Gut microbial resistance and metabolism of selective serotonin reuptake inhibitors drive multidrug resistance and contribute to antidepressant tachyphylaxis.
Journal
Drug metabolism and disposition: the biological fate of chemicals
Journal Volume
54
Journal Issue
5
Start Page
Article number 100273
ISSN
1521-009X
Date Issued
2026-05
Author(s)
Cheng, Ming-Che
Lin, Hsiao-Ching
Liaw, Chia-Ching
Lin, Yu-Chi
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are among the most widely used antidepressant medications in modern clinical practice. However, the underlying mechanisms of the rapid onset of tolerance to antidepressants (antidepressant tachyphylaxis [ADT]) led by SSRIs are not well-investigated. To clarify the roles of the interaction between gut microbes and SSRIs in the development of ADT and other adverse effects, we isolated 4 sertraline (STR; an SSRI)-resistant microbial strains, one of which was identified as uropathogenic Escherichia coli (E coli G5100a). Through transcriptomic analysis and multidrug efflux pump antagonism assays, resistance-nodulation-division-type and partially ABC-type multidrug efflux pumps were confirmed as the primary mechanisms by which E coli G5100a resists STR toxicity. The upregulation of these genes also led to increased resistance to chloramphenicol, rifampicin, and β-lactam-type antibiotics. Furthermore, Global Natural Product Social Molecular Networking-based metabolite analysis and liquid chromatography-mass spectrometry profiling revealed that E coli G5100a metabolized approximately 25% of STR in the culture medium. Two major STR metabolites were isolated and structurally elucidated as STR ketone (1) and N-acetylsertraline (2) using NMR and mass spectrometry analyses. Using the DeePred-BBB model, we confirmed that none of the putative SSRI-related metabolites were able to pass through the blood-brain barrier. These findings suggest that STR may induce multidrug resistance in gut microbiota, potentially contributing to clinical SSRI-related side effects and ADT. This study provides a novel perspective on the origins of SSRI-induced side effects in clinical settings, offering new insights for the future development of central nervous system-targeted pharmaceuticals. SIGNIFICANCE STATEMENT: Selective serotonin reuptake inhibitors may alter the composition of the intestinal microbiota. Specific gut microbes are likely to express metabolic resistance genes in response to selective serotonin reuptake inhibitor induction. The potential mechanisms in the development of SSRI tolerance from the perspective of the gut microbiome were identified.
Subjects
Gut microbes
Metabolism
Multiple-drug resistance
Selective serotonin reuptake inhibitors
Sertraline
Type
journal article