Dysbiosis, diabetes, obesity, hypercholesterolemia, hyperlipidemia, and inflammatory bowel disease.

Mechanism of Action

Berberine is a compound found in the protoberberine group of isoquinoline alkaloids, and is considered the major active component present in several plant species.1 Besides antioxidant, antimicrobial, and anti-inflammatory effects,2 recent studies have shown that berberine and its derivatives have significant biological effects upon the gastrointestinal system and other metabolic functions through modulation of the gut microbiome.

Studies have shown that the diversity and composition of the gut microbiome are altered in metabolic diseases.3 The importance of the gut microbiome in relation to drug response is now widely recognized, and orally administrated herbs and drugs can affect the microbiota and produce metabolites that are different from those generated by the host, and which possess novel features and bioactivities.4,5 For example, through modulation of the gut microbiota berberine has been reported to have antidiabetic effects, and to prevent hypercholesterolemia by both decreasing cholesterol absorption from the intestine and stimulating bile acid synthesis.6 By regulating bacterial fermentation in the intestines, berberine offers an approach to treating multiple disease states, and can be considered a multi-target agent with significant advantages.7

Berberine has been also found to affect specific bacterial species both in vitro and in vivo, including Bifidobacterium longum, Bifidobacterium bifidum, Clostridium perfringens, and Clostridium paraputrificum.8,9,10 It may also improve colitis by inhibiting the growth of gram-negative intestinal bacteria, such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis.11 Besides repressing or killing harmful gut bacteria, berberine has some positive effect on beneficial gut microbiota, such as Bifidobacterium adolescentis and Lactobacillus acidophilus.2

Several studies have shown that berberine may modulate the gut microbiota through enriching short-chain fatty acid (SCFA)-producing bacteria and reducing microbial diversity. This in turn inhibits dietary polysaccharide degradation and decreases caloric intake in the gut, which may improve energy metabolism and intestinal health; anti-inflammatory effects; and immune regulatory effects.12,14,15 SCFAs are small molecular weight compounds derived from intestinal microbiota through the bacterial fermentation of fiber from the diet.16 The major SCFAs are acetate, propionate, and butyrate. Among these, butyrate is considered a primary energy source, and has been widely documented in regards to its role in human health.17 Bacterial butyrate is mainly synthesized through the acetyl CoA-butyryl CoA butyrate pathway, in which the key enzymes are regulated based on levels of ATP and NADH.18,19

An animal study showed that oral administration of berberine enriched butyrate-producing bacteria in the gut through the acetyl CoA-butyryl CoA butyrate pathway, promoting the gut microbiota to synthesize more butyrate, which resulted in a reduction in blood lipid and glucose levels. Microarrays were used to analyze the composition change in the intestinal bacteria community after treatment with berberine. The authors concluded that berberine may clinically lower blood lipid and glucose levels via multi-target mechanisms, with one of the possible mechanisms being related to its effect on the SCFAs of the gut microbiota.20

Another study looked at the effects of berberine on the hormonal pathways of the microbiota–gut–brain axis to see if it could improve the metabolic status of high fat-fed rats. Eighteen rats were randomized to three groups, one of which was fed a normal diet (containing 10% fat), and the other two were fed high fat diets (containing 40% fat) for 4 months. After this period, one of the high fat groups was given 150 mg/kg/day berberine chloride, while the other group continued on the high fat diet alone for 4 months. Blood samples were collected at months 0, 4, and 8 to look at insulin, lipids (e.g., triglycerides, total cholesterol, free fatty acid and low-density lipoprotein cholesterol), and brain–gut peptides (including GLP-1, neuropeptide Y, and orexin A). Gene sequencing was used to detect any changes to the gut microbiota. When compared with the normal diet-fed rats, those fed a high fat diet over 4 months showed significant body weight increase, whereas the body weight of the rats given berberine plus the high fat diet was attenuated. Moreover, their plasma lipid profiles revealed that berberine could effectively decrease elevated low density lipoprotein and total cholesterol levels, and trends of improved insulin resistance and decreased endogenous glucose production were observed. Serum triglyceride and free fatty acid levels were found to be comparable between both groups. Additionally, the microbiota–gut–brain axis was found to be modulated by berberine, including structural and diversity changes of the gut microbiome and a significant decrease in its species diversity. Berberine was associated with elevated serum GLP-1 and neuropeptide Y, and with decreased orexin A levels. Glucagon-like peptide-1 receptor mRNA was also found to be up-regulated, and ultrastructural improvements to the hypothalamus were noted (i.e., berberine was found to reverse structural distortion and swelling of cells cause by high fat feeding). The authors concluded that berberine improved metabolic disorders induced by a high-fat diet, and could reduce weight gain though modulation of the microbiota–gut–brain axis.21

