by Dr. Miles Nichols and Aaron Mello, CNTP, MNT
Berberine is a yellow-colored alkaloid compound that has been a hot topic in the last several years in the health world. Berberine appears to have a wide range of health benefits, from treating diabetes and metabolic syndrome to obesity and even gut health. In addition to its antimicrobial effects that have been known for some time, recent research has illuminated benefits in metabolic disease that rival the effects of the medication metformin, which is a commonly prescribed hypoglycemic drug for the treatment of diabetes.
In this post I will review the latest research on berberine as it relates to metabolic diseases like reduced insulin sensitivity, metabolic syndrome and diabetes. I’ll also cover berberine’s role as a modulator of microbiota: berberine helps promote healthy intestinal bacteria while inhibiting pathogenic bacteria. In addition, I’ll talk a bit about the history of berberine and its long history of use in dysentery and alleviating traveler’s diarrhea. Although much of the research into berberine’s benefits are quite new, it has been used for thousands of years in Chinese, Native American and Ayurvedic medicine, primarily as an antimicrobial agent. Keep reading to learn more about the many positive health effects of berberine!
History of berberine
I always like to include a bit about the history of plant medicines that have a long history of use, and berberine is a great example. It has been used as an antimicrobial agent against bacteria, viruses, fungi, protozoa, parasitic worms and even Chlamydia. Berberines are present in several different plant species that appear to have grown on multiple continents for perhaps as long as the human race has existed (1). Some plants that contain this distinctive yellow-colored alkaloid include European barberry, goldenseal, goldthread, Oregon grape, phellodendron, Coptis root and tree turmeric. Berberines can be found in the stem, bark, roots and rhizomes of these plants. It’s important to note that tree turmeric (berberis aristata) is not the same plant as the spice turmeric (curcuma longa) and the latter does not contain berberine.
Berberine as an antimicrobial
Berberine’s long history of use as an antimicrobial has been confirmed in recent years by scientific research. For example, berberine has been demonstrated to enact antibacterial effects on Streptococcus agalactiae, probably by damaging the structure of bacterial cell membrane and inhibiting synthesis of its protein and DNA (2). Another study found that berberine was an effective antimicrobial agent against methicillin-resistant Staphylococcus aureus (3). A third study from 2014 evaluated the antibacterial effects of berberine when combined with antibacterial drugs on fourteen different strains of antibacterial-resistant Staphylococcus and found impressive synergistic benefits, especially when berberine was combined with linezolid, cefoxitin and erythromycin (4). Berberine-containing plants like turmeric can also be used topically on wounds as an antibacterial.
Berberine reduces biofilms
Another antibacterial mechanism for berberine appears to be its ability to inhibit the formation and adhesion of biofilms, which are protective matrices that surround certain pathogenic bacteria in the intestine. Biofilms protect pathogenic bacteria against the actions of antibiotics and allow the bacteria to grow rapidly. Berberine has been shown to inhibit biofilms for Staphylococcus epidermis (5) and Klebsiella pneumoniae (6). The biofilm matrix is made of polymers that rely on phenol soluble modulins (PSMs) for their architecture. Interestingly, there may be a connection between the biofilms created by Staphylococcus aureus strains and the amyloid-ß peptide formed in Alzheimer’s disease, as both share a similar ß-sheet structure. More research is necessary to further illuminate the connection, but it’s possible that berberines may also be helpful in preventing the pathalogical cascade in Alzheimer’s disease (7) (8).
Berberine and SIBO
Small intestinal bacterial overgrowth (SIBO) is a condition marked by excessive bacteria in the small intestine, which often translocates from the colon. SIBO is identified by a lactulose breath test and is often treated with antibiotics such as rifaximin, with somewhat limited results. but because of its many antimicrobial actions, berberine is another treatment option because it helps to inhibit bacteria. One study on SIBO patients compared the efficacy of rifaximin treatment to berberine and found impressive results for berberine. After treatment, 46% of the berberine treatment arm tested negative for SIBO, compared to only 34% of rifaximin users. In addition, there were fewer complications in the berberine group: The only complication from berberine was that one of the 37 berberine patients experienced diarrhea. In contrast, in the rifaximin treatment arm of 67 patients experienced the following complications: one case of anaphylaxis, two cases of hives, two cases of diarrhea and one case of Clostridium difficile (9).
Berberine to treat diarrhea
Ayurvedic and Chinese medicine have used berberine to treat diarrhea for hundreds of years or longer and multiple modern studies have now corroborated this use. One study of 185 patient with cholera found that berberine treatment reduced diarrheal stools by one liter (10). Berberine is also commonly used to treat bacterial dysentery, with a typical dose being 100-300mg three times per day (11). One study notes that Chinese goldthread or Coptis chinensis is effective at treating multiple intestinal infections, including gastroenteritis, cholera and bacillary dysentery (12). In addition, a 1988 study found berberine exhibited antibacterial effects against V. cholera and was able to inhibit bacterial adherence to mucosal and epithelial surfaces (13). In fact, berberine is great at alleviating traveler’s diarrhea and we recommend carrying it on trips abroad, especially to locations where the water may be questionable and the food is much different to what we’re used to eating. The benefits of berberine are not limited to diarrhea and intestinal infections; it also promotes a healthy gut microbiome and, as we’ll see shortly, can be an effective treatment for metabolic disorders.
