Following several indications that gut microbes may be key players in the obesity epidemic, a new study offers a mechanistic explanation of how the gut inhabitants directly cause 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 through 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. As a result, rodents began to eat more, develop insulin resistance – a precursor to diabetes – and become obese, the researchers report in Nature.
“This generates a positive feedback loop,” the authors conclude — which makes sense for animal foraging, they add. If a foraging animal stumbles upon high-calorie food in the wild, it would be beneficial if their guts signaled their brain to keep eating and store some energy, to stock up to survive lean times. However, in the setting of chronic exposure to calorically dense, abundant foods, this gut microbiota-brain β-cell axis promotes obesity and the related consequences of hyperlipidemia. [high levels of lipids in the blood]fatty liver and insulin resistance,” the authors write.
Further, the findings highlight “a previously unknown role for the gut” and provide “a hint as to how the microbiota might drive obesity,” said diabetes researchers Mirko Trajkovski and Claes Wollheim of the University of Geneva, who were not involved in the study. If human studies support the findings, they could point to new obesity treatments aimed at numbing the vagus nerve to acetate signals or thwarting the acetate-forming microbes in the gut, as in fecal transplants or bacterial transfers, the two researchers suggest.
For the study, led by Gerald Shulman at Yale University, researchers followed up on previous reports that changes in short-chain fatty acids in the blood are linked to obesity, overeating and metabolic problems. They quickly found one of those fatty acids, acetate, which they found was elevated 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 turned it acidic.
When the researchers injected acetate into the stomachs or brains of rats on a normal diet, the fatty acid prompted the animals to produce more insulin. This result disappeared when the researchers clipped off the rats’ vagus nerve 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 elevated 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 undergone a fecal transplant from normal mice. The germ-free mice had negligible amounts of acetate compared to the re-germinated mice. The researchers then took the ex-germ-free mice and fed them either normal chow or high-fat chow. The fat-fed mice had twice as much acetate as 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.”
Nature2016. DOI: 10.1038/nature18309 (About DOIs).