Dear Editor,
We sincerely appreciate the insightful editorial by Dr. Won and Dr. Suk discussing our recent work on microbiota-mediated berberine (BBR) metabolism in cholestatic liver disease (CLD) [
1]. Their thoughtful interpretation not only summarizes the major findings of our study but also situates them within the broader landscape of gut–liver axis research recently highlighted in
Clinical and Molecular Hepatology.
The editorial provides a comprehensive overview of the pathophysiology and clinical spectrum of CLD. Their summary accurately underscores the multifactorial nature of cholestasis, including intrahepatic and extrahepatic etiologies, and the substantial clinical burden ranging from progressive fibrosis to end-stage liver failure and hepatobiliary malignancy. This context highlights the pressing need for innovative therapeutic strategies beyond conventional bile acid–centered approaches.2 We are pleased that the editorial recognized the significance of our findings, demonstrating that gut microbiota–mediated conversion of BBR into dihydroberberine (dhBBR) exerts hepatoprotective effects by suppressing intestinal 5-HT production. The authors’ discussion of BBR’s historical use and its diverse pharmacologic properties provides valuable background for understanding the therapeutic potential of microbiota-dependent BBR metabolism. As highlighted in the editorial, BBR's dependence on microbial biotransformation is central to its biological efficacy, and our work advances this field by establishing a mechanistic link between microbial nitroreductase activity, enteroendocrine serotonin signaling, and cholestatic liver injury.
As the editorial summarized, oral BBR markedly attenuated BDL-induced liver injury, whereas intraperitoneal BBR exerted minimal benefit, clearly indicating that the therapeutic effect relies on gut-mediated metabolism. We appreciate the editorialists’ accurate description of our FMT and antibiotic depletion experiments, which demonstrated that transplantation of microbiota from BBR-treated mice was sufficient to restore hepatoprotection. These results reinforce the concept that microbially generated metabolites rather than BBR itself serve as the primary bioactive mediators of BBR’s beneficial effects in cholestatic liver injury.
The editorial emphasized our key conclusion that the gut microbiota is indispensable for transforming BBR into its bioactive metabolite dhBBR. As outlined by the authors, nitroreductase-producing taxa such as
Bacteroides and
Bifidobacterium—which are enriched in cholestatic settings—serve as primary microbial contributors to dhBBR production. This observation aligns with recent studies describing cholestasis-associated alterations in microbial enzymatic activity and bile acid metabolism that reshape microbial ecology and metabolic outputs [
3-
5].
We are also grateful for the editorial’s emphasis on the pathological relevance of the TPH1–5-HT–5-HTR axis. Previous studies have reported that dysregulated hepatic serotonin signaling contributes to cholestatic injury, fibrosis, and biliary proliferation through activation of MAPK-, STAT3-, and ROS-dependent pathways [
6]. Consistent with this evidence, our study identified dhBBR as an inhibitor of enterochromaffin cell–derived 5-HT production through a partially competitive interaction with TPH1. This reduction in intestinal 5-HT synthesis consequently diminishes hepatic 5-HT receptor activation by limiting the delivery of 5-HT to the liver via portal venous transport. We appreciate the authors’ recognition that targeting this enterohepatic serotonergic circuit introduces a novel mechanistic strategy beyond conventional bile acid–centered therapy [
2].
The editorial also thoughtfully highlighted the translational dimension of our work. Our pilot clinical trial showed that combining BBR hydrochloride with ursodeoxycholic acid (UDCA) improved liver enzyme profiles, lipid parameters, and circulating 5-HT levels compared with UDCA monotherapy. This perspective is well aligned with recent
Clinical and Molecular Hepatology publications that underscore the therapeutic potential of microbiota-directed strategies in liver diseases. These studies collectively indicate that microbial metabolites, commensal species, and probiotic strains can ameliorate cholestatic and metabolic liver dysfunction through defined host–microbe interactions [
7-
9]. We fully agree with the editorialists that larger, controlled trials are essential to validate dhBBR-based therapeutic strategies and to optimize dosing, safety, and patient selection.
We appreciate the authors’ constructive recommendations regarding future research directions. In particular, the call to address inter-individual variability in microbial BBR metabolism is especially relevant, as recent studies have demonstrated substantial heterogeneity in gut microbial composition among CLD patients [10–11]. Additionally, improving dhBBR bioavailability and delineating its interactions with hepatic metabolic and immune pathways remain important goals for translational advancement.
We thank the editorialists for their rigorous and balanced evaluation and for situating our findings within the evolving framework of microbiota-centered hepatology research. We hope that this exchange will stimulate further investigation into microbiota-dependent metabolic therapeutics for cholestatic liver disease.
FOOTNOTES
-
Authors’ contribution
Manuscript drafting: Shiming Yang. Manuscript edition and final approval: all authors.
-
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
cholestatic liver disease
REFERENCES
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