After several hints that gut microbes may be key players in the obesity epidemic, a new study provides a mechanistic explanation of how the intestinal inhabitants directly induce hunger, insulin resistance, and ultimately obesity in rodents.

After mice and rats were fed a high-fat diet, their gut microbes produced more acetate, a short-chain fatty acid made during bacterial fermentation. That acetate spread throughout the rodents’ bodies and into their brains where it activated the parasympathetic nervous system. This system, largely involving the vagus nerve, controls the body’s unconscious actions, such as digestion, excretion, and sexual arousal. By activating the parasympathetic nervous system, the microbe-made acetate spurred the rodents to produce more insulin, a hormone made by pancreatic β-cells that promotes calorie storage, as well as ghrelin, a hormone involved in hunger. The result was that rodents started eating more, developed insulin resistance—a precursor to diabetes—and became obese, the researchers report in Nature.

“This generates a positive feedback loop,” the authors conclude—which makes sense for foraging animals, they add. If a foraging animal stumbles upon a calorie-dense food in the wild, it would be advantageous if their gut signaled their brain to keep eating and store some energy, stocking up to survive leaner times. “However, in the setting of chronic exposure to calorically dense, abundant food, this gut microbiota–brain–β-cell axis promotes obesity and its related sequelae of hyperlipidaemia [high levels of lipids in the blood], fatty liver disease and insulin resistance,” the authors write.

Further, the findings “highlight a previously unknown role for the gut,” and offer “a hint as to how the microbiota might provoke obesity,” according to diabetes researchers Mirko Trajkovski and Claes Wollheim of the University of Geneva, who were not involved with the study. If studies in humans support the findings, they could point to new obesity treatments focused on numbing the vagus nerve to acetate signals or thwarting the acetate-making microbes in the gut, such as with fecal transplants or bacterial transfers, the two researchers suggest.

For the study, led by Gerald Shulman at Yale University, researchers followed up on earlier reports that changes in short-chain fatty acids in the blood are linked to obesity, over-eating, and metabolic problems. They quickly homed in on one of those fatty acids, acetate, which they found increased in rats fed high-fat diets. When the researchers scraped out the rats’ gut bacteria or gave them antibiotics, that boost in acetate disappeared, suggesting that the gut microbes were making the acid.

When the researchers infused acetate into the stomachs or brains of rats on a normal diet, the fatty acid spurred the animals to produce more insulin. This result vanished when the researchers snipped the rats’ vagus nerves or used drugs to block the parasympathetic nervous system.

In follow-up experiments, the rats on acetate ate more—doubling their daily caloric intake—gained weight, had increased levels of ghrelin in their blood, and became insulin resistant.

In a final set of experiments, the researchers looked at germ-free mice and ex-germ-free mice that had gone through a fecal transplant from normal mice. The germ-free mice had negligible amounts of acetate compared to the re-germed mice. The researchers then took the ex-germ-free mice and fed them either a normal chow or a high-fat chow. The mice feasting on fat had double the amount of acetate than the normal chow-fed mice, plus elevated levels of ghrelin.

Together, Trajkovski and Wollheim conclude, “these data suggest a mechanistic link between the onset of obesity and the gut microbiota.”

Nature, 2016. DOI: 10.1038/nature18309 (About DOIs).