Berberine: New Research on Mechanisms Via Which This Alkaloid May Impact Metabolic and Cardiovascular Health
By Carrie Decker, ND
Berberine, an orangish-yellow alkaloid found at high levels in the bark and root structures of plants including Oregon grape (Mahonia aquifolium), goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), and Chinese goldthread (Coptis chinensis), has a broad and wide history of use. Oregon grape, a North American source of this alkaloid, was used by the native inhabitants and European colonists in the Pacific Northwest as a blood toner, an antimicrobial, and to ease digestive distress.(1) As a bitter tonic, the extract from the roots and bark of these herbs was used to stimulate digestion, while its antimicrobial properties were taken advantage of both topically and internally.(2) Chinese goldthread, known as duǎn è huánglián, is one of the 50 fundamental herbs in traditional Chinese medicine,(3) where its bitter and cold properties are used to influence conditions of the Heart, Large Intestine, Liver, and Stomach.
In the digestive system, berberine exerts a multitude of actions. Berberine acts as an antimicrobial, having both a direct bactericidal effect as well as decreasing bacterial adherence to mucosal epithelial surfaces.(4,5) Berberine also directly influences intestinal permeability, improving tight junction integrity.(6,7) Berberine has evidence of exerting a tonifying effect on gastrointestinal motility – increasing motility and contractility in states of hypofunction, and relaxing the system when it is in an excessively contractile state.(8) Berberine has an antinociceptive effect, which may be in part due to its impact on contractility, or mediated via its interactions with the endogenous opioid system,(9) or via nitric oxide synthesis.(10) Berberine increases gut production of short chain fatty acids (SCFAs), in particular butyrate.(11) Butyrate has an anti-inflammatory effect in the colon, which may play a role not only in digestive disorders, but neurological and metabolic conditions as well.(12)
Because of its low bioavailability in its non-transformed state,(13) much of the research surrounding berberine has looked at the impact on the gut. The gut microbiota also plays a significant role in the absorption of berberine, as it transforms it to dihydroberberine, which has a five-fold increase in absorption over that of berberine.(14) Dihydroberberine then oxidizes back to berberine in the intestinal tissue and enters the blood. One cautionary note which must be remembered in practice is that berberine, at commonly used doses, moderately inhibits cytochrome P450 3A4 (CYP3A4), CYP2D6, and CYP2C9,(15,16) which may lead to increased levels of commonly used medications including lovastatin, clarithromycin, sildenafil, losartan, venlafaxine, and metoprolol, as well as many others.
Metabolic Balance and Healthy Cardiovascular Function: An Akkermansia Effect?
One type of bacteria in the gut that has been shown to impact metabolic balance and cardiovascular health is Akkermansia muciniphila.This gram-negative bacteria feeds on mucin, as well as certain sugars including N-acetylglucosamine, N-acetyl-galac-to-samine, and glucose.(17) Although A. muciniphila represents only a small fraction (3 to 5 percent) of the bacteria in the gut, the impact it may have on metabolism is significant. Reduced levels of A. muciniphila have been observed in patients with impaired glucose metabolism and obesity,(18,19) while higher levels of the genus Akkermansia have been found in athletes and individuals with a low body mass index (BMI).(20)
In mice, supplementation with A. muciniphila reduced weight gain and fat mass, and improved glucose tolerance and insulin sensitivity.(21) In one mouse study, excess weight due to high fat diet (HFD) feeding was reduced by more than half when supplemented with this bacterium. A. muciniphila may have this impact on metabolism by the reduction of chronic low-grade inflammation, as these changes were observed in conjunction with decreased lipopolysaccharide (LPS) signalling and increased anti-inflammatory factors such as α-tocopherol and β-sitosterol. Administration of A. muciniphila also has been shown to increase the intestinal levels of endocannabinoids, the endogenous cannabinoids produced by the body, which play a role in controlling inflammation, the gut barrier, and gut peptide secretion.(22) A. muciniphila also was shown to reduce the development of atherosclerosis, improving gut tight junction integrity, and attenuating LPS-induced inflammation.(23)
Both metformin and berberine have been shown to increase levels of Akkermansia spp., with both treatments increasing the number of mucin-producing goblet cells that produce the substrate (mucin) that serves as food for this bacterium.(24,25) Along with this finding, berberine was shown to improve HFD-induced atherosclerosis in the standard mouse model where development of atherosclerotic disease is inevitable, reducing inflammation systemically and in the atherosclerotic lesions.
