Compounds found that mimic effects of calorie restriction in mice

The researchers showed that altering the intestinal microbial communities of mice alone produced a number of health benefits. Keystone

Mice on a low-calorie diet have shown signs of better health and a longer lifespan, which Swiss and Swedish researchers believe is linked to their gut bacteria. The scientists also found molecules that could be used to reproduce this effect in anti-obesity treatments.

Scientists have known for some time that reducing calorie intake by up to 40% has a beneficial effect on animal health: study subjects lived longer, their blood sugar dropped more quickly, and their bodies burned more fat. But according to a new study by an international team of researchers led by University of Geneva (UNIGE) professor Mirko Trajkovski, most of those physiological changes can be attributed to intestinal bacteria.

The findings were published Thursday in the journal Cell MetabolismExternal link.

Toxic compounds

According to a press release from the Swiss National Science Foundation (SNSF),External link to reach their conclusion, the researchers reduced the caloric intake of mice for 30 days and observed how much beige fat – a type of adipose tissue that burns body fat and can contribute to weight loss – accumulated.

The scientists then sampled intestinal microbes in the upper portion of the colons of these dieting mice and transferred those microbes to the intestines of mice on a normal diet, who did not have their own gut microbiome due to their being raised in a sterile environment. This second group of mice then developed more beige fat cells and lost weight, despite eating normally.

By analysing the composition of the microbiome, the Geneva team showed that the intestinal bacteria from the mice on a restricted diet produced fewer toxic compounds called lipopolysaccharides (LPS). When the blood LPS levels returned to normal, the mice lost the health benefits of their diet.

Key immune system role

It’s known that LPS produced by gut microbes trigger an immune response by activating a specific receptor called TLR4. The scientists were able to reproduce the effect of the caloric restriction by genetically modifying mice to lack this receptor.

“Clearly, the immune system doesn’t just fight infections, it plays a key role in regulating the metabolism,” explained Trajkovski in the SNSF statement.

In addition to the increased accumulation of beige fat and weight loss, these mice also reacted better to insulin, their livers metabolised sugar and fat in a healthier way, and they were more resistant to cold.

“These discoveries open a whole new field of research on obesity,” added Trajkovski.

New therapies on the horizon?

The team then decided to test two molecules: one that reduced the production of toxic LPS by gut bacteria, and another that blocked the TLR4 receptor. In the mice, both had a positive impact comparable to eating less.

“It will perhaps be possible one day to give people suffering from obesity a treatment simulating caloric restriction,” Trajkovski said.

The study was funded by the SNSF as well as the European Research Council (ERC) the Clayton Foundation and the Louis-Jeantet Foundation and conducted by researchers from the AstraZeneca IMED Biotech Unit in Gothenburg, Sweden, and the Inselspital Bern as well as UNIGE.