Gut bacteria found to prevent obesity in mice

Friday, 09 August, 2019

Gut bacteria found to prevent obesity in mice

Researchers from the University of Utah Health have identified a specific class of bacteria from the gut that prevents mice from becoming obese, suggesting these same microbes may similarly control weight in people.

Published in the journal Science, the study shows that healthy mice have plenty of Clostridia — a class of 20 to 30 bacteria in the gut microbiome — but those with an impaired immune system lose these microbes from their gut as they age, at which point they inevitably become obese.

It all started when Charisse Petersen, working in the lab of June Round, saw that mice genetically engineered to lack myd88, a gene central to the immune response, were in her words “as fat as pancakes”. She had let the rodents age longer than usual, revealing an unappreciated link between immunity and obesity — but the observation didn’t explain why the animals became overweight in the first place.

Petersen suspected the microbiome was involved, having previously helped demonstrate that one role of the immune system is to maintain balance among the diverse array of bacteria in the gut. Impairing the body’s defences can cause certain bacterial species to dominate over others — and sometimes, the shift negatively impacts health.

Following a similar logic, Petersen and colleagues determined that the obesity observed in immune-compromised mice stemmed from the failure of the body’s defence system to appropriately recognise bacteria. These mice produced fewer of the antibodies that ordinarily latch onto the microbiome like target-seeking missiles. This change made the gut less hospitable for Clostridia, leading to excessive weight gain and even signs of type 2 diabetes. This obesity persisted even when the mice were fed a healthy diet.

The colleagues subsequently found that one or more molecules produced by Clostridia prevent weight gain by blocking the intestine’s ability to absorb fat. When mice were experimentally treated so that Clostridia were the only bacteria living in their gut, they were leaner with less fat than mice that had no microbiome at all. They also had lower levels of the gene CD36, which regulates the body’s uptake of fatty acids.

TFH cells regulate IgA production, which appropriately sculpts the microbiota. Loss of this instruction leads to expansion of Desulfovibrio that negatively affects the colonisation of beneficial Clostridia. Clostridia function to temper expression of CD36 and lipid absorption. Thus, a reduction in beneficial Clostridia can lead to obesity.

The researchers’ next step is to isolate these Clostridia molecules and further characterise how they work, to determine whether they could inspire focused treatments for obesity, type 2 diabetes and other related metabolic disorders. Round noted, “Now that we’ve found the minimal bacteria responsible for this slimming effect, we have the potential to really understand what the organisms are doing and whether they have therapeutic value.”

According to Round, such a therapeutic approach could have advantages over the faecal transplants and probiotics that are now being widely investigated as ways to restore a healthy microbiota. Therapeutics such as these, based on transferring living microbiome to the gut, won’t work for everyone due to differences in diet and other factors that influence which bacteria can survive and thrive.

Round added that research by others has shown that people who are obese similarly lack Clostridia, mirroring the situation in these mice. There are also some indications that people who are obese or have type 2 diabetes may have a suboptimal immune response. The hope is that understanding these connections will provide new insights into preventing and treating these pervasive health conditions.

“We’ve stumbled onto a relatively unexplored aspect of type 2 diabetes and obesity,” said Round. “This work will open new investigations on how the immune response regulates the microbiome and metabolic disease.”

Top image credit: © Duda

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