Rapid metformin effects on multiple intestinal functions in high-fat high-sucrose fed mice

Although the mechanism of action of the antidiabetic drug metformin is still a matter of discussions, it is well accepted that the gut plays an important role. To gain more insights into the mechanisms that occur in the different regions of the intestinal tract in response to metformin treatment, adult male mice were fed a high-fat-high sucrose (HFS) diet for 8 days. Metformin treatment by gavage (300 mg/day/kg body weight) during the HFS diet improved glucose tolerance. Metformin counteracted HFS diet-induced overexpression of a network of genes involved in the transport of glucose and fatty acids in the small intestine, and induced beneficial modification of secondary bile acid profile in the caecum, with reduction in DCA and LCA levels and increased abundance of UDCA and TUDCA, potentially leading to FRX inhibition. In parallel, metformin treatment was associated with specific changes in the microbiota composition in the lumen of the different regions of the gut, counteracting the effects of HFS diet on the abundances of some bacterial groups generally associated with metabolic disturbances (f-Lachnospiraceae, f-Petostreptococcaceae, g-Clostidium). In addition, metformin promotes a strong increase in the abundance of Akkermansia muciniphila in the intestinal lumen all along the gut. Therefore, the present work clearly emphasises the role of all the regions of the intestinal tract in the beneficial action of the antidiabetic drug metformin in a prediabetic mouse model.