Zhang Y, Gu Y, Ren H, et al. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun. 2020;11(1):5015.
To determine and compare the efficacy of probiotics+berberine (Prob+BBR), berberine+placebo (BBR), or probiotics+placebo (Prob), to that of placebo (Plac) in reducing glycemic hemoglobin (HbA1c) among participants diagnosed with type 2 diabetes (T2D).
This was a 12-week, double-blind, randomized, placebo-controlled trial consisting of 4 arms and performed on patients with newly diagnosed T2D from 20 centers in China.
The study consisted of 4 groups: berberine alone (BBR), berberine plus probiotics (Prob+BBR), probiotics alone (Prob), and placebo (Plac). All subjects were pretreated with gentamicin for 1 week before entering 1 of the treatment groups or the placebo group.
All participants received 1 week of antibiotic, gentamicin 80 mg twice daily, as pretreatment.
Medication and supplement dosages were as follows: berberine 600 mg twice daily before meals, and probiotic 4 grams once daily at bedtime. The probiotic was a proprietary mixture of 50 billion colony-forming units consisting of the following species and strains: Bifidobacterium longum BL88, Bifidobacterium breve BB8, Lactococcus gasseri LG23, Lactobacillus rhamnosus LR22, Lactobacillus salivarius LS86, Lactobacillus crispatus LCR15, Lactobacillus plantarum LP, Lactobacillus fermentum LF33, and Lactobacillus casei LC18.
Researchers randomized (1:1:1:1) 409 newly diagnosed type 2 diabetics to the treatment and placebo groups. All subjects were drug-naïve and had received at least 2 months of lifestyle education. At the time of data analysis, there was a total of 391 participants (104 subjects in the Prob+BBR group, 100 in the Prob group, 90 in the BBR group, and 97 in the Plac group).
The data were reported as mean +/- the standard deviation or as the median and interquartile range.
The gender distribution and the mean age (with the interquartile range specified) of subjects in the various groups were as follows: placebo group, 54 years (46–61) and 59.2% male; probiotic group, 54 years (45–59) and 54% male; Berberine group, 53 years (42–61) and 53% male; and the probiotic+berberine group, 53.5 years (47–60) and 53.5% male.
Study Parameters Assessed
Apart from the primary outcome measure, researchers compared multiple secondary outcome measures pre- and postintervention. These metabolic parameters included: weight, body mass index, waist circumference, systolic and diastolic blood pressure, fasting plasma glucose, postload plasma glucose, fasting insulin, postload insulin, fasting C-peptide, postload C-peptide, triglycerides, total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), homeostasis model assessment for insulin resistance (HOMA-IR; an assessment of insulin resistance), and HOMA-beta (an assessment of beta cell function).
This study also assessed changes in the gut microbiome through metagenomic and metabolomic testing, which compared the postgentamycin/pretreatment time point to the posttreatment/study end point for each arm.
Primary Outcome Measures
The primary outcome measure was glycosylated hemoglobin (HbA1c)
(Least-squares mean [95% CI])
The reductions in HbA1c at the end of the intervention in the Prob+BBR group (least-squares mean −1.04[95% CI −1.19, −0.89]%) and in the BBR group (−0.99[−1.16, −0.83]%) were significantly greater than in the Plac group and the Prob group (−0.59[−0.75, −0.44]%; −0.53[−0.68, −0.37]%, P<0.001).
There were no statistically significant differences in HbA1c between the Prob+BBR and the BBR groups or between the Plac and Prob groups.
In addition to the reduction in HbA1c the BBR-containing treatment groups also saw improvements in fasting plasma glucose, postload glucose, triglycerides, total cholesterol, and LDL. Interestingly the HOMA-IR was significantly lowered by the synergy of Prob-BBR but not in the BBR-alone group.
The groups taking BBR reported more gastrointestinal complaints than other groups.
In summary: BBR and Prob+BBR reduced HbA1c more than the placebo and more than the probiotic alone, and there was no difference in the change of HbA1c between the placebo and probiotic-alone groups.
Analysis of the gut microbiota showed that BBR alone or with probiotics significantly altered the microbiome compared to the baseline gut microbiota, the placebo group, and the probiotic treatment group. The composition of the gut microbiota (in terms of overall microbial composition and the biological functions of the microbes) in the BBR and the Prob+BBR groups ended up being similar after 13 weeks of intervention.
Researchers identified 36 microbial species as being the key species responsive to berberine. Berberine appeared to preferentially deplete species of bacteria that ferment polysaccharides and oligosaccharides and produce short-chain fatty acids or single sugar units from fermentation. Berberine also enhanced the relative abundance of some species including Bacteroides and those from the Gammaproteobacteria class. Interestingly these species have previously been noted to be responsive to metformin.1
In naturopathic terms, the use of berberine in this study may be considered an example of gently pushing the body in the direction of microbiome homeostasis.
