Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).

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• The use of berberine, as a specific antimicrobial agent, along with high strength probiotics may be beneficial for managing blood glucose and potentially other metabolic health markers alongside diet and lifestyle modifications

Introduction

Dysbiosis of the human gut microbiome has been associated with the development of type 2 diabetes (T2D). Research has found that, in part, mechanisms of action for the antidiabetic medications, Metformin and Acarbose, include alterations in the gut microbiome as well as the inhibition of bile acid (BA) metabolism and signalling. Remedies targeting the gut microbiota for treatment of T2D and other metabolic diseases have therefore been investigated.

Berberine (BBR) has been used in Indian Ayurvedic and Traditional Chinese Medicine to treat metabolic conditions for hundreds of years. Probiotics have also been extensively researched for their potential metabolic benefits. This randomised, double-blind, placebo-controlled trial aimed to investigate whether BBR and probiotics may be effective in managing T2D.

Methods

A total of 409 participants aged 42-61 years were recruited from 20 medical centres in China. All patients were newly diagnosed (<12 months) with T2D and had no previous antidiabetic medication history. Participants were randomised into 4 groups; Probiotics and BBR, BBR only, probiotics only or a placebo for 12 weeks. Subgroup analysis was also completed for those aged >50 and >54.

Dosage of BBR was 0.6 g prior to a meal, twice daily. 4 g of powdered multi-strain probiotics including 9 strains of lactic acid bacteria were taken at bedtime. All participants were given a 7-day broad-spectrum antibiotic treatment immediately prior to baseline. 391 people completed the trial. The primary outcome measurement was glycaemic haemoglobin (HbA1c). Secondary evaluations of additional metabolic markers included fasting and post-load plasma glucose (FPG, PPG), homeostasis assessment model index for insulin resistance (HOMA-IR), total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c) and serum triglycerides (TG).

Results

Results showed a reduction in glycaemic haemoglobin (HbA1c) for both the BBR plus probiotics group (least squares mean [95% CI] -1.04 [-1-19, -0.89]% ) and the BBR only group (-.99 [-1.16, 0.83]%). The results for these groups were significantly greater than the probiotics alone (-0.53 {-068, -0.37]%) and the placebo groups (0.59 [-0.75, -0.44]%).

Secondary metabolic evaluations for FPG and PPG, TC, LDL -c and TGs also showed similar improvements in the BBR and BBR plus probiotic groups only. Additionally, in the >50 and >54 subgroups BBR and probiotics marginally improved the HOMA-IR.

Metagenomic and metabolomic analysis of the gut microbiome was also undertaken after a one-week pre-treatment with antibiotics immediately prior to the trial and at week 13. These results showed that the blood glucose lowering effects of BBR may be due to decreased deoxycholic acid species (DCA) biotransformation by ruminococcus bromii.

Higher levels of adverse gastrointestinal side effects were reported in the BBR treatment groups, however, the authors reported that this did not affect glycemic control outcomes.

Conclusion

This study found that BBR had an antidiabetic effect through microbial alterations in the human gut microbiome

The authors declare no conflicts of interest.

• 600mg of BBR twice daily prior to a meal plus a multi-strain (lactic acid) probiotic of >50 billion colony forming units (CFU) for 12 weeks may be effective in lowering HbA1c in T2D clients diagnosed within the previous 12 months
• Further research is needed for clients with longer term T2D diagnosis
• Insulin resistance may be marginally improved in clients >50
• Practitioners should be aware that in this study, adverse gastrointestinal side effects were more likely to be be experienced with the use of BBR

The authors reported several limitations to this study:

• A population of Chinese people living in China may not be generalisable to other ethnic/racial populations
• The study was over a short duration. Longer studies are needed to confirm the results
• Participants had newly diagnosed T2D and had not received any previous medications. Future studies should include patients with a longer diagnosis time
• Records should be kept of any additional lifestyle changes made by the participants
• Adverse reactions were experienced in the BBR groups, in this study. It was reported that the gut microbiome and anti-diabetic effects were not affected, however, this may be something to be considered in longer trials.