Another study which looked at the hypolipidemic effect of berberine on diet-induced hyperlipidemic rats found that structural modulation of the gut microbiota occurred, and that the changes might have contributed towards enhanced energy metabolism. According to the alterations in metabolites from different types of samples and gut microbiota structure, berberine was determined to partially recover both metabolism dysfunction and intestinal environment through several metabolic pathways including glycolysis and TCA cycle β-oxidation of fatty acids; synthesis of fatty acid and cholesterol; amino acid metabolism; vitamin B6 metabolism; and secondary bile acid biosynthesis, as well as modulating the microbiota.22,23

The gut microbiome plays an important role in bile acid (BA) metabolism. BAs are known to regulate blood levels of triglycerides, cholesterol, glucose, and energy homeostasis. One study in mice suggested that at various doses, berberine had effects on modulating gut microbiota, as well as host BA metabolism and related genes. Specifically, Bacteroides spp., which deconjugate taurine-conjugated BAs, were enriched by berberine. This may have resulted in more rapid deconjugation of BAs in the intestine, thus leading to decreased amounts of BAs in the serum. In addition, Bacteroides were enriched exclusively in the terminal ileum and large intestine of mice treated with the higher doses of berberine, while Ruminococcus was decreased in the same areas. The authors concluded that various doses of berberine have effects on BA metabolism and signaling pathways, as well as gut microflora.24

Evidence-Based Research

Numerous biological activities of berberine have been reported in the last two decades, and at least a hundred clinical trials have been conducted. However, most studies that explored the effect of berberine on the microbiome have been in animal models.

One small clinical trial examined which bacterial species may be of primary importance in influencing blood concentrations of berberine. Ten healthy African males were compared to ten healthy Chinese males to explore possible mechanisms for differences in response to berberine (including mode of birth, age, diet, race, the environment, disease, and history of antibiotic use). The relationship of their individual gut microbiota was compared using fecal analysis with blood concentrations of berberine. Each participant provided a fecal sample and then took a single 600-mg dose of berberine. Blood samples were taken at regular intervals over the course of 12 hours. Results showed significant differences in the blood absorption and pharmacokinetic characteristics of berberine between groups, with differences being largely dependent on variations in gut microbiota, and their corresponding intestinal metabolic capacities. For example, one group showed a higher abundance of the bacterial genus Bacteroides (suggesting a healthy normal gut microbiota, as this genus is largely associated with the production of SCFAs). A higher abundance of these bacteria is considered responsible for the metabolism of berberine, and thus accounts for better metabolic capacities and higher metabolites in the gut. The authors concluded that significant pharmacokinetic differences of berberine observed between groups was partly attributable to variations in gut microbiota and their corresponding metabolic capacities.25

Safety in Pregnancy and Breastfeeding

There have been no investigations into the use of berberine in pregnancy and lactation to date. Most plants that contain berberine are considered emmenagogues/uterine stimulants, and have the ability to displace bilirubin so they are best avoided in both pregnancy and lactation.26

General Safety

Berberine is generally considered safe and the incidence of side effects is low, with no serious or life-threatening adverse reactions documented. Berberine may cause side effects related to its impact on bowel motility including abdominal pain, distention, nausea, vomiting, and constipation. The incidence of side effect appears to be dose-related, with higher doses resulting in a greater likelihood of side effects, such as low blood pressure, dyspnea, and flu-like symptoms.27,28


Berberine is generally considered safe up to 200–300 mg TID. Use caution if exceeding 1 g per day for longer than 3 months.29

Traditional Uses

Berberine is the principal component of many popular medicinal plants (e.g., in the genera Berberis, Coptis and Hydrastis among others) with a history of thousands of years of usage in traditional Chinese and Native American medicine.

