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

Anna Ralser, Alisa Dietl, Sebastian Jarosch, Veronika Engelsberger, Andreas Wanisch, Klaus Peter Janssen, Moritz Middelhoff, Michael Vieth, Michael Quante, Dirk Haller, Dirk H. Busch, Li Deng, Raquel Mejías-Luque, Markus Gerhard

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Objective Helicobacter pylori 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 H. pylori infection and colon cancer is lacking. Design We infected two Apc-mutant mouse models and C57BL/6 mice with H. pylori and conducted a comprehensive analysis of H. 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. Results H. pylori infection accelerated tumour development in Apc-mutant mice. We identified a unique H. 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. pylori 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 H. pylori-infected patients. Housing of Apc-mutant mice under germ-free conditions ameliorated, and early antibiotic eradication of H. pylori infection normalised the tumour incidence to the level of uninfected controls. Conclusions Our studies provide evidence that H. pylori infection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation of H. pylori status into preventive measures of CRC should be considered.

Original languageEnglish
Pages (from-to)1258-1270
Number of pages13
JournalGut
Volume72
Issue number7
DOIs
StatePublished - 1 Jul 2023

Keywords

  • Helicobacter pylori
  • colonic microflora
  • colorectal cancer
  • immune response
  • signaling

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