Alterations in the human gut microbiome associated with Helicobacter pylori infection.
ABSTRACT: Helicobacter pylori infection (HPI) is a prevalent infectious disease associated with gastric ulcer, gastric cancer, and many nongastrointestinal disorders. To identify genes that may serve as microbial markers for HPI, we performed shotgun metagenomic sequencing of fecal samples from 313 Chinese volunteers who had undergone a C14 breath test. Through comparing differences in intestinal microbial community structure between H. pylori-positive and H. pylori-negative individuals, we identified 58 HPI-associated microbial species (P < 0.05, Wilcoxon test). A classifier based on microbial species markers showed high diagnostic ability for HPI (AUC = 0.84). Furthermore, levels of gut microbial vitamin B12 (VB12) biosynthesis and plasma VB12 were significantly lower in H. pylori-positive individuals compared with H. pylori-negative individuals (P < 0.05, Wilcoxon test). This study reveals that certain alterations in gut microbial species and functions are associated with HPI and shows that gut microbial shift in HPI patients may indirectly elevate the risk of VB12 deficiency.
Project description:Helicobacter pylori (H. pylori) is known to colonize gastric mucosa, induce inflammation, and alter gastric microbiota resulting in a spectrum of gastric diseases. Likewise, changes in gut microbiota have recently been linked with various metabolic and inflammatory diseases. While extensive number of studies were published examining the relationship between H. pylori and gastric microbiota, little is known about the impact of H. pylori on downstream gut microbiota. In this study, we performed 16?S rRNA and ITS2-based microbial profiling analysis of 60 stool samples from adult individuals. Remarkably, the gut microbiota of H. pylori infected individuals was shown to be increased of members belonging to Succinivibrio, Coriobacteriaceae, Enterococcaceae, and Rikenellaceae. Moreover, gut microbiota of H. pylori infected individuals was shown to have increased abundance of Candida glabrata and other unclassified Fungi. These results links possible role for H. pylori-associated changes in the gut microbiota in intestinal mucosal barrier disruption and early stage colorectal carcinoma deployment. Altogether, the identified differences in bacterial and fungal composition provides important information that may eventually lead to the development of novel biomarkers and more effective management strategies.
Project description:BACKGROUND:Gastric Helicobacter pylori (H. pylori) is linked with chronic gastritis, peptic ulcer disease, and gastric malignancy. This study aims to investigate the association of gastric H. pylori with colorectal adenomatous polyps (CAP) in the Chinese population. METHODS:One thousand three hundred seventy five workers of China Petroleum and Chemical Corporation Sinopec Zhenhai Refining & Chemical Branch were recruited. Carbon-13 urea breathes test, and colorectal biopsies were utilized to detect H. pylori and CAP. The correlation between the number and distribution of CAP with H. pylori infection (HPI) was determined. Logistic regression models were applied to calculate the effect of H. pylori on the risk of CAP and pathway studio was used to attribute the cellular processes linking HPI and adenomatous polyps. RESULTS:One hundred Eighty participants were diagnosed as CAP, and 1195 participants were classified as healthy control. The prevalence of HPI in the CAP group was significantly higher than that in the healthy control group (57.8% verse 40.1%) (p<0.001). It was the number not the distribution of CAP corrected with H. pylori status. An increased risk of CAP was found to be associated with H. pylori (OR?=?3.237; 95.0% CI 2.184-4.798, p?=?0.00) even after multiple parameters adjustment. Pathway studio analysis demonstrated that HPI connected with CAP at multi-level. CONCLUSIONS:HPI is associated with an increased risk of CAP in the Chinese population.
