Gut bacteria and caloric restriction hold potential for obesity-fighting drug, mouse study says

31 Aug 2018 --- Mice with a lower calorie intake live longer and are both healthier and leaner, research has generally determined, and now, a study may have found the reason for this positive effect. The researchers identified that much of it is down to gut microbial communities and how they affect the immune system. The researchers hope that their work, published in Cell Metabolism, may one day make it possible to treat obese people with a drug that simulates caloric restriction, following the team uncovering compounds that can mimic caloric restriction.

Reducing the intake of calories by up to 40 percent has long been known to have a beneficial effect on animal health: the animals live longer, blood-sugar levels drop faster and they burn more body fat. 

The international team of researchers, led by Mirko Trajkovski Swiss National Science Foundation (SNSF) Professor at the University of Geneva, restricted the calorie intake of mice for 30 days and found an increased amount of beige fat, a type of fat tissue that burns body fat and contributes to weight loss.

When they transferred the caecum microbial communities from the calorie-restricted mice to other mice raised and still living in sterile conditions (i.e., without microbes in their gut), the receiving animals also developed more beige fat and were leaner despite eating normally. So, the change of the microbiome alone created health benefits for the mice.

When analyzing these microbial communities, Trajkovski's team found that the gut bacteria of mice on a calorie-restricted diet produced lower levels of a toxic molecule called Lipopolysaccharide (LPS). When the LPS-levels were reconstituted to normal levels in the blood, the mice lost many health benefits of the diet.

New compounds may help in treating obesity
The bacterial LPS molecule is known to trigger an immune response by activating a specific signal receptor known as the Toll-like receptor 4 (TLR4). Experimenting on mice with genetically modified immune cells lacking this receptor, the researchers were able to mimic the effect of the caloric restriction. 

“Clearly the immune system not only combats infections, but it also plays a key role in regulating metabolism,” says Trajkovski. Apart from more beige fat and weight loss, the mice react better to insulin, their livers process sugar and fat in healthier ways and the mice are better equipped to withstand colder temperatures. 

“This is turning into an entirely new field of research,” Trajkovski adds. Having dissected the mechanism behind caloric restriction, the researchers set out to test two compounds: one of them directly reduces toxic LPS production by the bacteria and the other blocks the TLR4 receptor that receives the LPS signal. Both had a positive effect on the mice that was similar to that of eating less. 

“It may one day become possible to treat obese people with a drug that simulates caloric restriction,” says Trajkovski. “We are currently investigating the precise changes in bacterial communities, and we are also testing other compounds that reduce LPS production and signaling.”