Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes

Aim: Gastrointestinal discomfort is the most common adverse event in metformin treatment for type 2 diabetes. The mechanism of action of metformin is associated with gut microbiota. However, the gut microbial community structure related to metformin-induced gastrointestinal adverse events remains unclear. This study aimed to investigate it.

Methods: 50 patients with newly diagnosed diabetes were treated with metformin 1500mg/d for 12 weeks. The patients were divided into two groups according to whether gastrointestinal adverse events occurred (group B) or did not occur (group A) after treatment. The fecal bacterial communities and short-chain fatty acids (SCFAs) were sequenced and compared. 70 diabetes mice were randomly divided into 8 groups and treated with metformin (Met), clindamycin (Clin) and/or SCFA, which were the Met+/Clin+, Met+/Clin-, Met-/Clin+, Met-/Clin-, Met+/SCFA+, Met+/SCFA-, Met-/SCFA+ and Met-/SCFA- group. After 4 weeks of metformin treatment, blood glucose, food intake, fecal SCFAs, gut microbiota and gut hormones were measured.

Results: Metformin increased the abundance of Phascolarctobacterium, Intestinimonas and Clostridium III. Functional prediction analysis showed that the propanoate metabolism pathway was significantly up-regulated. The concentrations of acetic acid and propanoic acid in feces were significantly increased. The abundance of Clostridium sensu stricto, Streptococcus and Akkermansia induced by metformin in group B was higher than that in group A. The propanoate metabolism pathway and propanoic acid in feces were significantly up-regulated in group B. In the animal experiments, the food intake decreased and glucose control increased in metformin groups compared with those in the control groups. The total GLP-1 level in the Met+/Clin- group was significantly higher than that in the Met-/Clin- group, while there was no statistical difference between the Met-/Clin- and Met+/Clin+ group. The total GLP-1 level in the Met-/SCFA+ group was significantly higher than that in the Met-/SCFA-group, while the levels of total GLP-1 and active GLP-1 in the Met+/SCFA- group and the Met+/SCFA+ group were significantly higher than those in the Met-/SCFA-group.

Conclusions: Our data suggest that metformin promotes the secretion of intestinal hormones such as GLP-1 by increasing the abundance of SCFA-producing bacteria, which not only plays an anti-diabetic role, but also may causes gastrointestinal adverse events.