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Gut microbiota biotransformation of drug glucuronides leading to gastrointestinal toxicity: Therapeutic potential of bacterial β-glucuronidase inhibition in mycophenolate-induced enteropathy.
- Source :
-
Life sciences [Life Sci] 2024 Aug 15; Vol. 351, pp. 122792. Date of Electronic Publication: 2024 Jun 08. - Publication Year :
- 2024
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Abstract
- Aims: Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity.<br />Main Methods: By using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model.<br />Key Findings: We observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions.<br />Significance: Collectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.<br />Competing Interests: Declaration of competing interest There are no competing interests to declare.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Caco-2 Cells
Male
Immunosuppressive Agents pharmacology
Immunosuppressive Agents toxicity
Immunosuppressive Agents metabolism
Intestinal Diseases chemically induced
Intestinal Diseases drug therapy
Intestinal Diseases metabolism
Intestinal Diseases microbiology
Cell Proliferation drug effects
Glycoproteins
Mycophenolic Acid metabolism
Mycophenolic Acid pharmacology
Gastrointestinal Microbiome drug effects
Glucuronidase metabolism
Glucuronidase antagonists & inhibitors
Glucuronides metabolism
Biotransformation
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0631
- Volume :
- 351
- Database :
- MEDLINE
- Journal :
- Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 38857657
- Full Text :
- https://doi.org/10.1016/j.lfs.2024.122792