Prebiotics strengthen the hypoglycemic effects of metformin through the gut microbiota in mice

Recent research has found that the gut microbiota may play an important role not only in the development of type 2 diabetes mellitus (T2DM), but also the therapeutic actions of the widely prescribed antidiabetic drug metformin. Although dietary fiber has documented effects on preventing T2DM and improving glucose metabolism in diabetic individuals, little is known about whether prebiotics could have an impact on the hypoglycemic effects of metformin.

A new study, led by Dr. Jinsong Shi from the Key Laboratory of Carbohydrate Chemistry and Biotechnology at the School of Pharmaceutical Sciences at Tsinghua University in China, has found that prebiotic mannan-oligosaccharides increase the hypoglycemic effects of metformin in parallel with changes in the gut microbiota in mice.

The researchers sought to investigate whether the combination usage of metformin with a prebiotic of konjac mannan-oligosaccharides (MOS) might have synergetic effects in a mice model of T2DM, which was induced with a high-fat diet and streptozotocin. Treatment regimens that were given orally for 5 weeks included metformin alone (administered at high—200 mg/kg/day—and low—75 mg/kg/day—dosages), MOS alone (administered at high—8 g/kg/day, medium—4 g/kg/day, and low—2 g/kg/day—dosages), and the combination of metformin and MOS (administered at different, randomly combined dosages). Normal mice treated with saline and diabetic mice (treated both with and without saline) were used as control groups. Blood samples for biochemical analysis, pancreas and liver samples for histological analysis and fecal samples for gut microbiota analysis were all collected.

A combination of metformin and MOS for 5 weeks gave superior results in terms of insulin sensitivity improvement in comparison with treatment either using only metformin or only MOS. This was reported through a significant reduction in levels of fasting blood glucose, hemoglobin A1c (HbA1C), and homeostasis assessment of the insulin resistance (HOMA-IR) index.

Metformin and MOS treatments ameliorated hepatic steatosis and b-cell dysfunction to different degrees in diabetic mice. The most predominantly repairing effects on pancreatic islets and hepatic histology were seen when metformin and MOS were used together.

Treatments with MOS alone or in combination with metformin led to different changes in the structure of the gut microbiota. A combination treatment of both metformin and MOS modulated a higher number of operational taxonomic units when compared with only metformin and only MOS treatments. It is worth noting that key bacterial species were modulated by metformin and MOS: the relative abundances of family Rikenellaceae and order Clostridiales decreased while an unnamed OTU05945 of family S24-7, Akkermansia muciniphila and Bifidobacterium pseudolongum increased. Furthermore, several associations were found between the alterations in gut microbial populations and host parameters related to diabetes, including fasting blood glucose, HOMA-IR, HbA1c and the area under the glucose concentration-time curve following oral glucose tolerance tests at different times.

Regarding the impact of treatment on the functional diversity of the gut microbiota, the combination of metformin with high-dose MOS exerted favorable effects by diminishing methane metabolism, glycolysis/gluconeogenesis metabolism, and starch and sucrose metabolism. These findings have previously been related to an improvement in lipid and carbohydrate metabolism in prediabetic subjects with obesity. In contrast, the gut microbiota’s energy metabolism in the diabetic group was significantly weakened, while carbohydrate metabolism was intensified compared to normal control.

To sum up, these experimental findings suggest that the concomitant use of MOS with metformin increases the hypoglycemic effects of metformin in parallel with changes in the gut microbiota composition. Human trials are needed to clarify the implications of dietary fiber on metformin’s therapeutic effects.



Zheng J, Li H, Zhang X, et al. Prebiotic mannan-oligosaccharides augment the hypoglycemic effects of metformin in correlation with modulating gut microbiota. J Agric Food Chem. 2018; 66(23):5821-31. doi: 10.1021/acs.jafc.8b00829.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados