Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature

Correspondence to Professor Markus Gerhard, Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, München 80333, Germany; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Helicobacter pylori infection is the most prevalent bacterial infection worldwide and is the most important risk factor for gastric cancer development.

• Infected individuals harbour a nearly twofold increased risk to develop colorectal cancer (CRC).

WHAT THIS STUDY ADDS

• H. pylori infection accelerates intestinal tumour development in Apc-mutant mice.

• H. pylori infection induces a pro-inflammatory and pro-carcinogenic environment in murine and human colon.

• The observed phenotype was normalised upon eradication therapy and is strongly dependent on microbiota.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• We provide evidence that H. pylori infection is a strong causal promoter of colorectal carcinogenesis and should be included into an adapted risk score for CRC.

• Eradication of H. pylori infection might be an effective measure to reduce this risk.

Introduction

Helicobacter pylori infection affects more than half of the world’s population and it is a main risk factor for gastric cancer. H. pylori induces a number of alterations in the gastric mucosa that together result in neoplastic transformation of the epithelium. Thus, H. pylori infection first triggers a complex plethora of immune cascades, directed towards H. pylori and orchestrated by the bacterium itself, which originate from priming at the Peyer’s patches and the mesenteric lymph nodes of the small intestine.^{1 2} The major pro-inflammatory response towards H. pylori consists of a mixed T helper (Th)1 and Th17 response,¹ and is to a large extent related to the presence and activity of a type 4 secretion system,³ which mediates translocation of the oncogenic and highly immunogenic protein CagA into gastric epithelial cells.⁴ This leads to chronic inflammation and results in the activation of pro-inflammatory signalling pathways such as activating nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signalling, which are major drivers of H. pylori-induced gastric carcinogenesis.⁵ However, H. pylori has evolved counter mechanisms in order to establish and maintain chronic infection, for example, by reprogramming dendritic cells (DCs) to induce regulatory T cells (Treg),^{6 7} which counterbalance the local pro-inflammatory response in the stomach,⁸ and...