Helicobacter pyloripromotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature

Abstract

ObjectiveHelicobacter pyloriinfection 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 betweenH. pyloriinfection and colon cancer is lacking.DesignWe infected twoApc-mutant mouse models and C57BL/6 mice withH. pyloriand conducted a comprehensive analysis ofH. pylori-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.ResultsH. pyloriinfection accelerated tumour development inApc-mutant mice. We identified a uniqueH. pylori-driven immune alteration signature characterised by a reduction in regulatory T cells and pro-inflammatory T cells. Furthermore, in the intestinal and colonic epithelium,H. pyloriinduced 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 fromH. pylori-infected patients. Housing ofApc-mutant mice under germ-free conditions ameliorated, and early antibiotic eradication ofH. pyloriinfection normalised the tumour incidence to the level of uninfected controls.ConclusionsOur studies provide evidence thatH. pyloriinfection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation ofH. pyloristatus into preventive measures of CRC should be considered.