Berberine was traditionally used mainly as an antimicrobial for various kinds of gastrointestinal inflammation. Many herbs containing berberine are known as therapies for treating gastrointestinal diseases, such as acute gastroenteritis, cholera, and dysentery. They were also used topically for various skin diseases.

Berberine has long been used as a natural dye due to its bright yellow color.

Berberine was first isolated in 1917 from goldenseal (Hydrastis canadensis).


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2 Am J Chin Med. 2014;42(5):1053–70. Effects of berberine in the gastrointestinal tract – a review of actions and therapeutic implications. Chen C, et al.

3 Nature. 2012;489:242–9. Functional interactions between the gut microbiota and host metabolism. Tremaroli V, Backhed F.

4 Int J Pharm. 2008;363:1–25. The gastrointestinal microbiota as a site for the biotransformation of drugs. Sousa T, et al.

5 Sci Rep. 2015;5:12155. Transforming berberine into its intestine-absorbable form by the gut microbiota. Feng R, et al.

6 ISME J. 2015;9:552–62. Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula. Xu J, et al.

7 Sci China Life Sci. 2015;58:854–9. Learning from berberine: treating chronic diseases through multiple targets. Yao J, Kong W, Jiang J.

8 PLoS One. 2014;9(5):e97514. Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity. Sun N, et al.

9 J Agric Food Chem. 1999;47(3):934–8. Growth-inhibiting effects of Coptis japonica root-derived isoquinoline alkaloids on human intestinal bacteria. Chae S, et al.

10 Arzneimittelforschung. 1961;11:450–4. The effect of berberine chloride on the intestinal flora of infants. Homma N, et al.

11 Folia Microbiol (Praha). 2002;47(4):375–8. Antimicrobial activity of berberine–a constituent of Mahonia aquifolium. Cernáková M, Kostálová D.

12 J Clin Invest. 2011;121:2126–32. Gut microbiome, obesity, and metabolic dysfunction. Tilg H, Kaser A.

14 Nature. 2009;461(7268):1282–6. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Maslowski K, et al.

15 Br J Nutr. 2008;100(2):297–305. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Suzuki T, et al.

16 Cell Host Microbe. 2013;14:582–90. Microbial modulation of energy availability in the colon regulates intestinal transit. Wichmann A, Allahyar A, Greiner TU, Plovier H, Lundén GÖ, Larsson T, et al.

17 Nat Immunol. 2011;12:5–9. Diet, gut microbiota and immune responses. Maslowski KM, Mackay CR.

18 J Bacteriol. 2004;186:2099–106. Restricted distribution of the butyrate kinase pathway among butyrate-producing bacteria from the human colon. Louis P, Duncan SH, McCrae SI, Millar J, Jackson MS, Flint HJ.

19 J Bacteriol. 1994;176:6433–8. Regulation of Clostridium acetobutylicum metabolism as revealed by mixed-substrate steady-state continuous cultures: role of NADH/NAD ratio and ATP pool. Girbal L, Soucaille P.

20 Metabolism. 2017;70:72–84. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Wang Y, et al.

21 Obes Facts. 2016;9(6):365–78. Modulation of microbiota-gut-brain axis by berberine resulting in improved metabolic status in high-fat diet-fed rats. Sun H, et al.

22 J Transl Med. 2016;14(1):237. Integrative analysis of metabolome and gut microbiota in diet-induced hyperlipidemic rats treated with berberine compounds. Li M, et al.

23 PLoS One. 2011;6(9):e24520. Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6J mice. Xie W, et al.

24 BMC Complement Altern Med. 2016;16(1):394. Dose-response effect of berberine on bile acid profile and gut microbiota in mice. Guo Y, et al.

25 Sci Rep. 2016;6:27671. Significant pharmacokinetic differences of berberine are attributable to variations in gut microbiota between Africans and Chinese. Alolga R, et al.

26 Biol Neonate. 1993;63(4):201–8. Displacement of bilirubin from albumin by berberine. Chan E.

27 J Ethnopharmacol. 2015;161:69–81. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. Lan J, et al.

28 Effect of Berberine on Blood Glucose, Blood Lipid and Serum Adiponect in of Primary Type 2 Diabetes Mellitus Patients (M.S. thesis). Shanxi Medical University; 2008. Ren Y.

29 Sci Rep. 2015;5:14405. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Zhang W, et al.