24 May 2017

Gut bacteria have taken up the fight against diabetes

Anna Kaznadzei, N+1

Scientists from the Universities of Gothenburg and Girona have found out that when treating type 2 diabetes with metformin, the composition and characteristics of the intestinal microbiome change. This has a significant auxiliary effect in therapy, establishing a system for regulating the level of sugar and glycosylated hemoglobin in the blood. The study is published in Nature Medicine (Wu et al., Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug).

Metformin is a drug that is often used for patients with type 2 diabetes. It helps to lower blood sugar levels by reducing its production in the liver, activating, in particular, 5'AMP-activated protein kinase. However, the mechanism of its action is almost unknown. It works even when using drugs with a low concentration, in addition, it works better with oral administration than with intravenous. According to a number of studies of various types of drugs, its main work takes place in the lower intestine. Scientists decided to find out whether metformin affects the composition of intestinal bacteria, and whether this plays a role in the treatment of diabetes.

For four months, 40 volunteers with type 2 diabetes followed a low-calorie diet and participated in a double-blind study, taking either metformin or a placebo. Both groups lost weight at the end of the experiment, but only the metformin group significantly decreased blood glucose and HbA1c (glycosylated hemoglobin, a high level of which is characteristic of diabetics). After six months, the body mass index in people of the metformin group stopped decreasing, but the level of glucose and HbA1c in their blood continued to fall.

To assess how much the composition of the intestinal microbiome has changed in the studied groups, DNA sequencing of 131 fecal samples was performed and data on the corresponding metagenomes were obtained. In the placebo group, the composition of bacterial strains remained almost unchanged, and in the metformin group, changes occurred in more than eighty strains, most of which belonged to gammaproteobacteria. The level of Esherichia has significantly increased and the level of Intestinibacter has decreased. For example, the number of Akkermansia muciniphila bacteria has also increased – this was previously associated with the action of metformin, but in this study, scientists did not find a reliable correlation between the number of these bacteria in the intestine and the level of HbA1c reduction.

Some part of the placebo group also underwent metformin treatment six months later, and showed the same results as the metformin group in the first part of the project. They also had an increase in the level of bacteria of the genus Bifidobacterium. It turned out that metformin directly affects the replication processes in Bifidobacterium adolescentis and Akkermansia muciniphila, increasing the growth of these bacteria, but does not have such an effect, for example, on bacteria of the genus Esherichia. Scientists have shown that the drug has a significant effect on the positive connections between different bacteria, strengthening them, so it affects many individual species not directly, but indirectly.


Strengthening of positive connections between different groups of bacteria under the influence of metformin. The connections are shown at the beginning of the experiment (M0, blue) and two months later (M2, purple), as well as negative connections (gray). A drawing from an article in Nature Medicine.

Fecal samples were taken from three people taking metformin before and after the experiment. These samples were fed to mice that do not have their own microbiomes, which were previously brought to a state similar to type 2 diabetes with the help of a high-calorie diet. In two out of three cases, as well as when combining samples of three people in one, the mice showed significant improvements in their ability to control blood sugar levels and in reducing HbA1c. In the control group of mice that received fecal samples from the placebo group, no improvement was observed.

It turned out that metformin influenced the regulation of many bacterial genes, with the most significant changes occurring in the period from 2 to 4 months of taking the drug. The genes responsible for membrane transport, sugar metabolism, drug resistance and a number of others were affected. It is curious that the metabolism of bacteria changed differently in the intestines of men and women: in particular, the level of butyrates and acetates (short-chain fatty acids) increased in the samples of men, but not women, but the level of lactate and succinate increased equally in both.

The experiment was supplemented by processing samples with a constant flow of metformin for a week, and an even more complete picture of changes in the microbiome under the influence of this substance was obtained. In some bacteria, the synthesis of RNA increased (that is, the metabolism changed), in others – DNA (that is, they began to multiply more intensively). Among other things, it turned out that metformin significantly affects the bacterial transport of metal-containing proteins and the synthesis of complexes responsible for the transport of various metals. Scientists suggest that, perhaps, it is through these systems that metformin exerts its initial effect on bacterial cells.

In the future, the researchers plan to find out exactly how the change in the composition and functioning of the microbiome after taking metformin affects the mechanisms of regulation of blood sugar levels.

Portal "Eternal youth" http://vechnayamolodost.ru  24.05.2017

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