Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer

• Published in: Nature communications Vol. 14; no. 1; pp. 755 - 18
• Main Authors: Sun, Lulu, Zhang, Yi, Cai, Jie, Rimal, Bipin, Rocha, Edson R., Coleman, James P., Zhang, Chenran, Nichols, Robert G., Luo, Yuhong, Kim, Bora, Chen, Yaozong, Krausz, Kristopher W., Harris, Curtis C., Patterson, Andrew D., Zhang, Zhipeng, Takahashi, Shogo, Gonzalez, Frank J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14/63; 38/91; 42; 631/67/1504/1885/1393; 631/67/580; 64; 64/60; 692/4028/67/1504/1885/1393; 82/1; 82/58; 96; 96/1; Amidohydrolases - genetics; Animals; Bacteroides; Bacteroides - genetics; Bacteroides - metabolism; beta Catenin - metabolism; Bile; Bile acids; Bile Acids and Salts; Bile salts; Body weight; Cancer; Carcinogenesis; Carcinogens; CD25 antigen; Chemokines; Colon; Colonic Neoplasms; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Deoxycholic acid; Diet; Feces; Foxp3 protein; High fat diet; Humanities and Social Sciences; Hydrolase; Immunosuppression; Lymphocytes T; Metabolic disorders; Mice; multidisciplinary; Obesity; Obesity - complications; Overweight; Salts; Science; Science (multidisciplinary); Therapeutic targets; Tumorigenesis; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36089-9

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 + T reg 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. Non-enterotoxigenic Bacteroides fragilis (NTBF) is abundant in colorectal cancer (CRC) patients and in a high-fat diet (HFD)-induced CRC model. Here the authors show that bile salt hydrolase-expressing NTBF is enriched in CRC patients with overweight and promotes tumor growth in an HFD-induced CRC mouse model.