may play an important role in the progression of disease. More studies involving the microbiota-host-environment interactions, including the effect of diet, geography, culture, and gender, are needed to fully understand the role of gastric bacteria in human health and disease.
Lactobacillus
Lactobacillus species are found in the stomachs of all mammals, and several studies have reported Lactobacillus species colonizing the human gastric mucosa. Lactobacilli are rod-shaped, gram-positive, micro-aerophilic bacteria with some similarities to H pylori. The distinguishing feature of Lactobacillus metabolism is the conversion of lactose to lactic acid, and this leads to acidification of the bacterial microenvironment, resulting in acidification of the gastric mucous layer. Acidophilic gastric Lactobacilli are able to adapt sufficiently to the acid environment and colonize the stomach due to these acidophilic properties. Moreover, some Lactobacilli have a urease enzyme with an optimum activity at pH 3 to 4, which is similar to that of H pylori .
Acidification of the gastric antral mucosa causes rapid inhibition of gastrin and a reduction in gastric acid secretion. Thus, acid-generating Lactobacilli close to the surface of the antral gastric epithelium may decrease gastric acid secretion ( Fig. 1 ). In contrast, H pylori alkalinizes the gastric antral mucosa, increasing gastrin and consequently also acid secretion. Lactic acid produced by Lactobacilli neutralizes ammonia produced by H pylori , which would result in a null net effect on pH at the surface of the gastric epithelium when both H pylori and Lactobacilli are colonizing the stomach together (see Fig. 1 ). The impact of Lactobacilli colonizing the gastric mucosa may be different in the antrum and body of the stomach; however, it can only result in acidification and thus trends to a lower mucosal surface pH, leading to subsequent inhibition of gastrin secretion. In support of this observation, a study in Finland found in H pylori– infected patients that taking a probiotic, which included Lactobacillus rhamnosus , significantly decreased serum gastrin-17. Some Lactobacilli have an inhibitory effect on H pylori , and probiotics isolated from dairy products or human feces have been shown to have suppressive effects on H pylori infection. In a clinical trial on 40 H pylori– infected mice randomized to 4 groups undergoing triple therapy together with Lactobacillus fermenti , Lactobacillus acidophilus , and normal saline confirmed that Lactobacillus strains had a significant activity against H pylori . Another study of 147 H pylori –infected patients showed that Will yogurt (a Korean brand of L acidophilus HY2177, Lactobacillus casei HY2743, Bifidobacterium longum HY8001, and Streptococcus thermophilus B-1) added to triple therapy increased the H pylori eradication rate, although adverse effects were unaltered. Other studies also suggest that Lactobacillus preparations may increase eradication rates of H pylori infection or even limit related manifestations of disease or symptoms. Lactic acid produced by Lactobacilli inhibits the growth of H pylori at concentrations of 1% and 3%.
Further mechanisms by which Lactobacillus species may influence H pylori infection are by direct effects. L reuteri DSM17648 was found to act as a highly specific binding antagonist to H pylori . In a single-blinded, randomized, placebo-controlled pilot study, this strain coaggregated the pathogen in vitro and in vivo and significantly reduced the load of H pylori in healthy, yet infected adults. The investigators then showed a rapid and efficient coaggregation of H pylori by a specific Lactobacillus strain under gastric conditions. Reducing the amount of H pylori in the stomach by selective bacteria-bacteria cell interaction might be a new way for treating H pylori , given that the eradication is associated with potential side effects or antibiotic resistance. These investigators suggested that Lactobacillus interferes with H pylori motility and the organisms’ adherence to the gastric mucosa by aggregating them and masking H pylori surface sites that are ordinarily available for binding to human epithelial cells.