The researchers note that BBR affected bile acid metabolism and the blood pool of bile acids by affecting gut microbes involved in the transformation of bile acids. Specifically there were more conjugated bile acids in the blood in the berberine treatment groups. The authors hypothesize that this alteration in the transformation of bile acids by gut microbes may contribute to the antidiabetic effect of berberine. It was thought that microbe-induced changes in deconjugation and dehydroxylation of bile acids were inhibited by berberine and this was driving the positive effects on HbA1c, fasting plasma glucose, postprandial glucose, and total cholesterol. The data indicate that Ruminococcus bromii was the key species inhibited by berberine. The researchers hypothesize that inhibiting Ruminococcus bromii resulted in less deconjugation of deoxycholic acid, which triggered less genetic expression of the bile acid receptor known as the farnesoid X receptor (FXR) in the gut, thus creating the antidiabetic effect.
I remember when berberine first started being used to improve glycemic control. I had a couple questions that immediately came to mind. First, “Is it a good thing to use berberine on a long-term basis? Will that alter gut microbiota too much and cause other issues?” Secondly, “How in the world does berberine lower blood sugar?” I think many of my peers may have wondered the same things.
Many of us are familiar with the use of berberine to affect dysbiosis. Berberine has generally been thought of as an agent that can spare the “good” gut microbes and decrease “dysbiotic” organisms. It is often recommended based on the results of functional stool testing of microbiota populations, where berberine is a suggested agent to decrease dysbiosis, be it fungal or bacterial. This is the first study of which I am aware that begins to answer some of my initial questions regarding the use of berberine to improve glycemic control.
Clinically it is interesting to note that this study did, in fact, show that berberine kills some gut microbes and enhances others. This supports the long-existing naturopathic idea that berberine is a gut microbiome modulator. For centuries, people have also used berberine-containing plants in traditional Chinese herbal formulas to support gut health without specifically understanding their gut microbiome–modulating properties.2
In naturopathic terms, the use of berberine in this study may be considered an example of gently pushing the body in the direction of microbiome homeostasis. I find it fascinating that the downstream domino effect of giving berberine is an improvement in glycemic control through the modulation of end products of gut-microbe metabolism.
The depths of data analysis used in this study was hardly imaginable 30 years ago. This research group performed in-depth “metagenomic” and “metabolomic” analysis of their data. Like a Sherlock Holmes novel, they boiled down the data to a final deduction: Berberine inhibited the biotransformation of deoxycholic acid by inhibiting Ruminococcus bromii, which then lowered the gut activity of FXR, a regulator of glucose and lipids in the body. This chain of events may have caused the noted antidiabetic effect. Talk about a domino effect.
The secondary findings of this study are intriguing. The authors make an interesting statement in their results section. They state, “The reconstitution of the gut microbiome after probiotics was similar to that after Plac treatment except for the enrichment of the ingested probiotic species.” They then go on to clarify, “Thus, probiotics treatment showed similar effects not only on glycemic control but also on resilience of the gut microbiota after gentamycin pretreatment with placebo.”
If taken at face value, these statements would seem to indicate that the probiotics in this study, when used alone, were no better than placebo at recovering overall gut microbiota and improving glycemic control after gentamicin pretreatment.
Upon further consideration, one may think that “enrichment of the ingested probiotics species” would be a significant benefit to a patient after an antibiotic treatment. This is especially true given the known beneficial effects of the various probiotic species used in this study.3
To me, it is somewhat surprising that, despite probiotic use, the subjects’ gut microbiota populations were not back to baseline 13 weeks after their antibiotic treatment. Not to induce guilt in practitioners when an antibiotic prescription is indicated, but this is good to keep in mind. Perhaps some “prebiotics” may be of use here?
Now let’s look at the other side of the coin. The authors state that probiotics may delay the recovery of the microbiome “symbiosis” after antibiotic treatment. I found this statement counterintuitive at first glance. If we look at this from a completely different perspective, this may be a good thing. The authors aptly note that this situation might represent an opportunity to “reset” the diseased microbiome known to be associated with diabetes in the first place.
The noted lack of effect of probiotics on glycemic control in this study differs from previous studies. A meta-analysis of randomized, placebo-controlled studies on probiotics found improvements in HbA1C, triglycerides, C-reactive protein (CRP), fasting insulin, fasting blood sugar, and blood pressure across multiple studies.4
To conclude, it is tempting to mention another secondary finding of this study. The genomic analyses showed that berberine enhanced microbes involved in xenobiotic degradation. I cannot help but wonder if berberine could help improve detoxification and hormonal balance in diabetics and other populations. This question will, I hope, be answered by future studies that we will be reviewing in years to come.