Metformin's Effect in Diabetes Linked to Gut Microbiota Changes

Nancy A. Melville

November 29, 2018

The glucose-lowering effects of the first-line treatment for type 2 diabetes, metformin, have long been thought to be mediated through effects on liver cells, but new research suggests the drug may also significantly affect the gut microbiota and that this may independently contribute to glucose control.

"These results suggest that oral metformin treatment regulates the gut microbiota and bile acid metabolism in individuals with type 2 diabetes," the authors report in research published in Nature Medicine.

Although evidence links metformin's effects to activity in hepatocytes, the oral drug reaches high concentrations in the small intestine. In a previous study, people who had undergone treatment with metformin were indeed found to have alterations in gut microbiota.

To further investigate this, Changtao Jiang, MD, PhD, of the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, China, and colleagues enrolled 22 patients with newly diagnosed type 2 diabetes who had not previously been treated with metformin. The patients were treated with 1000 mg of metformin twice daily for 3 days. Serum and stool samples were collected from these patients both before and after they had undergone treatment with metformin.

Analysis of Human Stools Shows Metformin Acts on Gut Microbiota

Genetic and metabolic analyses of serum and stool samples showed notable decreases in Bacteroides fragilis, in addition to increases in glycoursodeoxycholic acid (GUDCA), a bile acid, following metformin treatment.

In addition, the posttreatment samples showed an inhibition of signaling of intestinal farnesoid X receptor (FXR), a nuclear receptor involved in the regulation of hepatic bile acid that is involved in various metabolic diseases.

In the distal ileum, FXR, activated by bile acids, induces expression of the FGF19 gene in humans. Levels of the protein produced by this gene were found to be substantially decreased after metformin treatment, the authors report.

"FGF19 levels in serum of individuals with type 2 diabetes were dramatically decreased, and 7α-hydroxy-4-cholesten-3-one (C4) levels were markedly increased after metformin treatment, suggesting that intestinal FXR signaling was suppressed and hepatic CYP7A1 activity was increased," they explain.

To further analyze the effect, the investigators transferred stool samples that had been collected from the diabetes patients both before treatment with metformin and after treament into mice that had been fed a high-fat diet.

Consistent with the findings in humans, they discovered that levels of B fragilis were substantially lower in those mice that had received stool from patients who had been given metformin than in the mice that had been given stool from patients who had not yet received metformin.

In mice that had been colonized with B fragilis, body weight was increased, glucose tolerance was more impaired, and insulin sensitivity was lower than in control mice.

Furthermore, the bile acid GUDCA was found to be beneficial in mice. GUDCA, which acts as an intestinal FXR antagonist, was associated with improvements in metabolic endpoints in the obese animals.

The authors caution that human and mouse bile acid profiles differ in important ways. Nevertheless, the findings reveal important insights into key effects that metformin has in the human gut, they say.

"The current study revealed that metformin treatment increased the levels of the bile acid GUDCA in the gut by decreasing the abundance of species of B fragilis and its bile salt hydrolase (BSH) activity in the intestines of individuals with T2D [type 2 diabetes], as revealed by metagenomics sequencing analysis and metabolomics analysis," they explain.

"Furthermore, we identified GUDCA as a new endogenous antagonist of intestinal FXR," they write.

Overall, the findings suggest that that the metformin-induced improvement of metabolism is mediated by a B fragilis–GUDCA–intestinal FXR axis in humans. This could have important clinical implications, the authors stress.

"Moreover, oral GUDCA supplementation or a synthetic FXR antagonist may be of potential translational value in the clinical treatment of T2D," they state.

The authors have disclosed no relevant financial relationships.

Nat Med. Published online November 5, 2018. Abstract


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