Metformin is a drug that helps people with type 2 diabetes control their blood glucose level, but nobody really knows how it works.
There is evidence that metformin suppresses the hepatic output of glucose by altering the activity of AMPK-dependent and independent signaling pathways. However, some studies suggest that its glucose-lowering activity occurs in the bowel, and researchers at Sahlgrenska Academy knew that the microbiome is altered in people with diabetes.
To determine how the microbiome is affected by metformin, they sequenced the microbiomes of 22 people with newly diagnosed diabetes - before and after they started taking metformin or a placebo. They also transferred human fecal samples to mice and studied the effects of these microbes on glucose metabolism.
First, the group performed whole-genome shotgun sequencing on fecal samples to characterize the microbiome. The abundance of only one type of bacteria changed in the placebo group, but metformin significantly altered the abundance of 86 strains after 4 months of treatment. The majority of these belonged to the γ-proteobacteria and Firmicutes. Specifically, metformin altered the abundance of Escherichia and Intestinibacter species.
Next, they investigated whether the metformin-altered microbiota had any effect on blood glucose. To do this, they transferred fecal samples from humans to germ-free mice and measured glucose tolerance. Mice that received fecal samples from people treated with metformin for 4 months (versus untreated) improved their glucose tolerance.
Not only did metformin alter the abundance of some groups of bacteria, it also altered bacterial gene expression. For example, metformin treatment increased the expression of genes for bacterial secretion systems, two-component systems, ATP-binding cassette transporters, chemotaxis, antimicrobial peptide resistance, LPS biosynthesis, and certain metabolic pathways.
Gut bacteria are known to produce short-chain fatty acids (SCFAs) and regulate bile acid metabolism. It’s possible that these activities could work with metformin to benefit the host. Male subjects who were treated with metformin for four months had higher concentrations of fecal propionate and butyrate (SCFAs). Metformin also increased the fecal concentrations of organic acids such as lactate and succinate. As for bile acids, metformin did not alter bile acid metabolism in the gut, but plasma bile acid concentrations did increase.
According to study author Fredrik Bäckhed, “imagine if we can change the intestinal flora in the future so that more people respond to treatment, and that adverse events can be reduced by changing the gut microbiota of patients who will take metformin.”