Berberine and glycemic control

Relation

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.

Study objective

To determine and compare the effectiveness of probiotics + berberine (Prob + BBR), berberine + placebo (BBR), or probiotics + placebo (Prob) with that of placebo (Plac) in lowering glycemic hemoglobin (HbA_1c) among participants diagnosed with type 2 diabetes (T2D).

Draft

This was a 12-week, double-blind, randomized, placebo-controlled study consisting of 4 arms conducted in 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 inclusion in either treatment group or placebo group.

Interventions

All participants received an antibiotic gentamicin 80 mg twice daily for 1 week as pretreatment.

The dosage of medications and supplements was as follows: berberine 600 mg twice daily before meals and probiotic 4 grams once daily before bed. The probiotic was a proprietary blend of 50 billion colony forming units consisting of the following species and strains:Bifidobacterium longumBL88,Bifidobacterium breveBB8,Lactococcus gasseriLG23,Lactobacillus rhamnosusLR22,Lactobacillus salivariusLS86,Lactobacillus crispatusLCR15,Lactobacillus plantarumRecord,Lactobacillus fermentumLF33 andLactobacillus caseiLC18.

Participant

Researchers randomized (1:1:1:1) 409 newly diagnosed type 2 diabetics into the treatment and placebo groups. All subjects were drug naive and had received at least 2 months of lifestyle education. At the time of data analysis, there were 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).

Data were reported as mean +/- standard deviation or as median and interquartile range.

The gender distribution and median age (with interquartile range) of subjects in the different 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

In addition to the primary outcome measure, researchers compared several secondary outcome measures before and after the intervention. 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 evaluated changes in the gut microbiome through metagenomic and metabolomic assays comparing the post-gentamicin/pretreatment time point to the post-treatment/study endpoint for each arm.

Primary outcome measures

The primary endpoint was glycosylated hemoglobin (HbA_1c)

Key insights

(Least squares mean [95% CI])

The reduction of HbA_1cat the end of the intervention in the Prob+BBR group (least square mean −1.04[95% CI −1.19, −0.89]%) and in the BBR group (−0.99[−1.16, −0.83]%) were significantly larger 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 HbA_1cbetween the Prob+BBR and the BBR groups or between the Plac and Prob groups.

In addition to lowering HbA_1cThe BBR-containing treatment groups also saw improvements in fasting plasma glucose, postload glucose, triglycerides, total cholesterol and LDL. Interestingly, HOMA-IR was significantly decreased by the synergy of Prob-BBR, but not in the BBR-alone group.

The groups that took BBR reported more gastrointestinal symptoms than other groups.

In summary: BBR and Prob+BBR reduced HbA_1cmore than the placebo and more than the probiotic alone, and there was no difference in the change in HbA_1cbetween the placebo and probiotic groups.

Gut microbiota analysis 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 biological functions of microbes) in the BBR and Prob+BBR groups was similar after 13 weeks of intervention.

The researchers identified 36 microbial species as the key species that respond to berberine. Berberine appears to preferentially decimate bacterial species that ferment polysaccharides and oligosaccharides and produce short-chain fatty acids or single sugar units through fermentation. Berberine also increased the relative abundance of some species, includingBacteroidsand those from the class Gammaproteobacteria. Interestingly, these species have previously been found to respond to metformin.¹

From a naturopathic perspective, the use of berberine in this study can be viewed as an example of gently pushing the body toward microbiome homeostasis.

The researchers note that BBR affects bile acid metabolism and the blood pool of bile acids by affecting gut microbes involved in the conversion of bile acids. Specifically, there were more conjugated bile acids in the blood in the berberine treatment groups. The authors suggest that this change in how bile acids are converted by gut microbes may contribute to the antidiabetic effects of berberine. It was hypothesized that microbe-induced changes in deconjugation and dehydroxylation of bile acids were inhibited by berberine and this drives the beneficial effects on HbA_1c, fasting plasma glucose, postprandial glucose and total cholesterol. The data points to thisRuminococcus bromiiwas the key species inhibited by berberine. The researchers suspect that this inhibitsRuminococcus bromiiresulted in less deconjugation of deoxycholic acid, which triggered less genetic expression of the bile acid receptor known as farnesoid X receptor (FXR) in the intestine, thereby producing the antidiabetic effect.

Practice implications

I remember when berberine was first used to improve glycemic control. I had a few questions that immediately came to mind. First, "Is it good to use berberine long-term? Will it change the gut microbiota too much and cause other problems?" Second, “How on earth does berberine lower blood sugar?” I think many of my colleagues may have been wondering the same things.

Many of us are familiar with the use of berberine to influence dysbiosis. Berberine has generally been viewed as an agent that can spare the “good” gut microbes and reduce “dysbiotic” organisms. It is often recommended based on the results of functional stool testing of microbiota populations, where berberine is a recommended agent for reducing dysbiosis, whether fungal or bacterial. This is the first study I am aware of that begins to answer some of my initial questions regarding the use of berberine to improve glycemic control.

Clinically, it's interesting to note that this study actually showed that berberine kills some gut microbes and boosts others. This supports the long-standing naturopathic idea that berberine is a gut microbiomemodulator. For centuries, people have also used berberine-containing plants in traditional Chinese herbal formulas to support gut health without fully understanding their gut microbiome-modulating properties.²

From a naturopathic perspective, the use of berberine in this study can be viewed as an example of gently pushing the body toward microbiome homeostasis. I find it fascinating that the downstream domino effect of berberine administration is an improvement in glycemic control by modulating the end products of gut microbial metabolism.

The depth of data analysis used in this study was difficult to imagine 30 years ago. This research group conducted an in-depth “metagenomic” and “metabolomic” analysis of their data. Like a Sherlock Holmes novel, they reduced the data to a final conclusion: berberine inhibited the biotransformation of deoxycholic acid by inhibitionRuminococcus bromii, which then decreased the intestinal activity of FXR, a regulator of glucose and lipids in the body. This chain of events could have caused the mentioned antidiabetic effect. Talk about a domino effect.

The secondary results of this study are intriguing. The authors make an interesting statement in their results section. They note: “Reconstitution of the gut microbiome after probiotics was similar to that after Plac treatment, except for the enrichment of ingested probiotic species.” They then clarify: “Therefore, treatment with probiotics showed similar effects not only on glycemic control but also on gut microbiota resilience after gentamycin pretreatment with placebo.”

Taken at face value, these statements appear to indicate that the probiotics in this study, when used alone, were no better than placebo at restoring overall gut microbiota and improving glycemic control after pretreatment with gentamicin.

Upon closer inspection, one might think that “enrichment of ingested probiotic species” would provide a significant benefit to a patient following 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 the subjects' gut microbiota populations had not returned to baseline despite probiotic use 13 weeks after their antibiotic treatment. Not to make doctors feel guilty when prescribing antibiotics is indicated, but this is something to keep in mind. Maybe some “prebiotics” can be of use here?

Now let's look at the other side of the coin. The authors state that probiotics maydelayrestoring the “symbiosis” of the microbiome after antibiotic treatment. I found this statement counterintuitive at first glance. If we look at this from a completely different perspective, this can be a good thing. The authors aptly note that this situation may 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 trials of probiotics found improvements in HbA_1CTriglycerides, C-reactive protein (CRP), fasting insulin, fasting blood glucose and blood pressure in several studies.⁴

Finally, it is tempting to mention another secondary finding of this study. The genomic analyzes showed that berberine enhanced microbes were involved in the breakdown of xenobiotics. I can't help but wonder if berberine might help improve detoxification and hormonal balance in diabetics and other populations. This question will hopefully be answered by future studies that we will review in the coming years.