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

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.

Differences in Metabolite Profiles of Dihydroberberine and Micellar Berberine in Caco-2 Cells and Humans—A Pilot Study

“…Previous research has suggested that the gut microbiome plays a significant role in the metabolism and potentiation of biological effects of berberine in humans [ 17 , 21 ]. One proposed mechanism for the blood glucose lowering effects of berberine is through its modulation of the gut microbiota [ 52 ], as demonstrated in animal models of diabetes [ 53 , 54 ].…”

“…While berberine has demonstrated the ability to improve the metabolic syndrome through modulation of gut microbiota and enhancement of the integrity of the intestinal barrier [ 16 , 19 , 20 ], the pharmacological activity of berberine is also mediated by its metabolites, which play crucial roles both in direct biological activities and in their interactions with the gut microbiome [ 21 ]. Notable among these metabolites are jatrorrhizine, columbamine, demethyleneberberine, berberrubine, and thalifendine, each contributing to the pharmacological effects of berberine through distinct mechanisms [ 22 ].…”

Microbiome and metabolome analyses reveal significant alterations of gut microbiota and bile acid metabolism in ETEC-challenged weaned piglets by dietary berberine supplementation

“…Furthermore, the potentially beneficial bacteria Blautia plays an important role in maintaining intestinal homeostasis and preventing inflammation ( Liu et al, 2021 ), and involved in bile acid metabolism due to its BSH activity ( Song et al, 2019 ). A recent study revealed that Blautia may be a key bacterium involved in BBR metabolism by conversion of BBR into a more readily absorbed methylated metabolite ( Dehau et al, 2023b ). These results confirmed the efficacy of BBR in ameliorating the gut microbiota imbalance induced by ETEC and enhancing the abundance of beneficial bacteria in piglets.…”

The gut-liver axis in fatty liver disease: role played by natural products

“…Research indicates that BBR exhibits low absorption into the bloodstream, with a significant accumulation in the intestines where it exerts its pharmacological effects locally. BBR affects the gut-liver axis at several interrelated levels, including modulation of the gut microbiota structure, alteration of gut microbe-derived metabolites, etc., which reduces • Increases the ability of short-chain fatty acids (SCFAs) to produce bacteria Frontiers in Pharmacology frontiersin.org microbial exposure and the pro-inflammatory environment of the liver and modulates liver metabolism (Peng et al, 2019;Dehau et al, 2023;Zhu and Li, 2023). Zhang et al (2015) collected feces from C57 mice fed a high-fat diet (HFD) for 10 weeks and collected feces from non-alcoholic hepatitis model mice fed BBR (100 mg/kg body weight) for eight consecutive weeks and performed 16sRNA sequencing.…”