Treating diabetes by mimicking gut bacteria effects

In Nature Chemical Biology, the international team headed by Graeme Milligan from University of Glasgow report that drugs might mimic the effects of gut microbes that counteract development of type II diabetes.

So far, the mechanisms how bacteria of the gut microbiome mediate health benefits are not understood. However, it has been hypothesized that gut bacteria activate G-protein coupled receptor proteins (GPCRs) by means of  short chain fatty acids (SCFAs), fermentation products of starch in food such as oats and pulses.

In a four-year study, the team used a combination of genetics and pharmacology (chemogenetics) to find out whether he short chain free fatty acid receptor 2 (FFA2) generate responses in the body that underpin the health benefits of gut bacteria, when activated by ligands.

Using an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to its natural ligand acetic acid, but is activated by sorbic acid, they found out that blood glucose levels and fat in our bodies can be controlled by gut bacteria activating the free fatty acid receptor 2. When they activated FFA2 adipocytes and colonic crypt enteroendocrine cells of mouse, these started lipolysis and released glucagon-like peptide-1 (GLP-1), which controls blood glucose levels and the release of fat from fat tissue. Futher in vivo studies showed that FFA2 activation is crucial for accelerating gut transit.

“We believe that the positive health benefits of gut bacteria can be mimicked by drugs that activate this receptor protein,” commented co-author Andrew Tobin, Professor of Molecular Pharmacology at the University’s Institute of Molecular Cell & Systems Biology. “

The scientists believe that FFA2 could be a target for new drugs in diseases where our response to food intake is dysfunctional, such as in type II diabetes. Prof Tobin stressed: “This is a major advance in our understanding our how our bodies respond to food and how the bacteria in our gut provide health benefits. Whereas many people are trying to capture the health benefits of the gut microbiome through probiotics, our study indicates that we can bypass the bacteria in our gut and directly target our bodies’ receptors with drugs that mimic the gut bacteria to provide health benefits in diseases such as type II diabetes.”