Berberine’s effects on the microbiota
As mentioned in the introduction, berberine has been demonstrated to exert positive effects on the microbiome by promoting healthy bacteria and inhibiting pathogenic bacteria. Berberine appears to be poorly absorbed in the intestine and its effects on the microbiota may help to explain its anti-diabetic and anti-obesity effects, in spite of its low bioavailability (14). Multiple rat studies demonstrate anti-diabetic effects which appear to result from changes to the microbiota through several mechanisms, including improvement of the intestinal mucosal barrier, modulation of intestinal bacteria and reduction of intestinal inflammation.
Dysfunction of the intestinal mucosal barrier plays an important role in the development of diabetes. One study found that diabetic rats displayed a 2.77-fold increase in intestinal permeability and that treatment with berberine reduced permeability by 27.5%. In addition, glucose and triglyceride levels decreased and improved inflammatory markers including Nuclear Factor-κB, which is positively correlated with intestinal inflammation (15).
Another rat study which compared rats fed a high fat diet to normal diet controls found that the phyla Actinobacteria and Verrucomicrobia were significantly higher in the high fat group. These higher abundances were completely reversed by berberine co-administration. Other prevalent phyla of Firmicutes, Bacteroidetes and Protobacteria were not altered between the groups in this study. Berberine therapy also resulted in significantly increased short chain fatty acids (SCFA) concentrations in the high fat diet rats by increasing the abundance of SCFA producing bacteria (16).
A third benefit of berberine therapy as it relates to the microbiome is the attenuation of systemic and gut inflammation. Increased SCFA production is one primary mechanism for this result. Other mechanisms include suppression of pro-inflammatory markers, including TNF-α, IL-1β, IL-6, MCP-1, inducible nitric oxide synthase, and cyclooxygenase-2. Another study found significantly reduced LPS-induced intestinal damage and decreased levels of inflammatory cytokines in an LPS-injured rat model (17). In addition to these benefits, reducing inflammation appears to enhance insulin sensitivity, an important accomplishment for reducing metabolic disorders like diabetes. In the next section I’ll talk more about berberine as it relates to metabolic disease.
Berberine and metabolic disease
In addition to berberine’s long history of use as an antimicrobial, more recent research has demonstrated many health benefits in metabolic diseases like insulin resistance, metabolic syndrome and diabetes. In fact, the anti-diabetic effects of berberine appear to have a long history as well, so perhaps this is another instance of modern science confirming what some had long been believed to be true in Chinese and Ayurvedic medicine. One study notes that the ancient berberine-containing Chinese herb Coptis chinensis French has been used to treat diabetes for thousands of years (18).
This study evaluated the effects of berberine hydrochloride on 84 Chinese subjects with type 2 diabetes. Blood sugar management was evaluated through HbA1c levels as a primary marker, with fasting blood glucose (FBG), postrapndial blood glucose (PBG), plasma triglycerides, total cholesterol, HDL and LDL as secondary markers. The berberine group demonstrated significant decreases in HbA1c, FBG, PBG, triglycerides and total cholesterol. There were no significant differences in HDL or LDL. Impressively, berberine treatment resulted in identical improvements in glucose regulation, FBG, PPBG, fasting insulin and postprandial insulin as compared to metformin. Even more impressive, berberine outperformed metformin in the regulation of lipid metabolism, and triglycerides and total cholesterol were significantly lower in the berberine group by the end of the 13 week study.
Therapeutic doses of berberine range between 250mg twice per day on the low end up to 500mg three times per day. Many patients seemed able to tolerate the higher dosage, but those who experienced diarrhea or abdominal discomfort reduced the dosage, commonly to 300mg two to three times per day. Some other subjects experienced mild constipation. One meta analysis of fourteen randomized trials involving 1068 patients found that berberine resulted in a similar glycemic improvement compared to hypoglycemic drugs like metformin, glipizide and rosiglitazone, and had a mild antidyslipidemic effect. Across all these studies, no serious adverse effects were reported from berberine and no severe hypoglycemia was reported in all the included trials. The most positive outcomes seemed to result from a combination of berberine and medication therapies. One limitation of this meta analysis was that all subjects were Chinese, and other ethnic groups may respond differently (19).
