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.