Project description:<i>Helicobacter pylori</i> infection in stomach leads to gastric cancer, gastric ulcer, and duodenal ulcer. More than 1 million people die each year due to these diseases, but why most <i>H. pylori</i>-infected individuals remain asymptomatic while a certain proportion develops such severe gastric diseases remained an enigma. Several studies indicated that gastric and intestinal microbiota may play a critical role in the development of the <i>H. pylori</i>-associated diseases. However, no specific microbe in the gastric or intestinal microbiota has been clearly linked to <i>H. pylori</i> infection and related gastric diseases. Here, we studied <i>H. pylori</i> infection, its virulence genes, the intestinal microbiota, and the clinical status of Trivandrum residents (<i>N</i> = 375) in southwestern India by standard <i>H. pylori</i> culture, PCR genotype, Sanger sequencing, and microbiome analyses using Illumina Miseq and Nanopore GridION. Our analyses revealed that gastric colonization by virulent <i>H. pylori</i> strains (<i>vacAs1i1m1cagA</i>+) is necessary but not sufficient for developing these diseases. Conversely, distinct microbial pools exist in the lower gut of the <i>H. pylori</i>-infected vs. <i>H. pylori</i>-non-infected individuals. <i>Bifidobacterium</i> (belonging to the phylum Actinobacteria) and <i>Bacteroides</i> (belonging to the phylum Bacteroidetes) were present in lower relative abundance for the <i>H. pylori</i>+ group than the <i>H. pylori</i>- group (<i>p</i> < 0.05). On the contrary, for the <i>H. pylori</i>+ group, genus <i>Dialister</i> (bacteria belonging to the phylum Firmicutes) and genus <i>Prevotella</i> (bacteria belonging to the phylum Bacteroidetes) were present in higher abundance compared to the <i>H. pylori-</i> group (<i>p</i> < 0.05). Notably, those who carried <i>H. pylori</i> in the stomach and had developed aggressive gastric diseases also had extremely low relative abundance (<i>p</i> < 0.05) of several <i>Bifidobacterium</i> species (e.g., <i>B. adolescentis</i>, <i>B. longum</i>) in the lower gut suggesting a protective role of <i>Bifidobacterium</i>. Our results show the link between lower gastrointestinal microbes and upper gastrointestinal diseases. Moreover, the results are important for developing effective probiotic and early prognosis of severe gastric diseases.
Project description:Helicobacter pylori colonization is highly prevalent among humans and causes significant gastric disease in a subset of those infected. When present, this bacterium dominates the gastric microbiota of humans and induces antimicrobial responses in the host. Since the microbial context of H. pylori colonization influences the disease outcome in a mouse model, we sought to assess the impact of H. pylori challenge upon the pre-existing gastric microbial community members in the rhesus macaque model. Deep sequencing of the bacterial 16S rRNA gene identified a community profile of 221 phylotypes that was distinct from that of the rhesus macaque distal gut and mouth, although there were taxa in common. High proportions of both H. pylori and H. suis were observed in the post-challenge libraries, but at a given time, only one Helicobacter species was dominant. However, the relative abundance of non-Helicobacter taxa was not significantly different before and after challenge with H. pylori. These results suggest that while different gastric species may show competitive exclusion in the gastric niche, the rhesus gastric microbial community is largely stable despite immune and physiological changes due to H. pylori infection.
Project description:Gastric cancer is the end result of a complex interplay between host genetics, environmental factors, and microbial factors. The link between gut microbiome and gastric cancer has been attributed to persistent activation of the host's immune system by gut microbiota. The end result of this dysregulated interaction between host epithelium and microbes is a state of chronic inflammation. Gut bacteria can promote anti-tumor immune responses through several mechanisms. These include triggering T-cell responses to bacterial antigens that can cross-react with tumor antigens or cause tumor-specific antigen recognition; engagement of pattern recognition receptors that mediate pro-immune or anti-inflammatory effects or via small metabolites that mediate systemic effects on the host. Here we review the role of the gut microbiome including H. pylori and non-H. pylori gastric bacteria, the immune response, and immunotherapy using checkpoint inhibitors. We also review the evidence for cross talk between the gut microbiome and immune response in gastric cancer.
Project description:Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma; however, most infected individuals never develop this malignancy. Strain-specific microbial factors, such as the oncoprotein CagA, as well as environmental conditions, such as iron deficiency, augment cancer risk. Importantly, dysbiosis of the gastric microbiota is also associated with gastric cancer. To investigate the combinatorial effects of these determinants in an in vivo model of gastric cancer, Mongolian gerbils were infected with the carcinogenic cag+ H. pylori strain 7.13 or a 7.13 cagA isogenic mutant, and microbial DNA extracted from gastric tissue was analyzed by 16S rRNA sequencing. Infection with H. pylori significantly increased gastric inflammation and injury, decreased ?-diversity, and altered microbial community structure in a cagA-dependent manner. The effect of iron deficiency on gastric microbial communities was also investigated within the context of infection. H. pylori-induced injury was augmented under conditions of iron deficiency, but despite differences in gastric pathology, there were no significant differences in ?- or ?-diversity, phyla, or operational taxonomic unit (OTU) abundance among infected gerbils maintained on iron-replete or iron-depleted diets. However, when microbial composition was stratified based solely on the severity of histologic injury, significant differences in ?- and ?-diversity were present among gerbils harboring premalignant or malignant lesions compared to gerbils with gastritis alone. This study demonstrates that H. pylori decreases gastric microbial diversity and community structure in a cagA-dependent manner and that as carcinogenesis progresses, there are corresponding alterations in community structure that parallel the severity of disease.IMPORTANCE Microbial communities are essential for the maintenance of human health, and when these communities are altered, hosts can become susceptible to inflammation and disease. Dysbiosis contributes to gastrointestinal cancers, and specific bacterial species are associated with this phenotype. This study uses a robust and reproducible animal model to demonstrate that H. pylori infection induces gastric dysbiosis in a cagA-dependent manner and further that dysbiosis and altered microbial community structure parallel the severity of H. pylori-induced gastric injury. Ultimately, such models of H. pylori infection and cancer that can effectively evaluate multiple determinants simultaneously may yield effective strategies for manipulating the gastric microbiota to prevent the development of gastric cancer.