Cholesterol-lowering effects of berberine
High cholesterol is a big concern for many people these days, with 28% of Americans over age 40 taking a cholesterol-lowering statin drug as of 2012 (20). Given the widespread concern over high cholesterol, it’s interesting to note that berberine has been demonstrated to lower cholesterol. I mentioned this in the last section, and in fact berberine’s cholesterol-lowering effects have been studied specifically, independent of other markers. One study on hamsters fed a high fat diet found that berberine reduced liver cholesterol levels in the hyperlipidemic hamsters by increasing excretion of cholesterol into the bile (21). These findings were corroborated in a human study, which found that cholesterol was further reduced when adding berberine to the conventionally used medications for glucose control (22).
Mechanisms of action
Berberine appears to have different mechanisms of action than metformin and other hypoglyemic medications. These mechanisms are complex and have not yet been fully identified. Primary mechanisms appear to include activation of glucose transporters GLUT1 and GLUT4 and inhibition of glucose absorption in the intestine. A third possible mechanism for berberine is activation of AMP-activated protein kinase, or AMPK, but research has delivered conflicting results on this.
Berberine treatment increases the expression of GLUT1 and GLUT4, which transport glucose into cells in the body. GLUT1 transports glucose into erythrocytes (red blood cells), whereas GLUT4 shuttles glucose into skeletal muscle, where it is either oxidized to produce energy or stored as glycogen. GLUT4 in particular is a major regulator of whole body glucose homeostasis.
A second mechanism of action for berberine appears to be its ability to inhibit the enzyme α-glucosidase, which decreases glucose transport across the intestinal epithelium. Berberine appears to work by decreasing the activity of maltase and sucrase enzymes in Caco-2 cells. This is the same mechanism of action as α-glucosidase medications like acarbose, but these drugs often cause adverse side effects such as flatulence, abdominal distension and diarrhea, which is probably due to colic bacterial fermentation of unabsorbed carbohydrates. Although berberine shares the same mechanism of action, these adverse effects are less common, presumably due to its antimicrobial effects. With that being said, the inhibition of these enzymes may be a contributing factor to the mild diarrhea that some people experience when taking berberine. In one in vitro study, berberine was demonstrated to inhibit sucrase and maltase as effectively as acarbose (23).
A third possible mechanism of action may be activation of AMP-activated protein kinase, or AMPK. However, this has not been demonstrated conclusively and studies have found conflicting results. Although some research has found that part of berberine’s hypoglycemic effects are due to insulin pathway-dependent stimulation of AMPK (24) (25), other research has found that activation of AMPK by AICAR inhibits, rather than activates glucose uptake (26). More research needs to be done to elucidate the relationship between AMPK and glucose regulation.
Using berberine clinically
For targeted treatment of metabolic disorders like insulin resistance, metabolic syndrome and diabetes, berberine containing herbs or isolated berberine supplements can be indicated.
A good starting dose of berberine for metabolic control or SIBO is 500mg three times per day, ideally about 30 minutes before a meal. In the case of adverse reactions like diarrhea, constipation or abdominal discomfort, the dose can be reduced to 250-300mg two to three times per day. Although research has not shown that berberine lowers blood sugar so drastically as to cause hypoglycemia, it’s not outside the realm of possibility, so in the unlikely case of hypoglycemic symptoms like sweating, shaking, cloudy thinking, blurred vision or dizziness, try reducing the dose as well.
In addition to metabolic control, berberine is an effective remedy for dysentery and traveler’s diarrhea, as I discussed earlier. It’s a great idea to carry some berberine like Coptis root or berberine capsules when traveling to areas where the water quality is questionable. Use berberine at the first sign of diarrhea to alleviate the symptoms and attack the pathogenic bacterium that is causing the symptoms. It’s our go-to remedy for traveler’s diarrhea.
In addition to berberine hydrochloride supplements, other preparations are available:
- Coptis root is our favorite berberine-containing herb. We use it in many formulas for small intestinal bacterial overgrowth (SIBO) and blood sugar.
- Goldenseal is available as a raw herb or bulk powder, which can be made into a tea. It’s also available as a tincture or in capsule or tablet form.
- European barberry fruit contains berberines and is also high in Vitamin C. The dried fruit can also be eaten on its own, or sprinkled on a salad. In addition, it can be used to make a sharp-tasting tea and it is also used to make a Russian candy called Барбарис (Barberis).
- Goldthread is available in tincture form but has been overharvested. Be sure to obtain goldthread from reputable sources.
- Oregon grape root is also available as a tincture and can be used both internally and topically for acute infections.
- Phellodendron root is another source of berberines that is an important herb in traditional Chinese medicine. Also called Huang bai, it can be obtained in supplement form.
Berberines appear to offer many health benefits and have a long history of safe use in multiple cultures. Although science is still illuminating exact mechanisms of action for berberine, it shows great potential at preventing and potentially even reversing metabolic disease, as well as exerting antibacterial effects and positive changes to the microbiota. Research has established a clear role for berberine in health.
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