Low Bifidobacterium Abundance in the Lower Gut Microbiota Is Associated With Helicobacter pylori-Related Gastric Ulcer and Gastric Cancer.

T Barani Devi,Bhabatosh Das,V T Jissa,Deepak Chouhan,Krishnadas Devadas,Meekha George,Sanjai Dharmaseelan,A Gandhimathi,Sneha Mary Alexander,Sivakumar Krishnankutty Chandrika,R J Retnakumar,Santanu Chattopadhyay,G Balakrish Nair,Jijo Varghese

doi:10.3389/fmicb.2021.631140

Abstract

Helicobacter pylori 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 H. pylori-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 H. pylori-associated diseases. However, no specific microbe in the gastric or intestinal microbiota has been clearly linked to H. pylori infection and related gastric diseases. Here, we studied H. pylori infection, its virulence genes, the intestinal microbiota, and the clinical status of Trivandrum residents (N = 375) in southwestern India by standard H. pylori culture, PCR genotype, Sanger sequencing, and microbiome analyses using Illumina Miseq and Nanopore GridION. Our analyses revealed that gastric colonization by virulent H. pylori strains (vacAs1i1m1cagA+) is necessary but not sufficient for developing these diseases. Conversely, distinct microbial pools exist in the lower gut of the H. pylori-infected vs. H. pylori-non-infected individuals. Bifidobacterium (belonging to the phylum Actinobacteria) and Bacteroides (belonging to the phylum Bacteroidetes) were present in lower relative abundance for the H. pylori+ group than the H. pylori- group (p < 0.05). On the contrary, for the H. pylori+ group, genus Dialister (bacteria belonging to the phylum Firmicutes) and genus Prevotella (bacteria belonging to the phylum Bacteroidetes) were present in higher abundance compared to the H. pylori- group (p < 0.05). Notably, those who carried H. pylori in the stomach and had developed aggressive gastric diseases also had extremely low relative abundance (p < 0.05) of several Bifidobacterium species (e.g., B. adolescentis, B. longum) in the lower gut suggesting a protective role of Bifidobacterium. 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.

Highlights

One of the most intriguing fundamental challenges in infectious disease research is to understand the combination of “microbial factors” and “other factors” that collectively determine clinical outcomes
Among the 83 H. pylori-positive cases, disease severity is high among males compared with females (34.3% vs. 6.25%)
Among the H. pylori positives, males have a 7.8 times higher odds of detecting with severe disease compared with females

Summary

Introduction

One of the most intriguing fundamental challenges in infectious disease research is to understand the combination of “microbial factors” and “other factors” that collectively determine clinical outcomes. It is well known that the vacuolating cytotoxin A (vacA) and the cytotoxin-associated gene A (cagA) are the most critical bacterial genes that contribute to clinical outcomes (Isomoto et al, 2010; Hatakeyama, 2014) Both genes have polymorphic allelic structures and encode multitasking toxins. The CagA protein is injected by the bacterium into cells, where it interferes with actin cytoskeleton and tight junctions, and subverts pathways that regulate cell cycles (Hatakeyama, 2014) The role of these two toxins in gastric cancer and peptic ulcer were evaluated and confirmed by in vitro, in vivo, and clinical studies (Malfertheiner et al, 2014). This implies that additional factors must contribute to the risks of overt diseases (Dorer et al, 2009)

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Conclusion