Project description:Eradication of Helicobacter pylori has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and H. pylori-related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were Bacteroidetes, Firmicutes, and Proteobacteria with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current H. pylori infection compared with negative subjects. As for the differential bacteria, the average relative abundance of Bacteroidetes was found to significantly decrease from H. pylori negative (66.16%) to past infection group (33.01%, p = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, p = 0.027). For Firmicutes and Proteobacteria, the average relative abundances showed elevated trends in the past H. pylori infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, p = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, p = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both p < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of Bacteroidetes, Firmicutes and Proteobacteria, may be involved in the process of H. pylori-related gastric lesion progression and provide hints for future evaluation of microbial changes after H. pylori eradication.
Project description:Emerging evidence shows that the human microbiota plays a larger role in disease progression and health than previously anticipated. Helicobacter pylori, the causative agent of gastric cancer and duodenal and gastric ulcers, was early associated with gastric disease, but it has also been proposed that the accompanying microbiota in Helicobacter pylori-infected individuals might affect disease progression and gastric cancer development. In this study, the composition of the transcriptionally active microbial community and H. pylori gene expression were determined using metatranscriptomic RNA sequencing of stomach biopsy specimens from individuals with different H. pylori infection statuses and premalignant tissue changes. The results show that H. pylori completely dominates the microbiota not only in infected individuals but also in most individuals classified as H. pylori uninfected using conventional methods. Furthermore, H. pylori abundance is positively correlated with the presence of Campylobacter, Deinococcus, and Sulfurospirillum Finally, we quantified the expression of a large number of Helicobacter pylori genes and found high expression of genes involved in pH regulation and nickel transport. Our study is the first to dissect the viable microbiota of the human stomach by metatranscriptomic analysis, and it shows that metatranscriptomic analysis of the gastric microbiota is feasible and can provide new insights into how bacteria respond in vivo to variations in the stomach microenvironment and at different stages of disease progression.
Project description:Helicobacter pylori have been shown to influence physiological regulation of metabolic hormones involved in food intake, energy expenditure and body mass. It has been proposed that inducing H. pylori-induced gastric atrophy damages hormone-producing endocrine cells localized in gastric mucosal layers and therefore alter their concentrations. In a recent study, we provided additional proof in mice under controlled conditions that H. pylori and gut microbiota indeed affects circulating metabolic gut hormones and energy homeostasis. In this addendum, we presented data from follow-up investigations that demonstrated H. pylori and gut microbiota-associated modulation of metabolic gut hormones was independent and precedes H. pylori-induced histopathological changes in the gut of H. pylori-infected mice. Thus, H. pylori-associated argumentation of energy homeostasis is not caused by injury to endocrine cells in gastric mucosa.
Project description:BACKGROUND:Helicobacter pylori (H. pylori) infection is associated with remodeling of gastric microbiota. However, comprehensive analyses of the impact of H. pylori infection, eradication therapy and probiotic supplementation on gut microbiota are still lacking. We aimed to provide evidence for clinical decision making. METHODS:Seventy H. pylori-positive and 35 H. pylori-negative patients (group C) were enrolled. H. pylori-positive patients were randomly assigned to group A (14-day bismuth-containing quadruple therapy) and group B (quadruple therapy supplemented with Clostridium butyricum). Stool samples of group A and B were collected on day 0, 14 and 56 while stool samples of group C were collected on day 0. Gut microbiota was investigated by 16S rRNA sequencing. FINDINGS:The Sobs index (richness estimator) was significantly higher in H. pylori-positive samples than H. pylori-negative samples (p?<?.05). Several metabolic pathways were more abundant in H. pylori-positive communities while some disease-associated pathways had higher potential in H. pylori-negative community through KEGG pathway analysis. Abundances of most butyrate-producing bacteria significantly decreased, while several detrimental bacteria increased after eradication therapy. Probiotic supplementation was associated with improved gastrointestinal symptoms as well as increased Bacteroidetes:Firmicutes ratio. INTERPRETATION:While H. pylori infection may not be necessarily detrimental in all patients, eradication of H. pylori was associated with widespread changes in gut microbial ecology and structure. Probiotic supplementation could relieve more gastrointestinal symptoms by inducing alterations in gut microbiota and host immune responses. As such, the decision to eradicate H. pylori should be based on comprehensive analysis of individual patients.