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However, the key pathophysiological mechanisms of CLD remain elusive, and therapeutic efficacy is unsatisfactory.Methods: We administered berberine (BBR) or dihydroberberine (dhBBR) in bile duct ligation-, ANIT-, and mdr2&lt;sup&gt;-\/-&lt;\/sup&gt; CLD mouse models to evaluate the anti-CLD effect. We conducted fecal microbiota transplantation to determine the role of gut microbiota in BBR\u2019s effect. We conducted a randomized, controlled clinical trial to evaluate the effects of BBR in patients with CLD.Results: Oral BBR alleviates cholestatic liver injury in multiple mouse models. Gut microbes can transform BBR into dhBBR, which suppresses 5-hydroxytryptamine (5-HT) production in gut enterochromaffin cells by antagonizing tryptophan hydroxylase 1 (TPH1) activity and downregulating &lt;i&gt;Tph1&lt;\/i&gt; transcription. This further ameliorates CLD by interrupting the 5-HT\/5-HTR axis. A clinical study validated that BBR improved blood biochemical indicators in patients with CLD and decreased 5-HT levels.Conclusions: BBR is transformed by gut microbiota to ameliorate CLD via inhibiting 5-HT, suggesting potential novel strategies for further clinical use.<\/jats:p>","DOI":"10.3350\/cmh.2025.0577","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:26:40Z","timestamp":1760488000000},"page":"221-238","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Gut microbiota-mediated berberine metabolism ameliorates cholestatic liver disease by suppressing 5-hydroxytryptamine 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