AUTHOR=Xin He , Zhu Chi , Zhu Chan , Zhang Xing , Chen Dongsheng , Wang Qingping 

TITLE=Beyond the stomach: the association between Helicobacter pylori and the spectrum of digestive cancers

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1633227

DOI=10.3389/fcimb.2025.1633227

ISSN=2235-2988

ABSTRACT=Helicobacter pylori (H. pylori) is a Group 1 gastric carcinogen increasingly implicated in extragastric digestive malignancies. This review synthesizes evidence on its role in liver, biliary, esophageal, colorectal, and pancreatic cancers. Based on its unique spiral morphology, flagellar motility bundle, and urease activity-mediated acidic niche adaptation, H. pylori disrupts host cellular homeostasis through multifactorial virulence mechanisms involving CagA/VacA synergy, and exploits antigenic variation and immunomodulatory strategies to achieve persistent gastric mucosal colonization and chronic infection. Emerging evidence suggests associations between H. pylori infection and nongastric digestive cancers, though relationships vary by site. For hepatocellular carcinoma (HCC), epidemiological studies indicate increased risk (OR 4.75), particularly with HCV coinfection, but mechanistic and cohort data remain conflicting. Biliary tract cancer (BTC) shows stronger epidemiological links, especially for cholangiocarcinoma (OR 4.18), supported by virulence factor detection. In esophageal cancer, H. pylori particularly CagA+ strains demonstrates a protective effect against adenocarcinoma but no significant association with squamous cell carcinoma. Colorectal cancer exhibits complex associations, with meta-analyses suggesting increased risk in East Asian populations and potential benefits from eradication therapy. Pancreatic cancer links remain inconsistent. Proposed mechanisms of H. pylori in extragastric cancers include chronic inflammation, virulence factor activity and microbiome disruption. This comprehensive review synthesizes contemporary evidence on the bacterium’s role in non-gastric digestive malignancies, examines pathways underlying its oncogenicity, and outlines translational implications for risk stratification and therapeutic innovation.