Cholestatic liver disease (CLD) encompasses a spectrum of disorders characterized by impaired bile flow, resulting in the accumulation of bile constituents in the systemic circulation [
1]. Both intrahepatic and extrahepatic etiologies contribute to cholestasis, ultimately leading to injury of bile ducts and hepatocytes [
2]. The CLD can lead to a variety of clinical presentations, from fibrosis due to biliary obstruction to liver failure and hepatobiliary malignancy [
3,
4]. Despite its rising global prevalence, effective therapeutic strategies remain limited, underscoring the urgent need for novel treatments. In this context, Tu et al. [
5] recently demonstrated that gut microbiota-mediated metabolism of berberine (BBR) ameliorates CLD through suppression of 5-hydroxytryptamine (5-HT) production.
BBR is a quaternary protoberberine-type isoquinoline alkaloid derived from the roots and stem bark of several medicinal plants, including
Hydrastis canadensis, Berberis aristata, and
Berberis vulgaris [
6]. Historically, BBR has been widely used in Eastern medicine for its antimicrobial and antiprotozoal properties, particularly in the treatment of diarrhea and gastroenteritis [
7]. Beyond its antimicrobial effects, BBR exerts diverse disease-modifying actions, many of which are mediated through its interactions with the gut microbiota either by altering microbial composition or through biotransformation into bioactive metabolites [
8]. Based on these pharmacologic and physiological roles, Tu et al. [
5] investigated the ameliorating effects of BBR on CLD.
In their study, cholestatic liver injury was induced through bile duct ligation (BDL) in mice, and oral BBR administration significantly attenuated liver damage. In contrast, intraperitoneal BBR exerted minimal hepatoprotective effects, suggesting that its therapeutic action depends primarily on gut-mediated metabolism. Fecal microbiota transplantation and antibiotic cocktail experiments further strengthened this link, demonstrating that gut microbiota from BBR-treated animals or the presence of specific microbial populations was essential for BBR’s beneficial effects. These findings strongly indicate that BBR-derived metabolites, rather than BBR itself, play a pivotal role in hepatoprotection.
The authors focused on dihydroberberine (dhBBR), a major BBR metabolite generated by gut microbial nitroreductases. They found that nitroreductase-producing bacteria including
Bacteroides and
Bifidobacterium were enriched in BDL models, consistent with previous reports identifying species such as Bacteroides,
Staphylococcus aureus, Enterobacter cloacae, and
Enterococcus faecium as key nitroreductase producers [
8,
9]. This microbial enrichment provides a mechanistic basis for the enhanced conversion of BBR into dhBBR within the cholestatic gut environment.
To elucidate downstream mechanisms, Tu et al. [
5] performed untargeted metabolomic profiling of liver tissues, revealing significant alterations in the tryptophan metabolic pathway, particularly in relation to 5-HT synthesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis confirmed these findings. Prior studies have shown that upregulation of hepatic 5-HT receptors (5-HTR2A/2B/2C) exacerbates cholestatic injury in BDL and multidrug resistance protein (
mdr2) / mouse models [
10]. Activation of these receptors promotes oxidative stress and apoptosis through MAPK, STAT3, ROS, and PKA pathways [
11]. In the present study, dhBBR reduced hepatic 5-HT levels and decreased the number of ChgA
+/5-HT
+ enterochromaffin cells in the intestine. Mechanistically, dhBBR partially competes with tryptophan for binding to tryptophan hydroxylase 1 (TPH1), thereby inhibiting 5-HT biosynthesis. Collectively, these findings demonstrate that dhBBR mitigates cholestatic liver injury by targeting the TPH1–5-HT–5-HTR axis.
Finally, Tu et al. [
5] extended their findings into a randomized clinical trial in patients with CLD, where co-administration of BBR hydrochloride with ursodeoxycholic acid (UDCA) resulted in improved liver enzyme profiles, lipid parameters, and reductions in circulating 5-HT relative to UDCA monotherapy. These translational data highlight the therapeutic promise of BBR as an adjunct treatment for CLD.
In conclusion, this study elegantly demonstrates that the gut microbiota transforms BBR into dhBBR, a bioactive metabolite that attenuates cholestatic liver injury by suppressing intestinal and hepatic 5-HT synthesis and signaling. BBR thereby represents a promising candidate for microbiota-dependent therapy in CLD. Future work is needed to characterize inter-individual variability in microbial BBR metabolism, optimize dhBBR bioavailability, and elucidate its broader metabolic interactions. Larger preclinical and clinical studies will be essential to validate these findings and enhance their generalizability. Nevertheless, this work provides compelling evidence that targeting the enterohepatic 5-HT axis may serve as an innovative therapeutic strategy for CLD.
FOOTNOTES
-
Authors’ contribution
Sung-Min Won: Writing draft. Ki Tae Suk: Conceptualization, critical revision of the manuscript and supervision.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
5-hydroxytryptamine receptor
cholestatic liver disease
Kyoto Encyclopedia of Genes and Genomes
multidrug resistance protein
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Citations
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- Correspondence to editorial on “Gut microbiota-mediated berberine metabolism ameliorates cholestatic liver disease by suppressing 5-hydroxytryptamine production”
Dianji Tu, Cheng Lu, Bo Tang, Shiming Yang
Clinical and Molecular Hepatology.2026; 32(3): e358. CrossRef
