Effect of Helicobacter pylori eradication and microbiome manipulation on colorectal cancer development

• Applicants: Professorin Dr. Li Deng; Professor Dr. Markus Gerhard
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535013688

Helicobacter pylori infects more than half of the world´s population, and although the bacterium exclusively colonizes the stomach, chronic infection is also associated with extragastric diseases. Epidemiological studies showed that H. pylori infected individuals harbor a nearly twofold increased risk to develop colorectal cancer (CRC), but the underlying mechanisms that confer this increased risk were unclear. We showed that Apc-mutant mice infected with H. pylori developed twice as any tumors compared with uninfected controls and showed a pro-inflammatory and pro-carcinogenic immune signature in the murine colon. Housing of Apc-mutant mice under germ-free conditions reduced tumor numbers, and the observed phenotype was normalized by early antibiotic eradication of H. pylori. Similar immune and epithelial alterations were found in human biopsies from H. pylori-infected patients, as well as an increase in pro-carcinogenic bacterial species. With these data, we proved that H. pylori infection promotes colorectal carcinogenesis and that these tumor-promoting effects are ameliorated by early antibiotic treatment. However, in our previous experimental setting, we used a short-term model of infection and eradication, which cannot fully recapitulate the long-term adaptation of H. pylori and its host observed in humans. It is conceivable that certain alterations, such as changes in epithelial homeostasis or alteration of microbiota and virome signatures, may become imprinted and not be reversible anymore after decades of chronic H. pylori infection. Thus, whether the changes elicited by H. pylori infection can be fully reverted upon eradication using antibiotics or H. pylori-specific phages is still an open question that needs to be addressed. In the current project, we propose to explore weather eradication of chronic (>6 months in mice) H. pylori infection can still abrogate or reduce the development of tumors in intestine/colon of tumor-prone mice, in order to better recapitulate the human long term infection situation. Further, we will investigate which specific pro-carcinogenic microbiota/virome signatures are present in H. pylori-infected CRC patients, and if these are still present in eradicated CRC patients. We will also analyse if microbiota/virome consortia from H. pylori-infected CRC patients are still pro-carcinogenic in germ-free tumor-prone mice. We will then explore which specific bacterial strains can be identified and isolated in this pro-carcinogenic consortia, what their functions are, and if the minimal consortia generated from these strains are sufficient to induce the observed H. pylori-induced phenotype in germ-free mice. Finally, in a translational approach, we will explore weather this minimal consortium be modified through the addition of probiotics in order to lower or prevent the pro-tumorigenic effects after transfer in germ-free tumor-prone mice.

• DFG Programme: Research Grants