Abstract
Metformin is a common drug for the management of type 2 diabetes mellitus; however, it causes various adverse gastrointestinal effects, especially after prolonged treatment. It is thus of interest to identify an adjuvant treatment that synergizes with the efficacy of metformin while mitigating its adverse effects. Since previous evidence supports that the gut microbiota is a target of metformin, this study investigated the beneficial effect and mechanism of the coadministration of probiotics with metformin in the management of type 2 diabetes mellitus by conducting a 3-month randomized, double-blind, placebo-controlled clinical trial (n = 27 and 21 in the probiotic and placebo groups, respectively, who completed the trial). Clinical results showed that the coadministration of probiotics with metformin significantly reduced glycated hemoglobin compared with metformin taken alone (P < 0.05). Metagenomic and metabolomic analyses showed that the coadministration of probiotics increased the abundance of gut short-chain fatty acid (SCFA)-producing bacteria and bile acids. Significantly or marginally more bile acids and related metabolites were detected in the probiotic group than in the placebo group postintervention. Taken together, the results of our study showed that the coadministration of probiotics with metformin synergized with the hypoglycemic effect in patients with type 2 diabetes mellitus, which was likely through modulating the gut microbiome and, subsequently, SCFA and bile acid metabolism. Our findings support that cotreatment with probiotics and metformin is beneficial to patients with type 2 diabetes mellitus. IMPORTANCE Metformin causes variable adverse gastrointestinal effects, especially after prolonged treatment. We found that cotreatment with Probio-X and metformin for the management of type 2 diabetes mellitus may promote gut SCFA-producing bacteria and the levels of specific bile acids, thus increasing the secretion of related gastrointestinal hormones and ultimately improving glucose homeostasis.