Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer

Lulu Sun, Yi Zhang, Jie Cai, Bipin Rimal, Edson R. Rocha, James P. Coleman, Chenran Zhang, Robert G. Nichols, Yuhong Luo, Bora Kim, Yaozong Chen, Kristopher W. Krausz, Curtis C. Harris, Andrew D. Patterson (), Zhipeng Zhang (), Shogo Takahashi () and Frank J. Gonzalez ()
Additional contact information
Lulu Sun: National Cancer Institute
Yi Zhang: Peking University Third Hospital
Jie Cai: National Cancer Institute
Bipin Rimal: Pennsylvania State University
Edson R. Rocha: Brody School of Medicine, East Carolina University
James P. Coleman: Brody School of Medicine, East Carolina University
Chenran Zhang: National Cancer Institute
Robert G. Nichols: Pennsylvania State University
Yuhong Luo: National Cancer Institute
Bora Kim: National Cancer Institute
Yaozong Chen: National Cancer Institute
Kristopher W. Krausz: National Cancer Institute
Curtis C. Harris: National Cancer Institute
Andrew D. Patterson: Pennsylvania State University
Zhipeng Zhang: Peking University Third Hospital
Shogo Takahashi: National Cancer Institute
Frank J. Gonzalez: National Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Bile salt hydrolase (BSH) in Bacteroides is considered a potential drug target for obesity-related metabolic diseases, but its involvement in colon tumorigenesis has not been explored. BSH-expressing Bacteroides is found at high abundance in the stools of colorectal cancer (CRC) patients with overweight and in the feces of a high-fat diet (HFD)-induced CRC mouse model. Colonization of B. fragilis 638R, a strain with low BSH activity, overexpressing a recombinant bsh gene from B. fragilis NCTC9343 strain, results in increased unconjugated bile acids in the colon and accelerated progression of CRC under HFD treatment. In the presence of high BSH activity, the resultant elevation of unconjugated deoxycholic acid and lithocholic acid activates the G-protein-coupled bile acid receptor, resulting in increased β-catenin-regulated chemokine (C-C motif) ligand 28 (CCL28) expression in colon tumors. Activation of the β-catenin/CCL28 axis leads to elevated intra-tumoral immunosuppressive CD25+FOXP3+ Treg cells. Blockade of the β-catenin/CCL28 axis releases the immunosuppression to enhance the intra-tumoral anti-tumor response, which decreases CRC progression under HFD treatment. Pharmacological inhibition of BSH reduces HFD-accelerated CRC progression, coincident with suppression of the β-catenin/CCL28 pathway. These findings provide insights into the pro-carcinogenetic role of Bacteroides in obesity-related CRC progression and characterize BSH as a potential target for CRC prevention and treatment.

Date: 2023
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DOI: 10.1038/s41467-023-36089-9

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