Berberine-microbiota interplay: orchestrating gut health through modulation of the gut microbiota and metabolic transformation into bioactive metabolites

Tessa Dehau; Marc Cherlet; Siska Croubels; Michiel Van De Vliet; Evy Goossens; Filip Van Immerseel

doi:10.3389/fphar.2023.1281090

Berberine-microbiota interplay: orchestrating gut health through modulation of the gut microbiota and metabolic transformation into bioactive metabolites

Front Pharmacol. 2023 Dec 7:14:1281090. doi: 10.3389/fphar.2023.1281090. eCollection 2023.

Authors

Tessa Dehau¹, Marc Cherlet², Siska Croubels², Michiel Van De Vliet³, Evy Goossens¹, Filip Van Immerseel¹

Affiliations

¹ Livestock Gut Health Team (LiGHT) Ghent, Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty Of Veterinary Medicine, Merelbeke, Belgium.
² Laboratory of Pharmacology and Toxicology, Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
³ Laboratory of Microbiology, Department of Biochemistry and Microbiology, Faculty of Sciences, Ghent University, Ghent, Belgium.

Abstract

Berberine is an isoquinoline alkaloid found in plants. It presents a wide range of pharmacological activities, including anti-inflammatory and antioxidant properties, despite a low oral bioavailability. Growing evidence suggests that the gut microbiota is the target of berberine, and that the microbiota metabolizes berberine to active metabolites, although little evidence exists in the specific species involved in its therapeutic effects. This study was performed to detail the bidirectional interactions of berberine with the broiler chicken gut microbiota, including the regulation of gut microbiota composition and metabolism by berberine and metabolization of berberine by the gut microbiota, and how they contribute to berberine-mediated effects on gut health. As previous evidence showed that high concentrations of berberine may induce dysbiosis, low (0.1 g/kg feed), middle (0.5 g/kg feed) and high (1 g/kg feed) doses were here investigated. Low and middle doses of in-feed berberine stimulated potent beneficial bacteria from the Lachnospiraceae family in the large intestine of chickens, while middle and high doses tended to increase villus length in the small intestine. Plasma levels of the berberine-derived metabolites berberrubine, thalifendine and demethyleneberberine were positively correlated with the villus length of chickens. Berberrubine and thalifendine were the main metabolites of berberine in the caecum, and they were produced in vitro by the caecal microbiota, confirming their microbial origin. We show that members of the genus Blautia could demethylate berberine into mainly thalifendine, and that this reaction may stimulate the production of short-chain fatty acids (SCFAs) acetate and butyrate, via acetogenesis and cross-feeding respectively. We hypothesize that acetogens such as Blautia spp. are key bacteria in the metabolization of berberine, and that berberrubine, thalifendine and SCFAs play a significant role in the biological effect of berberine.

Keywords: berberine; berberrubine; blautia; demethylation; gut microbiota; thalifendine.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Special Research Fund (BOF) of Ghent University for the GOA project “Elucidating the details of the interaction between specific nutrients-microbiota-intestinal health and the consequences for inflammatory diseases” under grant number [BOFGOA2019000203].