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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.
- Helicobacter pylori
- colorectal cancer
- immune response
- signaling
- colonic microflora
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. Raw single cell RNA sequencing and 16S rRNA sequencing data have been deposited with links to BioProject accession number PRJNA808836 in the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA808836/).
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Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. Raw single cell RNA sequencing and 16S rRNA sequencing data have been deposited with links to BioProject accession number PRJNA808836 in the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA808836/).
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Footnotes
RM-L and MG contributed equally.
Contributors AR, RM-L and MG conceived the study. AR, AD and RM-L designed and analysed experiments. SJ contributed and provided code and support to single cell RNA sequencing and chip cytometry. VE and AW contributed to experiments. SJ and DHB provided methodological expertise. AD, SJ, RM-L and DHB contributed to data interpretation. MV, MM and MQ provided human biopsies. KPJ provided mouse models and critically revised the article. DH, DHB and LD critically revised the article. AR and RM-L wrote the article. AR, RM-L and MG revised the article. MG acquired the funding and is the guarantor of the article. All authors read and reviewed the article.
Funding This work was funded by the Deutsche Forschungsgemeinschaft (DFG (German Research Foundation)) SFB1371/1-395357507 (project P09 and project P04).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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