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

Cheng, Kai-Wen and Tseng, Chih-Hua and Chen, I.-Ju and Huang, Bo-Cheng and Liu, Hui-Ju and Ho, Kai-Wen and Lin, Wen-Wei and Chuang, Chih-Hung and Huang, Ming-Yii and Leu, Yu-Lin and Roffler, Steve R. and Wang, Jaw-Yuan and Chen, Yeh-Long and Cheng, Tian-Lu (2022) Inhibition of gut microbial β-glucuronidase effectively prevents carcinogen-induced microbial dysbiosis and intestinal tumorigenesis. Pharmacological Research, 177 . Art. No. 106115. ISSN 1043-6618. doi:10.1016/j.phrs.2022.106115.

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The bidirectional interaction between carcinogens and gut microbiota that contributes to colorectal cancer is complicated. Reactivation of carcinogen metabolites by microbial β-glucuronidase (βG) 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 βG inhibitor TCH-3511 in carcinogen azoxymethane (AOM)-treated APC^(Min/+) mice. AOM induced intestinal βG activity, which was reflected in increases in the incidence, formation, and number of tumors in the intestine. Notably, inhibition of gut microbial βG by TCH-3511 significantly reduced AOM-induced intestinal βG 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 mucin-degrading 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 βG in promoting AOM-induced gut microbial dysbiosis and intestinal tumorigenesis, indicating the chemoprotective benefit of gut microbial βG inhibition against carcinogens via maintaining the gut microbiota balance and preventing cancer-associated gut microbial dysbiosis. Thus, the bacterial-specific βG inhibitor TCH-3511 is a potential chemoprevention agent for colorectal cancer.

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Cheng, Kai-Wen0000-0001-9888-9773
Additional Information:© 2022 Elsevier. Received 1 November 2021, Revised 13 January 2022, Accepted 1 February 2022, Available online 3 February 2022, Version of Record 10 February 2022. We thank Dr. Chern-Hsiung Lai (Director of the Research & Diagnostic Laboratory for Anaerobic and Oral Microbiological, Kaohsiung Medical University, Taiwan) for providing the anaerobic workstation, Dr. Yu-Lun Kuo at BIOTOOLS Co., Ltd in Taiwan for kindly supporting analysis of NGS data, and Dr. Jia-Ming Chang at Development Center for Biotechnology in Taiwan for supporting pharmacokinetic study. This work was supported by grants from the Ministry of Science and Technology, Taipei, Taiwan (MOST 107-2320-B-037-024-MY3, MOST 109-2320-B-037-010-MY3, MOST 110-2320-B-214-008, MOST 110-2627-M-037-001); the National Health Research Institutes, Taiwan (NHRI-EX108-10729EI); the Ministry of Education, Taiwan (108RSB0029); the KMU-KMUH Co-Project of Key Research (KMU-DK109001) and Research Foundation (KMUTC109A03-1, KMU-DK109004, KMU-DK(B)111001, KMU-DK(B)111004, KMU-M111005, 110KK008) from Kaohsiung Medical University, Kaohsiung, Taiwan; the Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan (kmtth-110-036). This work was also supported partially by Kaohsiung Medical University Research Center Grant (Drug Development and Value Creation Research Center) (KMU-TC108A03, KMU-TC108A03-2, KMU-TC109A03-1). Data Availability. The raw sequence data of 16S rRNA gene sequencing generated and analyzed during the current study are available at NCBI under Bioproject PRJNA758380. Ethics approval and consent to participate All APC^(Min/+) mice experiments performed at the Animal Center of the Kaohsiung Medical University were approved by the Kaohsiung Medical University Institutional Animal Care and Use Committee. The pharmacokinetic experiments were conducted at Development Center for Biotechnology, Taipei, Taiwan proved by the Institutional Animal Care and Use Committee. CRediT authorship contribution statement. T.-L. Cheng and Y.-L. Chen conceived the project. K.-W. Cheng designed and performed experiments. C.-H. Tseng prepared and analyzed compounds. I.-J. Chen assisted in data analysis and manuscript preparation. B.-C. Huang, H.-J. Liu, K.-W. Ho, W.-W. Lin, C.-H. Chuang, M.-Y. Huang, Y.-L. Leu, and J.-Y. Wang assisted in eliminating problems during experiments and provided suggestions. K.-W. Cheng wrote the manuscript with the input from T.-L. Cheng and I.-J. Chen. S.R. Roffler edited the manuscript. The authors declare that they have no competing interests.
Funding AgencyGrant Number
Ministry of Science and Technology (Taipei)MOST 107-2320-B-037-024-MY3
Ministry of Science and Technology (Taipei)MOST 109-2320-B-037-010-MY3
Ministry of Science and Technology (Taipei)MOST 110-2320-B-214-008
Ministry of Science and Technology (Taipei)MOST 110-2627-M-037-001
National Health Research Institutes (Taipei)NHRI-EX108-10729EI
Ministry of Education (Taipei)108RSB0029
Kaohsiung Medical UniversityKMU-DK109001
Kaohsiung Medical UniversityKMUTC109A03-1
Kaohsiung Medical UniversityKMU-DK109004
Kaohsiung Medical UniversityKMU-DK(B)111001
Kaohsiung Medical UniversityKMU-DK(B)111004
Kaohsiung Medical UniversityKMU-M111005
Kaohsiung Medical University110KK008
Kaohsiung Municipal Ta-Tung Hospitalkmtth-110-036
Kaohsiung Medical UniversityKMU-TC108A03
Kaohsiung Medical UniversityKMU-TC108A03-2
Kaohsiung Medical UniversityKMU-TC109A03-1
Subject Keywords:Gut microbiota; Carcinogens; Gut microbial βG; Chemoprevention; Colorectal cancer
Record Number:CaltechAUTHORS:20220513-557966000
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Official Citation:Kai-Wen Cheng, Chih-Hua Tseng, I.-Ju Chen, Bo-Cheng Huang, Hui-Ju Liu, Kai-Wen Ho, Wen-Wei Lin, Chih-Hung Chuang, Ming-Yii Huang, Yu-Lin Leu, Steve R. Roffler, Jaw-Yuan Wang, Yeh-Long Chen, Tian-Lu Cheng, Inhibition of gut microbial β-glucuronidase effectively prevents carcinogen-induced microbial dysbiosis and intestinal tumorigenesis, Pharmacological Research, Volume 177, 2022, 106115, ISSN 1043-6618,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114748
Deposited By: George Porter
Deposited On:13 May 2022 22:28
Last Modified:13 May 2022 22:28

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