Commensal microbiota-derived metabolite agmatine triggers inflammation to promote colorectal tumorigenesis

ABSTRACT

Colorectal cancer (CRC), a malignant tumor worldwide, is associated with gut microbiota. The influence of gut microbe-derived metabolites on CRC has attracted a lot of attention. However, the role of immunity mediated by commensal microbiota-derived metabolites in tumorigenesis of CRC is not intensively explored. Here we monitored the gut microbial dysbiosis in CRC mouse model (Apc^Min/+ model) without dietary and pharmacological intervention, followed by characterized of metabolites enriched in CRC model mice. Profound changes of gut microbiome (bacteriome) were observed during intestinal disorders. Metabolomic profiling indicated that agmatine, derived from the gut bacteria i.e. Blautia, Odoribacter, Alistipes and Paraprevotella, could interact with Rnf128 to suppress the Rnf128-mediated ubiquitination of β-catenin to further upregulate the downstream targets of β-catenin including Cyclin D1, Lgr5, CD44 and C-myc, thus activating Wnt signaling. The activated Wnt signaling pathway promoted dysplasia of intestinal cells and inflammatory infiltration of lymphocytes via inducing the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) and downregulation of anti-inflammatory cytokine (IL-10), thereby contributing to colorectal carcinogenesis. Therefore, our study presented novel insights into the roles and mechanisms of gut microbiota in pathogenesis of CRC.

KEYWORDS:

• Gut microbiota
• colorectal cancer
• metabolite
• Wnt signaling
• immunity

Acknowledgments

This work was financially supported by National Key Research and Development Program of China (2023YFC2811503) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai) (SML2023SP236).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Xiaobo Zhang performed conceptualization, funding acquisition, project administration, supervision, writing and editing. Yu Lu carried out data curation, validation, formal analysis, methodology, validation, resources, software and writing. Aoxi Cui participated data curation, methodology, validation and resources.

Ethics statement

All animal studies were approved by the Institutional Animal Care and Use Committees of Zhejiang University (Approval No.14843) and were carried out according to the protocols approved by Institutional Animal Care and Use Committee (IACUC).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2348441

Additional information

Funding

This work was financially supported by National Key Research and Development Program of China (2023YFC2811503) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai) (SML2023SP236).