Interestingly, a new strain of L johnsonii No. 1088 was isolated from the juice of a healthy Japanese male volunteer. L johnsonii has shown the best acid resistance among several Lactobacilli examined with greater than 10% of organisms surviving at pH of 1 after 2 hours. L johnsonii also inhibited the growth of H pylori , Escherichia coli O-157 , Salmonella typhimurium , and Clostridium difficile in vitro and suppressed gastric acid secretion in mice. Although further studies are required, there might be a role for this microorganism in cotherapy for resistant H pylori infections.
Gastric microbiota in disease
Gastric Cancer
There is increasing evidence on the potential role of the gastric microbiota in the development of gastric cancer by inducing and maintaining the carcinogenic pathways by stimulation of inflammation, increase in cell proliferation, the dysregulation of stem cell physiology, and production of several metabolites. H pylori is the most important microbial risk factor that has been recognized by the International Agency for Research on Cancer as a class I carcinogen due its role in development of gastric cancer. However, recent evidence shows that other gastric microbiota may also be involved in gastric carcinogenesis. 16S rRNA gene sequencing analysis of the gastric mucosa of patients with gastric cancer showed a higher prevalence of Lactobacillus , Streptococcus mitis , Streptococcus parasanguinis , Prevotella , and Veillonella .
Patients with nonatrophic gastritis, intestinal metaplasia, and gastric cancer were studied using a microarray G3 PhyloChip. A lower diversity and a greater abundance of Pseudomonas were found in patients with gastric cancer compared with patients with nonatrophic gastritis. Interestingly, this study also found a gradual decrease in 2 Porphyromonas species from the TM7 phylum, Neisseria spp and Streptococcus spp, while showing a gradual increase in Lactobacillus coleohominis and Lachnospiraceae from gastritis to gastric metaplasia and cancer. Another study using a high-throughput sequencing platform (454 GS FLX Titanium) showed a greater bacterial diversity, a relative increase of Bacilli and the Streptoccocci spp , and a relative reduction of Helicobacteraceae in the cancer group compared with other groups.
Although these results are apparently different, this might indicate a change in gastric microbiota with the stepwise progression to gastric cancer from gastritis. In a recent study in 315 patients, including 212 with chronic gastritis and 103 with gastric cancer, the amount of bacteria per gram of gastric mucosa was determined using quantitative PCR. The bacterial load in the gastric mucosa was higher in H pylori– infected patients (7.80 ± 0.71 × 10 8 per gram) as compared with those who were uninfected (7.59 ± 0.57 × 10 8 per gram) ( P = .005). An increased bacterial load was also detected in gastric cancer (7.85 ± 0.70 × 10 8 per gram) as compared with those in patients with chronic gastritis ( P = .001). The presence of H pylori markedly altered the structure of microbial communities, but the relative proportions of the other members in the microbiota were not markedly changed. Patients with gastric cancer were found to have an enriched population of 5 genera of bacteria. These bacteria are all known to have the potential for cancer promotion and included Lactobacillus , Escherichia , Shigella , Nitrospirae , Burkholderia fungorum , and Lachnospiraceae, which were not cultured. Nitrospirae in particular was present in all patients with gastric cancer, but not found in patients with chronic gastritis.
Bacterial diversity decreases with the transition from nonatrophic gastritis to intestinal metaplasia and then to gastric cancer, with a decrease in the number of Porphyromonas , Neisseria , TM7 group, and Streptococcus sinensis but with a relative increase in L coleohominis and Lachnospiraceae. Pseudomonas was significantly more prevalent in gastric cancer than in nonatrophic gastritis. The presence of H pylori had little influence on the relative proportions of other members in the microbiota. In H pylori carriers, normal gastric mucosa had larger populations of Propionibacterium spp, Staphylococcus spp, and Corynebacterium spp with smaller populations of Clostridium and Prevotella .
