<i>Helicobacter pylori</i> promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature.

Abstract

<i>Helicobacter pylori</i> infection is the most prevalent bacterial infection worldwide. Besides being the most important risk factor for gastric cancer development, epidemiological data show that infected individuals harbour a nearly twofold increased risk to develop colorectal cancer (CRC). However, a direct causal and functional connection between <i>H. pylori</i> infection and colon cancer is lacking. We infected two <i>Apc</i>-mutant mouse models and C57BL/6 mice with <i>H. pylori</i> and conducted a comprehensive analysis of <i>H. pylori</i>-induced changes in intestinal immune responses and epithelial signatures via flow cytometry, chip cytometry, immunohistochemistry and single cell RNA sequencing. Microbial signatures were characterised and evaluated in germ-free mice and via stool transfer experiments. <i>H. pylori</i> infection accelerated tumour development in <i>Apc</i>-mutant mice. We identified a unique <i>H. pylori</i>-driven immune alteration signature characterised by a reduction in regulatory T cells and pro-inflammatory T cells. Furthermore, in the intestinal and colonic epithelium, <i>H. pylori</i> induced pro-carcinogenic STAT3 signalling and a loss of goblet cells, changes that have been shown to contribute-in combination with pro-inflammatory and mucus degrading microbial signatures-to tumour development. Similar immune and epithelial alterations were found in human colon biopsies from <i>H. pylori</i>-infected patients. Housing of <i>Apc</i>-mutant mice under germ-free conditions ameliorated, and early antibiotic eradication of <i>H. pylori</i> infection normalised the tumour incidence to the level of uninfected controls. Our studies provide evidence that <i>H. pylori</i> infection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation of <i>H. pylori</i> status into preventive measures of CRC should be considered.