promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature.

OBJECTIVE

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 infection and colon cancer is lacking.

DESIGN

We infected two -mutant mouse models and C57BL/6 mice with and conducted a comprehensive analysis of -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.

RESULTS

infection accelerated tumour development in -mutant mice. We identified a unique -driven immune alteration signature characterised by a reduction in regulatory T cells and pro-inflammatory T cells. Furthermore, in the intestinal and colonic epithelium, 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 -infected patients. Housing of -mutant mice under germ-free conditions ameliorated, and early antibiotic eradication of infection normalised the tumour incidence to the level of uninfected controls.

CONCLUSIONS

Our studies provide evidence that infection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation of status into preventive measures of CRC should be considered.