Gut microbiota plays a role in metformin mechanism of action
medwireNews: The antidiabetic effects of metformin may be mediated, in part, by alterations in the composition and function of the gut microbiota, a study in patients with type 2 diabetes suggests.
José Manuel Fernàndez-Real (University of Girona, Spain) and colleagues randomly assigned individuals with newly diagnosed type 2 diabetes on a calorie-restricted diet to receive treatment with placebo (n=18) or metformin 1700 mg/day (n=22) for 4 months.
Whole genome sequencing of fecal samples taken at baseline and after 2 and 4 months on treatment showed that only one bacterial strain was altered during this time in patients receiving placebo, despite a reduction in body mass index.
By contrast, the relative abundance of 81 and 86 bacterial strains, most commonly γ-proteobacteria (for example, Escherichia coli) and Firmicutes, were significantly altered at 2 and 4 months, respectively, among the patients receiving metformin.
These changes occurred in parallel with reductions in glycated hemoglobin (HbA1c) levels and fasting blood glucose concentrations, and were confirmed in 13 patients from the placebo group who switched to metformin after 6 months, the researchers report in Nature Medicine.
Typically, they found an increase in Escherichiaspp and a decrease in Intestinibacterspp in the metformin-treated group, as well as an increase in Bifidobacterium among the subgroup that switched from placebo to metformin.
The team also observed a negative correlation between the genomic peak-to-trough ratio of B. adolescentis and HbA1c level, “which suggests that increased growth of this bacterial species could potentially contribute to the antidiabetic effect of metformin.”
Next Fernàndez-Real and colleagues then transferred fecal samples collected before and 4 months after metformin treatment to germ-free mice. There was no difference in body weight, body fat, or fasting insulin between mice that received the before and after samples, but glucose tolerance was significantly improved in mice that received month 4 microbiota, compared with those that received pretreatment microbiota.
The researchers say this indicates “that metformin-adapted microbiota could contribute to the beneficial effects of metformin on glucose homeostasis.”
Finally, the team used an in vitro gut simulator to observe direct metformin–microbiota interactions. They found that pathways involved in lipopolysaccharide synthesis, butyrate and pyruvate metabolism, two-component systems, and the metabolism of cofactors and vitamins were enriched by metformin.
Furthermore, 81 of the 108 metformin-regulated genes encoded metalloproteins or metal transporters, which Fernàndez-Real et al say is interesting because “some metals are known to contribute to [type 2 diabetes] pathophysiology.”
However, they note that they “cannot conclude that the major mechanism of action of metformin is through the microbiota,” because other studies have shown that “the phosphorylation of acetyl-CoA carboxylases (ACC) 1 and 2 by AMPK [AMP-activated protein kinase] is required to observe the insulin-sensitizing effects of metformin.”
But they add: “[I]t is possible that the gut microbiota might also act through ACCs, given that we previously showed that diet-induced obesity involved cross-talk between the microbiota, AMPK, and downstream ACC2 phosphorylation.”
By Laura Cowen
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