Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice
Year: 2022
Type: article
Abstract: 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.
Source: Scientific Reports
Authors: Marine P. M. Letertre, Aadra P. Bhatt, Michael Harvey, Jeremy K. Nicholson, Ian D. Wilson, Matthew R. Redinbo, Jonathan R. Swann
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,190
Funders: Crohn's and Colitis Foundation, National Institute for Health and Care Research, Imperial College London, Servier, National Institute for Health Research Southampton Biomedical Research Centre, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1399919057, Mechanisms to Explain Variation in Serum Low Density Lipoprotein Cholesterol Response to Dietary Saturated Fat, G2153958074, A metabonomic approach to identify biomarkers for bovine mycotoxicosis, Microbiome-Targeted Probes to Eliminate Chemotherapy-Induced GI Toxicity, Establishing MRC-NIHR Phenome Centre, a world leading high-throughput metabolic phenotyping centre for humanpopulation disease-risk biomarker discovery., A metabonomic approach to identify biomarkers for bovine mycotoxicosis, Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health, Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes, Do systemic metabolites drive the chondroprotective effects of the IL18-/- gut microbiome in osteoarthritis?, Investigating the influence of gut microbial metabolism on normal age-related cognitive decline, G7607493927, The effect of early-life prebiotic feeding on adult hippocampal function, central and peripheral metabonomics and microbial metagenomics, Gastroenterology Research Training, Cancer Center Support Grant
OpenAlex ID: W4306784408