Berberine and Blood Vessel Function
Endothelial dysfunction is one contributing factor that leads to increased blood pressure and cardiovascular disease. There are many different facets of dysfunction which include diminished vasodilation in response to stimulation, increased leukocyte (white blood cell) adhesion, and frequently, increased platelet activation.(26) Collectively, these factors contribute to atherosclerosis and cardiovascular disease in addition to an increase in blood pressure. Endothelial dysfunction has also been observed in polycystic ovarian syndrome, migraines, and the vascular complications associated with diabetes.(27-29) Increased proinflammatory cytokines and decreased adiponectin (a hormone produced by adipose tissue) levels both contribute to altered endothelial homeostasis.(30)
Berberine increases activation of adenosine monophosphate–activated protein kinase (AMPK), a fuel-sensing enzyme that is present in all mammalian cells. When activated, AMPK stimulates energy-generating processes within the cell such as glucose uptake and decreases energy consuming processes such as lipid synthesis, reducing blood sugar and cholesterol production.(31,32) AMPK is also present in the endothelial cells of the blood vessels, and promotes normal function via anticontractile, anti-inflammatory, and antiatherogenic actions.(33) Consumption of HFD contributes to endothelial dysfunction in part via downregulation of the AMPK pathway.(34)
Although hyperglycemia leads to endothelial dysfunction, berberine has been observed to alleviate this negative effect and promote normal vasodilation via the AMPK pathway.(35) Via activation of AMPK, berberine reduces the pro-inflammatory response of macrophage foam cells, a cellular responder of the immune system which plays a role in the development of atherosclerotic plaques, to stimuli including hydrogen peroxide and LPS.(36) Berberine also inhibits the release of platelet-derived growth factor (PDGF) from vascular smooth muscle cells as well as smooth muscle hypertrophy via activation of the AMPK pathway. By doing so, berberine promotes normal endothelial function and the reduction of stenosis, that is, the narrowing of blood vessels.(37)
Berberine also induces vaso-relaxation via endothelial-independent mechanisms similar to a calcium-channel blocker, decreasing mean blood pressure and pulse pressure in the mouse model of atherosclerotic disease.(38) Endothelium-dependent relaxation has also been observed with berberine treatment, mediated by the endothelial release of nitric oxide.(39)
One additional mechanism via which berberine may improve cardiovascular system function and hemodynamics is via the inhibition of clot formation. In platelet aggregation assays, berberine was observed to inhibit thrombin-induced platelet aggregation.(40) Thrombin is a key enzyme in the blood coagulation cascade that converts fibrinogen to fibrin during blood coagulation. Berberine has been shown to have neuroprotective effects in animal models of stroke;(41) this may be one mechanism by which these benefits are seen.
Berberine and Dyslipidemia
In addition to improving lipid dysregulation via activation of AMPK,(42) there are several additional mechanisms via which berberine acts to restore cholesterol balance.(43) Berberine inhibits cholesterol absorption and promotes its excretion via the bile.(44,45) Berberine increases the expression of LDL receptors in the liver, which promotes bile formation and secretion.(46) In animals, oral supplementation with berberine was observed to reduce total cholesterol and non-HDL cholesterol levels by 29 to 33 percent and 31 to 41 percent respectfully, also reducing the absorption of dietary cholesterol by 40 to 51 percent.(47)
Berberine also alters the expression of genes related to cholesterol metabolism via interaction with the bile acid farnesoid X receptor (FXR) in the intestinal epithelial cells.(48) Interaction with FXR increases excretion of conjugated bile acids in the feces and reduces the accumulation of hepatic triglycerides and the development of HFD-associated obesity. Although the inhibition of HMG-CoA reductase is not the primary mechanism via which berberine reduces cholesterol, in the setting of hyperhomocysteinemia (common in cardiovascular disease, also contributing to increased hepatic cholesterol synthesis and lipid accumulation), berberine was observed to inhibit HMG-CoA reductase activity and reduce hepatic cholesterol content.(49)
Clearly, berberine has a broad range of effects on metabolism and the function of many systems of the body, some of which may be mediated via interactions with the microbes in the gut, and others which occur at a cellular and genetic level. Research continues to elucidate the mechanisms via which this botanical has such a broad impact on physiology. For our many predecessors and the pioneers of herbal medicine, this only serves to reinforce that which they already observed.
Dr. Carrie Decker, ND, graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Dr. Decker sees patients at her office in Portland, Oregon, as well as remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively. Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group as a member of their education and product development team.
1. Matthews HB, Lucier GW, Fisher KD. Medicinal herbs in the United States: research needs. Environ Health Perspect. 1999 Oct;107(10):773-8.
2. Dattner AM. From medical herbalism to phytotherapy in dermatology: back to the future. Dermatol Ther. 2003;16(2):106-13.
3. Wong M. La médecine chinoise par les plantes. Paris: Editions Tchou; 1976.
4. Jin JL, et al. Antibacterial mechanisms of berberine and reasons for little resistance of bacteria. Chin Herb Med. 2010;3:27-35.
