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Metformin (MTF) and berberine (BBR) share several therapeutic benefits in treating metabolic-related disorders. However, as the two agents have very different chemical structure and bioavailability in oral route, the goal of this study is to learn their characteristics in treating metabolic disorders. The therapeutic efficacy of BBR and MTF was systemically investigated in the high fat diet feeding hamsters and/or ApoE (-/-) mice; in parallel, gut microbiota related mechanisms were studied for both agents. We discovered that, although both two drugs had almost identical effects on reducing fatty liver, inflammation and atherosclerosis, BBR appeared to be superior over MTF in alleviating hyperlipidemia and obesity, but MTF was more effective than BBR for the control of blood glucose. Association analysis revealed that the modulation of intestinal microenvironment played a crucial role in the pharmacodynamics of both drugs, in which their respective superiority on the regulation of gut microbiota composition and intestinal bile acids might contribute to their own merits on lowering glucose or lipids. This study shows that BBR may be a good alternative for MTF in treating diabetic patients, especially for those complicated with dyslipidemia and obesity., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cardiovascular and metabolic disease (CMD) remains a main cause of premature death worldwide. Berberine (BBR), a lipid-lowering botanic compound with diversified potency against metabolic disorders, is a promising candidate for ameliorating CMD. The liver is the target of BBR so that liver-site accumulation could be important for fulfilling its therapeutic effect. In this study a rational designed micelle (CTA-Mic) consisting of α-tocopheryl hydrophobic core and on-site detachable polyethylene glycol-thiol shell is developed for effective liver deposition of BBR. The bio-distribution analysis proves that the accumulation of BBR in liver is increased by 248.8% assisted by micelles. Up-regulation of a range of energy-related genes is detectable in the HepG2 cells and in vivo. In the high fat diet-fed mice, BBR-CTA-Mic intervention remarkably improves metabolic profiles and reduces the formation of aortic arch plaque. Our results provide proof-of-concept for a liver-targeting strategy to ameliorate CMD using natural medicines facilitated by Nano-technology.

Short-chain fatty acids (SCFAs) of intestine microbial have caught accumulating attention for their beneficial effects on human health. Botanic compounds with low bioavailability such as berberine (BBR) and resveratrol might interact with intestinal microbial ecosystem and promote gut bacteria to produce SCFA, which contribute to their biological effects. In the present study, a comprehensive assay system was built to detect SCFAs production in intestinal bacteria, in which stringent anaerobic culture was applied for in vitro bacterial fermentation, followed by direct-injection GC detection (chemical detection) in combination with real time polymerase chain reaction (RT-PCR, biological detection). BBR was used as positive reference. The direct injection GC method was calibrated and successfully applied to analyze the concentration of SCFAs in gut microbiota and BBR was proved to be effective in the dose- and time-dependent up-regulation of SCFAs production. As compared to the saline group, the concentration of acetic acid, propionate acid and butyric acid (the main SCFAs in gut microbiota) were increased by 17.7%, 11.1% and 30.5%, respectively, after incubating intestinal bacteria with 20μg/mL BBR for 24h. The increase reached to 34.9%, 22.4% and 51.6%, respectively when the BBR was 50μg/mL. Additionally, consensus-degenerate hybrid oligonucleotide primers (CODEHOPs) were designed for the detection of acetate kinase (ACK), Methylmalonyl-CoA decarboxylase (MMD) and butyryl-CoA: acetate-CoA transferase (BUT), as they are the key enzymes in the synthetic pathway for acetic acid, propionate acid and butyric acid, respectively. After 24hr's incubation, BBR was shown to promote the gene expression of ACK, MMD and BUT significantly (86.5%, 27.2% and 60.4%, respectively, with 20μg/mL BBR; 130.2%, 84.2% and 98.4%, respectively, with 50μg/mL BBR), showing a solid biological support for the chemical detection. This comprehensive assay system might be useful in identifying SCFAs promoting agents with information on their mechanism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Berberine (BBR) clinically lowers blood lipid and glucose levels via multi-target mechanisms. One of the possible mechanisms is related to its effect on the short chain fatty acids (SCFAs) of the gut microbiota. The goal of this study is to investigate the therapeutic effect and mode of action of BBR working through SCFAs of the gut microbiota (especially, butyrate)., Methods: Gas chromatography (GC) was used to detect butyrate and other SCFAs chemically. The effect of BBR on butyrate production was investigated in vitro as well as in several animal systems. Microarrays were used to analyze the composition change in the intestinal bacteria community after treatment with BBR. BBR-induced change in the energy production and gene regulation of intestinal bacteria was examined in order to elucidate the underlying molecular mechanisms., Results: We show that oral administration of BBR in animals promoted the gut microbiota to produce butyrate, which then enters the blood and reduces blood lipid and glucose levels. Incubating gut bacterial strains in vitro with BBR increased butyrate production. Orally treating animals directly with butyrate reduced blood lipid and glucose levels through a mechanism different from that of BBR. Intraperitoneal BBR administration did not increase butyrate but reduced blood lipid and glucose levels, suggesting that BBR has two modes of action: the direct effect of the circulated BBR and the indirect effect working through butyrate of the gut microbiota. Pre-treating animals orally with antibiotics abolished the effect of BBR on butyrate. A mechanism study showed that BBR (given orally) modified mice intestinal bacterial composition by increasing the abundance of butyrate-producing bacteria. Furthermore, BBR suppressed bacterial ATP production and NADH levels, resulting in increased butyryl-CoA and, eventually, butyrate production via upregulating phosphotransbutyrylase/butyrate kinase and butyryl-CoA:acetate-CoA transferase in bacteria., Conclusion: Promotion of butyrate (etc) production in gut microbiota might be one of the important mechanisms of BBR in regulating energy metabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Gut dysbiosis has been found to be involved in the pathogenesis of energy metabolic disorders and might be a new strategy for these ailments. Berberine (BBR), a botanical medicine, shows therapeutic efficacy in patients with metabolic diseases. Numerous reports have shown BBR's modulating effect on gut microbiota, opening a new avenue to understand BBR's mechanism. In this study, a colon‐specific delivery system, BBR‐CS/PT‐NP, is investigated by the assembly of pH/gut microflora dual stimuli‐responsive nanoparticles for enhancing the interaction between BBR and gut microbiota. After oral administration, the delivering system remains stable in the stomach and small intestine, followed by a burst release of BBR after reaching the colon segment rich in intestinal bacteria. The enzymes produced by bacteria degrade the nanoparticle, causing direct exposure of BBR to gut microbiota. In the high fat diet‐induced obese hamsters, BBR‐CS/PT‐NP intervention inhibits weight‐gain and fat deposition, decreases plasma lipids and glucose levels, improves inflammation condition and insulin resistance, alleviates hepatic steatosis, at a level significantly higher than the pure BBR does. The mechanisms might be attributable to the enhanced interaction between BBR and the gut flora. The results provide a novel proof‐of‐concept for drug delivery targeting gut microbiota to ameliorate metabolic disorders. Gut dysbiosis is involved in the pathogenesis of energy metabolic disorders and represents a new strategy for treating these ailments. In this study, a pH/gut microflora dual stimuli‐responsive system, berberine (BBR)‐CS/PT‐NP with colon‐homing and microbiota‐targeting characteristics, is investigated to enhance the interaction between BBR and the gut microbiota. It provides a novel proof‐of‐concept for drug delivery targeting gut microbiota to ameliorate metabolic diseases. [ABSTRACT FROM AUTHOR]