Leigh MacMillan

Bacteria residing in the small intestines — the gut microbiota — produce a compound that protects against obesity, Vanderbilt researchers have discovered. The findings in a mouse model, reported in the journal Cell Host & Microbe, shed light on how disturbances in the microbiota, such as early-life exposure to antibiotics, increase risk for childhood obesity.

They also offer the intriguing possibility that providing beneficial probiotic bacteria or the compound they produce could help prevent antibiotic-associated childhood obesity.

“Other studies have shown that in children, antibiotics alone or high-fat diet alone can lead to obesity later in life through disruption of the microbiota,” said Mariana Byndloss, DVM, PhD, assistant professor of Pathology, Microbiology and Immunology. “But it has not been clear what happens when these risk factors are combined. We wanted to explore the idea that kids are being exposed to more than one risk factor at the same time.”

In studies led by graduate student Catherine Shelton, first author of the paper, the researchers developed a model in which young mice are simultaneously exposed to antibiotics and a high-fat diet. They found that this combined exposure increased weight gain, adiposity and metabolic dysfunction.

The researchers showed that the combination of antibiotics and a high-fat diet disrupted the small intestine microbiota. The combination reduced levels of a certain beneficial microbe in the Lactobacillus family and reduced levels of a metabolite produced by these bacteria, a compound called phenyllactic acid. They found that phenyllactic acid regulates a signaling pathway involved in fat metabolism in intestinal epithelial cells, the cells that line the intestines.

“The lack of this one microbe and its metabolite alters the way that intestinal epithelial cells package fat, so that the cells put more fat into the circulation,” Byndloss said. “Phenyllactic acid is a metabolite that normally tells the epithelial cells not to package and secrete as much fat. When the epithelial cells lose that signal from the microbiota, they start to behave differently, and the mice get fatter.”

It would be interesting, Byndloss said, to determine if giving children phenyllactic acid or Lactobacillus bacteria reduces the risk of obesity, especially for children who are taking antibiotics.

Lactobacillus bacteria are commonly used as probiotics, and both the bacteria and phenyllactic acid are found in fermented foods like kombucha, kimchi and probiotic milk products popular in Asia.

“Some cultures encourage their kids to drink fermented milk, so they may already be unintentionally providing this protective ‘therapeutic’ to their children,” Byndloss said.

In the mouse model, antibiotic exposure alone did not increase weight gain; only the combination of antibiotics and a high-fat diet increased obesity.

“One of the ways to mitigate the bad effects of antibiotics on the microbiota is for children to consume a healthy diet and not consume excess dietary fats,” Byndloss said.

The researchers were surprised to discover an important role for the intestinal epithelium in driving weight gain.

“Intestinal epithelial cells are not the first cells we think of as contributing to obesity, we’re more likely to think about adipose tissue and liver,” Byndloss said. “It was surprising that a single metabolite acting on intestinal epithelial cells had such an impact in preventing weight gain.”

In ongoing studies, Byndloss and her colleagues are examining the role of Lactobacillus and phenyllactic acid earlier in life during breastfeeding.

“We know that breast milk has a high fat content, and we’re looking to see if this pathway plays a protective role against obesity very early in life too,” she said.

This research was supported by the National Institutes of Health (grants T32AI112541, F31AI161882, T32ES007028, T32DK007673, R01DK131104, R01AI168302), Danone North America, Howard Hughes Medical Institute, Department of Veterans Affairs, The V Foundation for Cancer Research, The Pew Charitable Trusts, Department of Medicine at VUMC and Vanderbilt Institute for Clinical and Translational Research.