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

Abstract

ObjectiveHelicobacter pyloriinfection is the most prevalent bacterial infection worldwide. Besides being the most important risk factor for gastric cancer development, epidemiological data show that infected individuals harbour a nearly twofold increased risk to develop colorectal cancer (CRC). However, a direct causal and functional connection betweenH. pyloriinfection and colon cancer is lacking.DesignWe infected twoApc-mutant mouse models and C57BL/6 mice withH. pyloriand conducted a comprehensive analysis ofH. pylori-induced changes in intestinal immune responses and epithelial signatures via flow cytometry, chip cytometry, immunohistochemistry and single cell RNA sequencing. Microbial signatures were characterised and evaluated in germ-free mice and via stool transfer experiments.ResultsH. pyloriinfection accelerated tumour development inApc-mutant mice. We identified a uniqueH. pylori-driven immune alteration signature characterised by a reduction in regulatory T cells and pro-inflammatory T cells. Furthermore, in the intestinal and colonic epithelium,H. pyloriinduced pro-carcinogenic STAT3 signalling and a loss of goblet cells, changes that have been shown to contribute—in combination with pro-inflammatory and mucus degrading microbial signatures—to tumour development. Similar immune and epithelial alterations were found in human colon biopsies fromH. pylori-infected patients. Housing ofApc-mutant mice under germ-free conditions ameliorated, and early antibiotic eradication ofH. pyloriinfection normalised the tumour incidence to the level of uninfected controls.ConclusionsOur studies provide evidence thatH. pyloriinfection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation ofH. pyloristatus into preventive measures of CRC should be considered.

Synchronous gastric and colon cancers: Important to consider hereditary syndromes and chronic inflammatory disease associations

“…These changes with combination of pro-inflammatory cytokines and mucus degrading microbial signatures lead to carcinogenesis. Similar immune and epithelial alterations were described in human colon biopsies from H. pylori -infected patients[ 32 ].…”

Orally Administrated Hydrogel Harnessing Intratumoral Microbiome and Microbiota-Related Immune Responses for Potentiated Colorectal Cancer Treatment

“…Extensive literatures have demonstrated that Alistipes promotes the development of colorectal cancer by activating the IL-6/STAT3 signaling pathway [ 64 ]. Helicobacter is involved in chronic inflammation, promoting colorectal carcinogenesis by deregulating intestinal immunity and inducing degradation of the mucosal microbiota [ 65 , 66 ]. Clostridia induces amino acid degradation in colorectal cancer [ 67 ].…”

Relationship between Helicobacter pylori infection and colorectal polyp/colorectal cancer

“…Ralser et al [ 11 ] discovered that in the Apc mutant mouse model, H. pylori infection recruited CD3+ T cells within the colon tissue epithelium, upregulated CD8+ T cells, and caused Treg cell loss and differentiation into potentially pathogenic Foxp3+ IL-17A+ T cells[ 43 ], resulting in a specific pro-inflammatory immune response. Furthermore, the research found that H. pylori might activate the STAT3 cancer pathway in colon cells, further blocking Treg cell infiltration[ 44 ], which was followed by elevated Ki67 expression and reduced intestinal barrier marker PAS[ 11 ]. This research also provides the first direct evidence of a causal link between H. pylori infection and CRC.…”

“…Recent study has revealed that H. pylori promotes the enrichment of Akkermansia spp. and Ruminococcus spp., which breakdown intestinal mucus, in the colon tissue of H. pylori -infected mice, resulting in a pro-inflammatory and pro-carcinogenic microbiota signature[ 11 ]. It is possible that H. pylori infection weakens the intestinal barrier.…”

“…Although most people with H. pylori infection are asymptomatic, long-term infection may cause chronic gastritis and is linked to a variety of non-gastric ailments, including atherosclerosis[ 4 ], type 2 diabetes[ 5 ], anemia[ 6 ], osteoporosis[ 7 ], and some immune-related disorders[ 8 ]. Furthermore, 1%-3% of those infected with H. pylori develop gastric cancer[ 9 ], and H. pylori infection is also strongly related with mucosa-associated lymphoid tissue lymphoma[ 10 ] and colorectal cancer (CRC)[ 11 ]. As a result, the World Health Organization’s International Cancer Research Centre designated H. pylori as a Class I biological carcinogen[ 12 ].…”