The Effects of Berberine on the Gut Microbiome: A Critical Review
Berberine is an isoquinolone alkaloid with a distinctive yellow colour. It is an important constituent of several medicinal plants, including various species of Barberry (Berberis spp.), Golden Seal (Hydrastis canadensis), Chinese Goldthread (Coptis chinensis), and Phellodendron (Phellodendron amurense).1 Berberine has a broad spectrum of therapeutic activity and has shown benefit in a wide range of health conditions, including obesity, metabolic syndrome and diabetes, cardiovascular disease, hypertension and hyperlipidaemia, liver disease, kidney disease, bacterial infections, and diarrhoeal diseases.1,2 Due to its poor oral bioavailability and the chronic nature of many of these conditions, berberine is usually used at relatively high doses for longer periods of time.1,2 Coupled with its well-known antibacterial effects,2 this has raised some concerns that berberine could have negative effects on the gut microbiome.
Does berberine supplementation impact the microbiome?
These concerns were brought to centre stage by the 2020 PREMOTE study, which assessed the gut microbiome-related effects of berberine and probiotics in type 2 diabetes mellitus.3 After one week of gentamycin pre-treatment, 409 participants underwent randomisation to either berberine, probiotics, berberine plus probiotics, or placebo. The 12-week intervention assessed glycated haemoglobin (HbA1c) levels as the primary outcome. Additionally, through metagenomics and metabolomic studies, the researchers assessed changes in the microbiome over the course of the study. The results showed that the berberine group and the berberine plus probiotics group had significant improvements in HbA1c compared to placebo (p<0.001). Other metabolic parameters including fasting blood glucose, triglycerides and total cholesterol were similarly improved. It also found that berberine and berberine plus probiotics significantly altered the microbiome, suppressing numbers of some bacterial species, and enhancing the growth of others. Some readers expressed concerns that this indicates berberine is harmful to the microbiome. However, a closer examination of these results reveals that in fact, this microbiome-modulating effect may be the key to berberine’s efficacy in metabolic conditions. Berberine was found to suppress several bacterial strains which produce single sugars from fermenting polysaccharides or oligosaccharides, including Ruminococcus bromii. The authors showed that R. bromii produces the secondary bile acid deoxycholic acid (DCA),3 which negatively impacts glycaemic control by altering insulin signalling.4,5 This mechanism may explain the beneficial effect of berberine on glycaemic control. Additionally, berberine was found to increase beneficial microbial strains within the microbiota. The authors concluded that berberine supplementation beneficially modulated the microbiome, leading to the improvements in type 2 diabetes.3
Modulation of the microbiota: Good or bad? A review of reviews
Many other human and animal studies have investigated the effects of berberine on the microbiome. A 2022 review6 of ten in vivo studies found a clear impact of berberine on altering the structure of the entire microbiome, while also altering the abundance of specific bacteria in the gut, in metabolic disorders. Additionally, berberine strengthened intestinal barrier function, modulated systemic inflammation, improved bile acid signalling, and regulated the gut brain-axis, while attenuating metabolic endotoxaemia. These were highlighted as the strongest mechanisms in the effectiveness of berberine in metabolic disease.6
An additional 2022 systematic review7 of 35 studies expanded the scope by including in vivo and human clinical trials. It found that berberine improved the composition of the microbiota, decreased harmful bacteria and bacterial lipopolysaccharide (LPS), and increased the production of short chain fatty acids (SCFAs), particularly butyrate. The authors concluded that berberine is an effective prebiotic to modulate the gut microbiome and improve metabolic status.7
Interestingly a 2023 in vivo and in vitro study compared berberine to metformin in metabolic diseases, with both contributing to the modulation of the gut microbiome.8 In this study, berberine was found to increase the relative abundance of SCFA producing bacteria, aligning with the 2022 systematic review.7,8 Importantly, the regulation of the gut microbiome was a key factor in the pharmacodynamic effects of both berberine and metformin.8
Studies have shown that by modulating the microbiota, berberine also modulates the production of microbial-derived metabolites including SCFAs, bile acids, branched chain amino acids, and trimethylamine. These metabolites are known to have far-reaching effects on health throughout the body.9 Therefore, modulation of the microbiome may be the mechanism of action for berberine in a range of conditions, over and above metabolic conditions. Human studies have shown that berberine supplementation modulates the gut microbiota and thereby improves thyroid function in patients with Grave’s disease.10 Berberine also improved dysbiosis and altered the structure of the microbiome in patients with Parkinson’s disease. This was accompanied by a significant decrease in inflammatory markers.11 Finally, in addition to modulating the gut microbiome, preliminary studies suggest that berberine can modulate the oral microbiome12 and the vaginal microbiome13 with beneficial effects.
Is long-term supplementation of berberine safe?
A long-term study in 1108 colorectal cancer patients found that 600 mg per day of berberine taken for 24 months was safe, with no major adverse effects reported.14 Furthermore, a systematic review of berberine in cardiovascular disease found no safety concerns with the use of berberine at doses up to 1500 mg per day for up to 24 weeks.15 Minor adverse effects have been reported, primarily gastrointestinal complaints including diarrhoea, constipation, and abdominal pain. The risk of developing such side effects can be reduced by prescribing according to personalised medicine principles. This is a developing area of research known as precision medicine, assessing the individual’s genes, age, diet, body systems, microbiota, environment, and lifestyle, and adjusting treatment accordingly.9 Rather than prescribing berberine as an isolated constituent, naturopaths and herbalists typically prescribe berberine-containing herbs such as Phellodendron, which has a long history of safe traditional use.16
Conclusions
Numerous studies demonstrate that berberine supplementation does modulate the microbiome in a beneficial way, and that this may be a key mechanism whereby it exerts its therapeutic effects. Long-term use of relatively high doses has been shown to be safe with only mild adverse effects, which can be mitigated by utilising personalised medicine principles.
References
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