Non –H pylori microbiota may also play a role in the development of gastric cancer. Studies showed that in male mice with intestinal microbiota in their gastric samples, gastric pathology developed chronic gastritis extending to atrophy and dysplasia, independent of H pylori infection. The presence of commensal microbiota accelerated the progression to gastric intraepithelial neoplasia in H pylori– infected mice, although antibiotic therapy significantly delayed the onset of gastric neoplasia in H pylori– negative mice. Another study compared the human gastric microbiota in gastric cancer with controls by analyzing 63 antral mucosal and 18 corpus mucosal specimens by rRNA gene sequencing. Nitrosating or nitrate-reducing bacteria were found to be 2 times higher in the cancer groups than in the control groups, but this was not statistically significant, and the investigators concluded no significant difference of microbial composition between cancer and control groups.
Some studies have shown that the microbiota in gastric cancer have increased bacterial diversity, but bacterial overgrowth in the stomach has been reported in various precancerous conditions, including hypochlorhydria and gastric mucosal atrophy. Some investigators have suggested that the gastric microbiota is involved in the production of carcinogens through the promotion of inflammation. However, it is not clear if bacterial overgrowth is a consequence of the carcinogenic process by generating an environment that favors bacterial proliferation. Further research is required to clarify the mechanisms by which these changes occur, and the possible relationship to cause or effect.
Other data suggest that differences in the gastric microbiota might be responsible for a higher prevalence of gastric cancer in some regions. One case-control study in Colombia used deep sequencing of amplified 16S rDNA, in 2 age- and gender-matched populations, to compare the composition of the gastric microbiota in a high gastric cancer risk area in the Andes, which has a 25-fold greater risk than the comparator coastal low-risk area. The composition of the microbiota was highly variable between individuals, but showed a significant correlation with their area of origin. Multiple operational taxonomic units (OTUs) were detected exclusively in both areas. Two OTUs, Leptotrichia wadei and a Veillonella sp, were significantly more abundant in the high-risk Andes mountain area, and 16 OTUs, including a Staphylococcus sp, were significantly more frequent in the low-risk coastal area. There was no significant correlation with the H pylori population or carriage of the cagPAI pathogenicity island with the composition of the microbiota.
Atrophic Gastritis
Gastric acidity is a barrier to microbes in saliva and ingested food, mainly due to the acidity and digestive activity of gastric juice. The reduction of gastric acid secretion in patients with atrophic gastritis allows colonization of the stomach by more microbes. Although a reduction in acidity is not universal with old age, in one study 80% of healthy individuals were reported to have hypochlorhydria with 105 to 108 CFU/mL bacteria in a fasting gastric aspirate. Data on gastric microbiota composition in patients with atrophic gastritis are limited. In one study, microbial quantity was positively correlated with serum pepsinogen I/pepsinogen II ratio in Asian patients. In another study, Streptococcus species were replaced by Prevotella species in patients with atrophic gastritis. Current evidence is too limited to comment on the overall change in gastric microbiota in atrophic gastritis, and further studies are needed to evaluate this question.
Postinfectious Dyspepsia
Acute gastrointestinal infection can lead to persistent low-grade mucosal inflammation, followed by the onset of postinfectious irritable bowel syndrome. Several organisms are known to be responsible, including Campylobacter , Salmonella , E coli , and Shigella . Functional dyspepsia (FD) may also follow an infection that is currently recognized as postinfectious FD (PIFD). One study reported that 17% of patients with FD had experienced an episode of acute gastroenteritis, whereas the onset of PIFD was not correlated with H pylori infection. A prospective observational study found the incidence of FD significantly higher in patients 1 year after acute Salmonella gastroenteritis (13.4%) compared with controls (2%). A meta-analysis found the mean prevalence of FD following acute gastroenteritis was 9.55% in the adult population and the OR for PIFD was 2.54 (95% confidence interval: 1.76–0.65). The pathogenesis of PIFD is not clearly understood but might be explained by the altered immune response to dysbiosis in the upper gastrointestinal tract. However, it is not yet clear if acute gastroenteritis directly induces change in the gastric microbiota or only influences the development of postinfectious dyspepsia. Further studies in FD are underway and awaited with interest.
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