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

Abstract

<jats:p>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.</jats:p>

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

“…Previous studies have reported that obesity and T2D are associated with a reduction of butyrate-producing bacteria and an increase in opportunistic pathogens ( 7 , 45 )⁠⁠. A recent randomized pilot study in which the impact of probiotic supplement on metformin’s effect on glycaemia in prediabetic subjects was assessed, has identified an increase in the relative abundance of Anaerotruncus colihominis (Cluster IV) only in participants receiving both metformin and the probiotic but not in participants taking either metformin or probiotic alone ( 46 )⁠⁠. Our results show that metformin alone can impact the relative abundance of different Anaerotruncus species in opposite directions; Anaerotruncus sp.…”

A Newly Developed Synbiotic Yogurt Prevents Diabetes by Improving the Microbiome–Intestine–Pancreas Axis

“…One potential mechanism by which the gut microbiome influences metabolic disease and T2D is via the fermentation of indigestible fibers into SCFAs (i.e., acetate, propionate, and butyrate) and others, and these metabolites can regulate blood glucose levels and insulin release [ 36 ]. Supplementation of other multi-strain probiotics, which include species of Bifidobacterium , Lactobacillus , and Streptococcus have demonstrated beneficial modulations in the gut microbiome, which are associated with increased secretion of SCFAs (mainly butyrate), improved glycemic control and insulin sensitivity, and reduced gut permeability in T2D [ 17 , 37 , 38 , 39 ]. Therefore, the inclusion of our newly-isolated human-origin Lactobacillus probiotics in our synbiotic yogurt may have prevented T2D progression by beneficially shifting the gut microbiome composition (i.e., increasing bifidobacteria and preventing the colonization of enteropathogens), leading to the production of beneficial metabolites and improved gut physiology.…”

Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients

“…This taxonomic group has been recently associated with improved insulin sensitivity in obese human subjects [ 28 ], alleviated obesity and metabolic dysfunctions in mice [ 29 ], and has been proven to negatively correlate with fasting blood glucose levels [ 30 ]. In addition, some recent studies of metformin effects have observed an increase in the abundance of this species or obtained associations with therapy outcomes [ 31 , 32 ].…”