<i>Clostridium butyricum</i>, a Butyrate-Producing Probiotic, Inhibits Intestinal Tumor Development Through Modulating Wnt Signaling and Gut Microbiota

Abstract

Background: Gut microbiota dysbiosis is closely involved in intestinal carcinogenesis. A marked reduction of butyrate-producing bacteria has been reported in patients with colorectal cancer (CRC), nevertheless, the potential benefit of supplement of butyrate-producing bacteria against intestinal tumor development has not been fully investigated. Methods: The effects of Clostridium butyricum (C. butyricum, one of the clinically commonly used butyrate-producing bacteria) on CRC cells were examined. Apcmin/+ mice were fed a basal diet (BD) or high-fat diet (HFD) with or without C. butyricum (2×109 CFU 3-times a week) by gavage for 12 weeks. Human colonic tissues were collected to evaluate butyric acid recognition receptors, namely G-protein coupled receptors (GPRs) in relation to CRC. Findings: C. butyricum significantly inhibited HFD-induced intestinal tumor development in Apcmin/+ mice. Moreover, decreased proliferation and increased apoptosis were found in intestinal tumor cells treated with C. butyricum. Additionally, C. butyricum suppressed Wnt/β-catenin signaling pathway. C. butyricum modulated gut microbiota composition, which decreased some pathogenic bacteria and bile acids (BAs)-biotransforming bacteria, and increased some beneficial bacteria including short-chain fatty acids (SCFAs)-producing bacteria as shown by Illumina 16S rRNA sequencing. Accordingly, C. butyricum decreased fecal secondary BAs contents, increased caecal SCFAs quantities, and activated butyric acid recognition receptors, GPR43 and GPR109A. Clinically, we also observed that the expression of GPR43 and GPR109A was gradually down-regulated from human normal colonic tissue, adenoma, to carcinoma. Interpretation: Our results showed that C. butyricum could inhibit intestinal tumor development via modulating Wnt signaling and gut microbiota, suggesting the potential efficacy of butyrate-producing bacteria against CRC. Funding Statement: This study is supported by the grants (81570478, 81741075, and 81700456) from the National Natural Science Foundation of China, the grant (17JCYBJC24900) from Natural Science Foundation of Tianjin, the grant (2019M651049) from Postdoctoral Science Foundation of China, and the grant (2018242755) from Medical and Health Science and Technology Project of Zhejiang. Declaration of Interests: The authors declare no conflicts interest. Ethics Approval Statement: The written informed consents were obtained from all individuals prior to participation, and the study was approved by the Ethics Committee of General Hospital, Tianjin Medical University, China.