A Closer Look at Antidepressant–Microbiome Interactions: Is There Evidence for Bacterial Biotransformation?

A Closer Look at Antidepressant–Microbiome Interactions: Is There Evidence for Bacterial Biotransformation? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Closer Look at Antidepressant–Microbiome Interactions: Is There Evidence for Bacterial Biotransformation? Stefanie Malan-Müller, Fernanda Parraguez Contreras, Nto Johnson Nto, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8279190/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Antidepressants are among the most widely used neuropsychiatric drugs, yet their interactions with the gut microbiome remain mechanistically unresolved. Here, we synthesize evidence across microbial physiology, host metabolism, and in silico enzymatic predictions to delineate how selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) interface with bacterial systems. Although direct experimental confirmation of antidepressant biotransformation is lacking, convergent signals — induction of efflux pump genes, enhanced plasmid transfer, neurotransmitter modulation, transporter interference, and broad-spectrum duloxetine bioaccumulation — reveal multiple pathways through which these compounds reshape microbial function. Integrative enzyme analyses further identify a putative digallate acylhydrolase capable of biotransforming fluoxetine, providing the first mechanistically plausible candidate for SSRI metabolism by gut bacteria. We additionally map antidepressant-associated shifts in host tryptophan metabolites and systemic LPS levels, and identify bacterial taxa with functional potential across the indole, serotonin, and kynurenine pathways. Together, this review provides a unified mechanistic framework for antidepressant-microbiome interactions and outlines testable hypotheses toward microbiome-informed antidepressant strategies. Biological sciences/Computational biology and bioinformatics Biological sciences/Drug discovery Biological sciences/Microbiology Biological sciences/Neuroscience Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementarytablescombined20251204.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 09 Feb, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers invited by journal 02 Jan, 2026 Editor assigned by journal 23 Dec, 2025 Submission checks completed at journal 05 Dec, 2025 First submitted to journal 04 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8279190","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":588458807,"identity":"d56a2a5d-7792-4af3-a1b7-c3f9bbe33df7","order_by":0,"name":"Stefanie Malan-Müller","email":"","orcid":"","institution":"Complutense University of Madrid","correspondingAuthor":false,"prefix":"","firstName":"Stefanie","middleName":"","lastName":"Malan-Müller","suffix":""},{"id":588458808,"identity":"afb5fb1d-8874-4896-911f-3bc00197ae2e","order_by":1,"name":"Fernanda Parraguez Contreras","email":"","orcid":"","institution":"Vrije Universiteit 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