Berberine and Gut Microbiota Interactions in Treating Cholestatic Liver Disease Through the Serotonin Pathway
Nicole Maul
Study Objective
The objective of this study was to explore how berberine (BBR) and its active metabolite dihydroberberine interact with the gut bacteria to affect cholestatic liver disease (CLD), and to understand the role of serotonin in this process.
Key Takeaway
Berberine, metabolized by gut microbes into dihydroberberine, inhibits intestinal serotonin production, reducing liver injury and improving biochemical markers in CLD, revealing a novel gut-liver axis pathway. By inhibiting the activity of the tryptophan hydroxylase 1 (TPH1) enzyme and downregulating Tph1 transcription in gut enterochromaffin cells (ECs), thus ameliorating CLD by blocking 5-HT hydroxytryptamine receptor (5-HTR) signaling in the liver. Previous to this study, berberine and it’s pathway has been poorly understood.
Design
Randomized controlled trial with active control, the study was unblinded and did not include a placebo arm. Preclinical animal studies including mouse models and microbiota interventions.
Participants
Thirty three patients with CLD were randomized to receive either ursodeoxycholic acid (UDCA- 15 subjects) alone or UDCA plus berberine (treatment group- 18 subjects). Three mouse models were used, including bile duct ligation-induced, alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis, and mdr2-/- genetic models.
Intervention
Berberine hydrochloride tablets administered orally three times daily for fifteen days, in combination with standard UDCA therapy; oral feeding tube of berberine or dihydroberberine in mouse models.
Study Parameters Assessed
The study parameters assessed include serum biochemical liver markers (ALP, ALT, AST, GGT), serum and tissue serotonin (5-HT) levels, histopathological liver injury scores, gut microbiota composition, and enzyme activity assays.
The primary outcome the study was designed to assess was improvement in biochemical and histological indicators of cholestatic liver injury and reduction of serotonin signaling markers.
Key Findings
In the clinical trial: Patients receiving berberine plus UDCA showed a reduction in liver enzymes (GGT, ALP, ALT, and AST) compared to UDCA alone (p < 0.05, statistically significant).
Serum serotonin (5-HT) levels were decreased in the treatment group (p < 0.05, statistically significant).
In mouse models: Oral berberine and dihydroberberine treatment reduced histological liver necrosis scores and lowered serum markers of liver injury, including total bile acid (TBA), total bilirubin (TBIL) and direct bilirubin (DBIL) (p < 0.05, statistically significant).
Antibiotic-treated mice showed an attenuation of berberine’s protective effect, supporting its gut microbiota-dependent mechanism. Fecal microbiota transplantation from Berberine-treated mice improved liver injury scores and histology in recipient mice (p < 0.05, statistically significant).
This study demonstrated that dihydroberberine inhibits the enzyme tryptophan hydroxylase 1 (TPH1), reducing intestinal serotonin synthesis, a key factor in cholestatic liver damage.
Transparency
This study was funded by the National Natural Science Foundation of China. Authors declared no conflicts of interest.
Practice Implications & Limitations
Cholestatic liver disease (CLD) is a complex condition with limited effective treatment options. Current FDA-approved therapies, such as ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), provide some benefit but are often insufficient, leaving room for additional adjunctive approaches.¹ This study by Tu et al. presents evidence supporting berberine (BBR), a natural isoquinoline alkaloid, as a potential adjunct in managing CLD, particularly through its interaction with the gut microbiota and its influence on serotonin production pathways.²
For naturopathic and integrative practitioners, this study adds to the growing understanding of the gut-liver axis in health and disease. Berberine's effectiveness appears to depend on its microbial conversion into dihydroberberine (dhBBR), which inhibits tryptophan hydroxylase 1 (TPH1) in enterochromaffin cells, leading to reduced intestinal serotonin (5-HT) synthesis.³ Since elevated 5-HT contributes to liver fibrosis and inflammation, this identifies a molecular pathway worth considering in treatment.⁴ This mechanism fits with naturopathic perspectives that recognize the importance of gut microbiota.⁵
The findings also expand the conventional view of berberine, mostly known for glycemic control and metabolic effects, by highlighting a potential role in liver health through more complex biochemical interactions. However, several limitations should be kept in mind. The clinical trial involved only 33 patients over a 15-day period, which limits the ability to generalize results or evaluate longer-term outcomes. Larger, longer, and placebo-controlled studies will be needed to confirm these observations and establish optimal dosing.
While the mouse models used replicate key features of cholestatic injury and provide mechanistic insight, translating these findings to human disease is always a challenge. Variability in gut microbiota across individuals may affect berberine metabolism and clinical response, suggesting personalization may be important. Gut microbiome profiling could potentially improve treatment planning.²
The study did not assess potential interactions between berberine and other commonly prescribed medications in CLD or comorbid conditions. Given the complexity of its metabolism involving gut microbes, further investigation on drug-herb interactions is warranted.
Clinically, naturopaths may consider monitoring liver function tests and serotonin-related biomarkers to evaluate response and guide treatment adjustments. Patient education regarding berberine’s gut-dependent activity might help with adherence and managing expectations.
This study provides valuable insight into a gut microbiota-mediated mechanism of berberine action in CLD. While more research is needed, it offers a plausible biological rationale for integrating berberine in naturopathic care for cholestatic liver disease.
Author Conflict of Interest
Nicole Maul declares no conflicts of interest related to this work.
References
Tu D, Lu C, Guo J, et al. Gut microbiota-mediated berberine metabolism ameliorates cholestatic liver disease by suppressing 5-hydroxytryptamine production. Clin Mol Hepatol. 2026;32(1):221-238. doi:10.3350/cmh.2025.0577
Hasegawa S, Yoneda M, Kurita Y, et al. Cholestatic Liver Disease: Current Treatment Strategies and New Therapeutic Agents. Drugs. 2021;81(10):1181-1192. doi:10.1007/s40265-021-01545-7
Tu D, Lu C, Guo J, et al. Gut microbiota-mediated berberine metabolism ameliorates cholestatic liver disease by suppressing 5-hydroxytryptamine production. Clin Mol Hepatol. 2026;32(1):221-238. doi:10.3350/cmh.2025.0577
Roth W, Zadeh K, Vekariya R, Ge Y, Mohamadzadeh M. Tryptophan Metabolism and Gut-Brain Homeostasis. Int J Mol Sci. 2021;22(6):2973. Published 2021 Mar 15. doi:10.3390/ijms22062973
Ruddell RG, Oakley F, Hussain Z, et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol. 2006;169(3):861-876. doi:10.2353/ajpath.2006.050767
Yang S, Yu D, Liu J, et al. Global publication trends and research hotspots of the gut-liver axis in NAFLD: A bibliometric analysis. Front Endocrinol (Lausanne). 2023;14:1121540. Published 2023 Mar 9. doi:10.3389/fendo.2023.1121540
Nicole Maul
Nicole Maul holds a Master of Science in Clinical Research Administration and a Bachelor of Arts degree in Applied Linguistics. Originally from Washington state, she has lived in four countries, fostering a passion for travel, language learning, and cultural exploration. Nicole’s diverse background fuels her interest in integrative health, especially traditional and global healing modalities. She is committed to bridging research and holistic care to support patient-centered, evidence-informed naturopathic practice.