ORIGINAL RESEARCH article
Front. Immunol.
Sec. Microbial Immunology
This article is part of the Research TopicCommunity Series in Epigenetics in the microbiome-host crosstalk: from mechanisms to Therapeutics: Volume IIView all articles
Bacteroides ovatus-derived N-methylserotonin inhibit colorectal cancer via the HTR1D-mediated cAMP-PKA-NF-κB signaling axis
Provisionally accepted
- 1Youjiang Medical University for Nationalities, Baise, China
- 2University of Rochester, Rochester, United States
- 3Nanjing First Hospital, Nanjing, China
- 4Soochow University, Taipei City, Taiwan
- 5Inner Mongolia Medical University, Hohhot, China
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Abstract Objective: To analyze differences in gut microbiota composition, metabolites, and metabolic pathways between healthy individuals and colorectal cancer (CRC) patients, and to investigate the inhibitory effects of N-methylserotonin (NMS) produced by Bacteroides ovatus (B.o) from orange fiber on CRC progression and its underlying mechanisms. Methods: (1) Fecal samples from CRC patients (n=26) and healthy controls (n=20) were collected for metagenomic sequencing and untargeted metabolomics analysis; (2) The ability of B.o to produce NMS from orange fiber was validated in vitro; (3) A CRC mouse model was established using azoxymethane (AOM)/dextran sulfate sodium (DSS) induction, followed by evaluation of body weight, rectal bleeding, colorectal length, tumor number, and intestinal barrier function; (4) Network pharmacology, molecular docking, and western blot analysis were combined to verify the mechanism of action; (5) 16S rRNA sequencing was performed to analyze gut microbiota changes. Results: (1) CRC patients showed significantly increased metabolic pathways including glycolysis, methane metabolism, beneficial amino acid degradation, and linoleic acid degradation, along with significantly decreased B.o abundance and NMS levels, which were positively correlated; (2) NMS significantly inhibited CRC cell proliferation, migration, and invasion, while promoting apoptosis; (3) Combined treatment with B.o and orange fiber or NMS alone reduced tumorigenesis and improved intestinal barrier function; (4) Mechanistic studies revealed that these effects could be mediated through downregulation of 5-hydroxytryptamine receptor 1D (HTR1D) expression and inhibition of the cAMP/PKA/IκBα/NF-κB pathway; (5) The treatments optimized gut microbiota structure and metabolite composition. Conclusion: B.o and its metabolite NMS possibly inhibit CRC progression by modulating the HTR1D-mediated cAMP/PKA/NF-κB signaling pathway, while improving gut microbiota structure, providing a novel therapeutic target for CRC prevention and treatment.
Keywords: N-methylserotonin, Bacteroides ovatus, colorectal cancer, Gut Microbiota, Metabolites
Received: 01 Sep 2025; Accepted: 30 Oct 2025.
Copyright: © 2025 He, Jiaqi, Qu, Zhang, Fan, Lin, Huang, Liu and Jia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yanqiang Huang, 00435@ymcn.edu.cn
Yan Liu, 68269588@qq.com
Lizhou Jia, jlz@immu.edu.cn
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