Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature
Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature
ABSTRACT OBJECTIVEH. 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 harbor a nearly two-fold increased risk to develop colorectal cancer (CRC). However, a direct causal and functional connection between H. pylori infection and colon cancer is lacking. DESIGNWe 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 characterized and evaluated in germ-free mice and via stool transfer experiments. RESULTSH. pylori infection accelerated tumor development in Apc-mutant mice. We identified a unique H. pylori-driven immune alteration signature characterized by a reduction in regulatory T-cells and proinflammatory T-cells. Furthermore, in the intestinal and colonic epithelium, H. pylori induced pro-carcinogenic STAT3 signaling and a loss of goblet cells, changes that have been shown to contribute - in combination with pro-inflammatory and mucus degrading microbial signatures - to tumor 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 normalized the tumor incidence to the level of uninfected controls. CONCLUSIONSOur 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.
Gerhard Markus、Jarosch Sebastian、Dietl Alisa、Vieth Michael、Ralser Anna、Janssen Klaus Peter、Engelsberger Veronika、Quante Michael、Busch Dirk H.、Wanisch Andreas、Haller Dirk、Deng Li、Mej¨aas-Luque Raquel
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich||German Center for Infection Research (DZIF), Munich Partner SiteInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of MunichInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of MunichInstitute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Klinikum BayreuthInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of MunichTechnical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of SurgeryInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of MunichKlinik f¨1r Innere Medizin II, Gastrointestinale Onkologie, Universit?tsklinikum Freiburg||Klinik und Poliklinik f¨1r Innere Medizin II, Technical University of MunichInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich||German Center for Infection Research (DZIF), Munich Partner SiteInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of MunichChair of Nutrition and Immunology, Technical University of Munich||ZIEL Institute for Food & Health, Technical University of MunichInstitute of Virology, School of Medicine, Helmholtz Center Munich, Technical University of MunichInstitute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich||German Center for Infection Research (DZIF), Munich Partner Site
肿瘤学基础医学微生物学
Gerhard Markus,Jarosch Sebastian,Dietl Alisa,Vieth Michael,Ralser Anna,Janssen Klaus Peter,Engelsberger Veronika,Quante Michael,Busch Dirk H.,Wanisch Andreas,Haller Dirk,Deng Li,Mej¨aas-Luque Raquel.Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature[EB/OL].(2025-03-28)[2025-05-07].https://www.medrxiv.org/content/10.1101/2022.06.16.22276474.点此复制
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