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

Abstract

OBJECTIVE H. 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. DESIGN We 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. RESULTS H. 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. CONCLUSIONS Our 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.

Helicobacter hepaticus and Helicobacter bilis in liver and biliary cancers from ATBC and PLCO

“…It is possible that H . hepaticus and H. bilis can widely colonize the hepatobiliary tract, or that infection at a specific site within the tract may cause inflammation across the tract 30 …”

“…It is possible that H. hepaticus and H. bilis can widely colonize the hepatobiliary tract, or that infection at a specific site within the tract may cause inflammation across the tract. 30 Helicobacter hepaticus antigen, HH0407, which was associated with a higher risk of both liver and biliary cancer within PLCO, is a urease, a homolog of the H. pylori protein UreA, as is H. bilis antigen, HRAG01470. In the case of H. pylori, urease allows the bacteria to hydrolyse urea into ammonia and carbon dioxide allowing the bacteria to create its own micro-climate and colonize the acidic environment of the stomach.…”

Impact of Helicobacter pylori Infection and Treatment on Colorectal Cancer in a Large, Nationwide Cohort

“…[28][29][30][31][32] A pivotal study by Ralser et al recently confirmed this hypothesis by demonstrating that H. pylori infection induced proinflammatory and procarcinogenic pathways in the murine and human colon and accelerated intestinal tumor development in adenomatous polyposis coli-mutant mouse models. 33 Several of the hypothesized molecular pathways underlying the association between H. pylori infection and CRC overlap with those underlying the association between metabolic syndrome and CRC, as well as H. pylori-induced gastric carcinogenesis (eg, signal transducer and activator of transcription 3, insulin like growth factor 1 receptor, and peroxisome proliferator-activated receptors-gamma). 28,34,35 Notably, H. pylori-associated gastric atrophy, particularly more severe stages, is associated with a significantly higher risk of colorectal adenomas and CRC, 28,[36][37][38] suggesting that more robust, deleterious pathways might be coincident in the stomach and colon/rectum, leading to mucosal damage and propagation of neoplastic cascades in the setting of persistent H. pylori infection.…”

“…The authors thus concluded that H. pylori-induced intestinal carcinogenesis is a "multifactorial process involving the interplay of the proinflammatory immune response, alterations in the microbiota, and procarcinogenic signaling." 33 In addition to its novelty, other key strengths of this large, nationwide cohort study include comprehensive, individuallevel data, long-term follow-up, and use of rigorously validated phenotypes using manual chart review as the reference standard, including ascertainment of H. pylori status, treatment, and outcomes. We also confirmed that exposure to colonoscopy did not abrogate the association nor did removing individuals diagnosed with CRC within 1 year of study entry or considering non-CRC death as a competing risk; this further supports the robustness of our results.…”

Potential Ability of Probiotics in the Prevention and Treatment of Colorectal Cancer

“…The early use of antibiotics to eradicate H. pylori can restore the incidence rate of tumor in infected people to the level of uninfected people. 86 Probiotics stimulate the production of mucins that limit the adhesion of pathogens to intestinal surfaces, while producing SCFAs and other antibacterial substances that may reduce the density of H. pylori. L. reuteri exhibited the ability to inhibit the colonization of H. pylori on the human gastric mucosa and also produced a broad-spectrum antibiotic effective against H. pylori —reutericin.…”