Not All Bugs Are Bad: Novel Probiotic Formulation for T2DM

A recently published study suggests that probiotic supplementation with select strains of naturally occurring gut bacteria may improve postprandial glucose control in patients with type 2 diabetes. 

Alterations in the gut flora have been observed in patients with prediabetes and T2DM compared to healthy controls. Specific gut microbes responsible for these observations have differed between studies; however, findings consistently suggest that in patients with T2DM, there is a decrease in Akkermansia muciniphila and butyrate-producing anaerobic microbes.^1,2 In a study of obese mice, the administration of A. muciniphilia resulted in significant improvements in glucose tolerance. At the end of the study, metformin-treated mice had higher levels of A. muciniphilia than mice on the same diet without metformin.³ This increase in A. muciniphilia has been proposed as an additional mechanism by which metformin exerts its anti–diabetic effects.^1,3 Butyrate is a short-chain fatty acid and a byproduct of bacterial carbohydrate fermentation. It is the preferred source of energy for colonic cells. Butyrate is involved in regulating the release of pro-inflammatory cytokines, food intake, and energy expenditure partially via its effect on glucagon-like peptide 1.¹  

A recently published study by Perraudeau and colleagues was conducted to evaluate if exposure to two probiotic medical food formulations designed to increase butyrate production and A. muciniphilia could safely improve glycemic control and reduce inflammation in patients with T2DM. The study was a multicenter, double-blind, randomized placebo-controlled, proof-of-concept study that included a 12-week treatment period. Subjects were randomized to one of three treatment groups: placebo, a three probiotic strain formulation (WBF-010) that contained two butyrate producers, and a five probiotic strain formulation that included the three strains in WBF-010, an additional butyrate-producing strain, A. muciniphilia, Bifidobacterium infantis, and inulin, a source of dietary fiber. All subjects were instructed to take three capsules twice a day for 12 weeks.¹ 

Adult patients with T2DM, defined as a fasting plasma glucose ≥126 mg/dL or hemoglobin A1c ≥6.8%) with a BMI of 25-45 kg/m2, were included in the study. Subjects treated with diet and exercise only or metformin with or without a sulfonylurea were enrolled. Individuals treated with an antibiotic, antiviral, antifungal, or antiparasitic within the past 30 days were excluded. The primary glycemic control endpoint was a change from baseline to Week 12 in total glucose AUC 0-180 mins captured using a standard 3-hour meal tolerance test. The primary inflammatory endpoint was a change from baseline to Week 12 in C-reactive protein (CRP). Descriptive statistics were used to evaluate the primary endpoints, t-tests were calculated for hypothesis testing. The sample size was selected to achieve 80% power based on experience and clinical judgment.¹ 

A total of 76 subjects (placebo n=26; WBF-010 n=27, WBF-011 n=23) were enrolled at six sites in the US. On average, subjects were exposed to 77 and 78 days of probiotic treatment, depending on their allocated group. In general, the probiotic formulations were well-tolerated, with most side effects occurring during the first 3-5 days and rated as mild to moderate. The most frequently reported tolerability issues were related to the gastrointestinal tract, such as diarrhea, nausea, and vomiting, and were less frequent in the WBF-011 group (15%) compared to placebo (27%) and WBF-010 (26%). Treatment with WBF-011 was associated with a statistically significant mean change from baseline at Week 12 in total glucose AUC0-180min compared to placebo (-36.1 mg/dL/180 min; p=0.05). There was a non-significant decrease in total glucose AUC0-180min compared to the placebo (p=0.58) in the WBF-010 group. Long–term glucose control, fasting plasma glucose, and CRP levels did not differ significantly from placebo in either probiotic group after 12 weeks of treatment. Due to the small sample size, this POC study lacks statistical power to confirm these observations. All authors had competing interests listed in this industry-sponsored study.¹ 

Supplementation with select anaerobic bacteria that are part of the healthy gut flora, including butyrate-producing strains, was safe and well-tolerated in patients with T2DM. The improvements in glycemic control observed with the five-strain probiotic formulation were primarily due to reductions in 3-hour postprandial glucose levels. 

Practice Pearls: 

• Alterations in the gut flora have been observed in patients with T2DM compared to healthy controls. 
• Supplementation with select anaerobic bacteria that are part of the healthy gut flora, including butyrate-producing strains and A. muciniphilia, has shown promising results in reducing postprandial glucose. 
• Additional studies with larger sample sizes are needed to confirm these promising observations. 

1. Perraudeau Fanny, et al. “Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double-blind, randomized placebo-controlled trial of a novel probiotic formulation.” BMJ Open Diabetes Research and Care vol. 8 (2020)  
2. Sanna, Serena et al. “Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases.” Nature Genetics, vol. 51,4 (2019)  
3. Shin Na-Ri, et al. “An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.“ Gut vol. 63 (2014) 

Louise Brown, PharmD Candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences 

See more about probiotic therapy in type 2 diabetes.