Characterizing the metabolic effects of the selective inhibition of gut microbial beta-glucuronidases in mice

Letertre, Marine PM, Bhatt, Aadra P, Harvey, Michael, Nicholson, Jeremy K, Wilson, Ian D ORCID: 0000-0002-8558-7394, Redinbo, Matthew R and Swann, Jonathan R
(2022) Characterizing the metabolic effects of the selective inhibition of gut microbial beta-glucuronidases in mice. SCIENTIFIC REPORTS, 12 (1). 17435-.

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The hydrolysis of xenobiotic glucuronides by gut bacterial glucuronidases reactivates previously detoxified compounds resulting in severe gut toxicity for the host. Selective bacterial β-glucuronidase inhibitors can mitigate this toxicity but their impact on wider host metabolic processes has not been studied. To investigate this the inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine (UNC10201652, Inh 9) was administered to mice to selectively inhibit a narrow range of bacterial β-glucuronidases in the gut. The metabolomic profiles of the intestinal contents, biofluids, and several tissues involved in the enterohepatic circulation were measured and compared to control animals. No biochemical perturbations were observed in the plasma, liver or gall bladder. In contrast, the metabolite profiles of urine, colon contents, feces and gut wall were altered compared to the controls. Changes were largely restricted to compounds derived from gut microbial metabolism. This work establishes that inhibitors targeted towards bacterial β-glucuronidases modulate the functionality of the intestinal microbiota without adversely impacting the host metabolic system.

Item Type: Article
Uncontrolled Keywords: Animals, Mice, Bacteria, Morpholines, Glucuronidase, Xenobiotics, Gastrointestinal Microbiome
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 06 Jan 2023 11:08
Last Modified: 06 Jan 2023 11:08
DOI: 10.1038/s41598-022-21518-4
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