Inhibition of gut microbial β-glucuronidase effectively prevents carcinogen-induced microbial dysbiosis and intestinal tumorigenesis

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Title:	Inhibition of gut microbial β-glucuronidase effectively prevents carcinogen-induced microbial dysbiosis and intestinal tumorigenesis
Authors:	Cheng, Kai-Wen Tseng, Chih-Hua Chen, I. -Ju Huang, Bo-Cheng Liu, Hui-Ju Ho, Kai-Wen Lin, Wen-Wei Chuang, Chih-Hung Huang, Ming-Yii Leu, Yu-Lin Roffler, Steve R. Wang, Jaw-Yuan Chen, Yeh-Long Cheng, Tian-Lu
Contributors:	California Institute of Technology Kaohsiung Medical University Kaohsiung Municipal Ta-Tung Hospital I Shou University National Sun Yat Sen University Department of Pharmacy, Chia Nan University of Pharmacy & Science Academia Sinica - Taiwan
Keywords:	colorectal-cancer colon carcinogenesis mouse models sequences azoxymethane communities unifrac silva mice risk
Date:	2022
Issue Date:	2023-12-11 14:04:56 (UTC+8)
Publisher:	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Abstract:	The bidirectional interaction between carcinogens and gut microbiota that contributes to colorectal cancer is complicated. Reactivation of carcinogen metabolites by microbial beta-glucuronidase (beta G) in the gut potentially plays an important role in colorectal carcinogenesis. We assessed the chemoprotective effects and associated changes in gut microbiota induced by pre-administration of bacterial-specific beta G inhibitor TCH-3511 in carcinogen azoxymethane (AOM)-treated APC(Min/+) mice. AOM induced intestinal beta G activity, which was reflected in increases in the incidence, formation, and number of tumors in the intestine. Notably, inhibition of gut microbial beta G by TCH-3511 significantly reduced AOM-induced intestinal beta G activity, decreased the number of polyps in both the small and large intestine to a frequency that was similar in mice without AOM exposure. AOM also led to lower diversity and altered composition in the gut microbiota with a significant increase in mucindegrading Akkermansia genus. Conversely, mice treated with TCH-3511 and AOM exhibited a more similar gut microbiota structure as mice without AOM administration. Importantly, TCH-3511 treatment significant decreased Akkermansia genus and produced a concomitant increase in short-chain fatty acid butyrate-producing gut commensal microbes Lachnoospiraceae NK4A136 group genus in AOM-treated mice. Taken together, our results reveal a key role of gut microbial beta G in promoting AOM-induced gut microbial dysbiosis and intestinal tumorigenesis, indicating the chemoprotective benefit of gut microbial beta G inhibition against carcinogens via maintaining the gut microbiota balance and preventing cancer-associated gut microbial dysbiosis. Thus, the bacterial-specific beta G inhibitor TCH-3511 is a potential chemoprevention agent for colorectal cancer.
Relation:	PHARMACOLOGICAL RESEARCH, v.177, March 2022, 106115
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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