Targeting the Intestinal Microbiota to Prevent Type 2 Diabetes and Enhance the Effect of Metformin on Glycaemia: A Randomised Controlled Pilot Study

Abstract

Early treatment may prevent or delay the onset of type 2 diabetes mellitus (T2DM) in individuals who are at high risk. Lifestyle interventions and the hypoglycemic drug metformin have been shown to reduce T2DM incidence. The effectiveness of such interventions may be enhanced by targeting environmental factors such as the intestinal microbiota, which has been proven to predict the response to lifestyle interventions and play a part in mediating the glucose-lowering effects of metformin. Shifts in the intestinal microbiota "towards a more balanced state" may promote glucose homeostasis by regulating short-chain fatty acids' production. This study aimed to investigate the safety and effect of a multi-strain probiotic on glycemic, inflammatory, and permeability markers in adults with prediabetes and early T2DM and to assess whether the probiotic can enhance metformin's effect on glycaemia. A randomised controlled pilot study was conducted in 60 adults with a BMI ≥ 25 kg/m² and with prediabetes or T2DM (within the previous 12 months). The participants were randomised to a multi-strain probiotic (L. plantarum, L. bulgaricus, L. gasseri, B. breve, B. animalis sbsp. lactis, B. bifidum, S. thermophilus, and S. boulardii) or placebo for 12 weeks. Analyses of the primary outcome (fasting plasma glucose) and secondary outcomes, including, but not limited to, circulating lipopolysaccharide, zonulin, and short chain fatty acids and a metagenomic analysis of the fecal microbiome were performed at baseline and 12 weeks post-intervention. The results showed no significant differences in the primary and secondary outcome measures between the probiotic and placebo group. An analysis of a subgroup of participants taking metformin showed a decrease in fasting plasma glucose, HbA1c, insulin resistance, and zonulin; an increase in plasma butyrate concentrations; and an enrichment of microbial butyrate-producing pathways in the probiotic group but not in the placebo group. Probiotics may act as an adjunctive to metformin by increasing the production of butyrate, which may consequently enhance glucose management.

Keywords: intestinal microbiota; metformin; prediabetes; probiotics; short-chain fatty acids; type 2 diabetes mellitus.

Figure 1

CONSORT flowchart of participants’ progress through the study.

Figure 2

Shift in intestinal microbial profile after the 12-week intervention. (A) Microbial profile at the phylum level in each groups and timeline. (B) Principal coordinate analysis (PCoA) of Bray–Curtis distances at the species level between the intestinal microbial communities of subjects in each group.

Figure 3

Spearman correlation analysis between species abundance and clinical outcomes (* p < 0.05). LPS: lipopolysaccharide; LDL: low-density lipoprotein; HDL: High-density lipoprotein; TG: triglycerides; CT: Total Cholesterol; HbA1c: Hemoglobin A1c; HOMA: Homeostatic Model Assessment; FPG: Fasting Plasma Glucose; SBP: Systolic Blood Pressure; BMI: body mass index.

Figure 4

Plasma butyrate concentration. Box plots representing the effect on butyrate levels in participants taking metformin in the probiotic (n = 14) and placebo (n = 14) groups. * Wilcoxon matched-pairs signed rank test showing significant differences within the probiotic group (p < 0.05).