5. Sun D, et al. Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli. Antimicrob Agents Chemother. 1988 Aug;32(8):1274-7.
6. Gu L, et al. Berberine ameliorates intestinal epithelial tight-junction damage and down-regulates myosin light chain kinase pathways in a mouse model of endotoxinemia. J Infect Dis. 2011 Jun 1;203(11):1602-12.
7. Li N, et al. Berberine attenuates pro-inflammatory cytokine-induced tight junction disruption in an in vitro model of intestinal epithelial cells. Eur J Pharm Sci. 2010 Apr 16;40(1):1-8.
9. Feng Y, et al. Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system. Phytother Res. 2013 Oct;27(10):1564-71.
10. Tang QL, et al. Antinociceptive effect of berberine on visceral hypersensitivity in rats. World J Gastroenterol. 2013 Jul 28;19(28):4582-9.
11. Wang Y, et al. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism. 2017 May;70:72-84.
12. Stilling RM, et al. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int. 2016 Oct;99:110-132.
13. Pan GY, et al. The involvement of P-glycoprotein in berberine absorption. Pharmacol Toxicol. 2002 Oct;91(4):193-7.
14. Feng R, et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep. 2015 Jul 15;5:12155.
15. Wu X, et al. Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. Eur J Clin Pharmacol. 2005 Sep;61(8):567-72.
16. Guo Y, et al. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012 Feb;68(2):213-7.
17. Derrien M, et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004 Sep;54(Pt 5):1469-76.
18. Escobar JS, et al. The gut microbiota of Colombians differs from that of Americans, Europeans and Asians. BMC Microbiol. 2014 Dec 14;14:311.
19. Dao MC, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016 Mar;65(3):426-36.
20. Clarke SF, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014 Dec;63(12):1913-20.
21. Zhao S, et al. Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice. J Mol Endocrinol. 2017 Jan;58(1):1-14.
22. Everard A, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 28;110(22):9066-71.
23. Li J, et al. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe-/-mice. Circulation. 2016;133:2434-2446.
24. Shin NR, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014 May;63(5):727-35.
25. Zhu L, et al. Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe-/- mice. Atherosclerosis. 2018 Jan;268:117-126.
26. Anderson TJ. Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol. 1999 Sep;34(3):631-8.
27. Paradisi G, et al. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation. 2001 Mar 13;103(10):1410-5.
28. Tietjen GE, et al. Migraine and biomarkers of endothelial activation in young women. Stroke. 2009 Sep;40(9):2977-82.
29. Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond). 2005 Aug;109(2):143-59.
30. Shimabukuro M, et al. Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab. 2003 Jul;88(7):3236-40.
31. Viollet B, et al. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab. 2007 Dec;33(6):395-402.
32. Brusq JM, et al. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res. 2006 Jun;47(6):1281-8.
33. Salt IP, et al. AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System. Circ Res. 2017 May 26;120(11):1825-1841.
34. García-Prieto CF, et al. High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway. Mol Nutr Food Res. 2015 Mar;59(3):520-32.
35. Wang Y, et al. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res. 2009 Jun 1;82(3):484-92.
36. Jeong HW, et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E955-64.
37. Liang KW, et al. Berberine inhibits platelet-derived growth factor-induced growth and migration partly through an AMPK-dependent pathway in vascular smooth muscle cells. Eur J Pharmacol. 2008 Aug 20;590(1-3):343-54.
38. Wang J, et al. Berberine via suppression of transient receptor potential vanilloid 4 channel improves vascular stiffness in mice. J Cell Mol Med. 2015 Nov;19(11):2607-16.
39. Ko WH, et al. Vasorelaxant and antiproliferative effects of berberine. Eur J Pharmacol. 2000 Jul 7;399(2-3):187-96.
40. Wang X, et al. Identification of berberine as a direct thrombin inhibitor from traditional Chinese medicine through structural, functional and binding studies. Sci Rep. 2017 Mar 9;7:44040.
41. Zhou XQ, et al. Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci Lett. 2008 Dec 5;447(1):31-6.
42. Kim WS, et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E812-9.
43. Zhang Y, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008 Jul;93(7):2559-65.
44. Li XY, et al. Effect of berberine on promoting the excretion of cholesterol in high-fat diet-induced hyperlipidemic hamsters. J Transl Med. 2015;13:278.
45. Wang Y, et al. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters. Atherosclerosis. 2010;209:111–7.
46. Briand F, et al. Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters. Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):13-23.
47. Wang Y, et al. Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption. Metabolism. 2014 Sep;63(9):1167-77.
48. Sun R, et al. Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway. Mol Pharmacol. 2017 Feb;91(2):110-122.
49. Wu N, et al. Regulation of hepatic cholesterol biosynthesis by berberine during hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol. 2011 Mar;300(3):R635-43.