Molecule Linking Weight Gain To Gut Bacteria Found, Says Study

Researchers have found a key molecule that helps bacteria living in the guts of mammals to influence the body's process behind the absorption of dietary fat. The findings, published in the journal Science, may help understand the root causes of obesity in affluent countries, and malnutrition in impoverished countries. The researchers, including those from the University of Texas Southwestern Medical Center in the US, found a key molecule involved in synchronising the absorption of nutrients in the gut with our body's natural clock that lets one's cells perceive the day-night cycle.

They found that the beneficial microbes in the gut wind up the body's biological clock, or circadian rhythm, by activating a protein called histone deacetylase 3 (HDAC3) which is made by cells lining the gut.

These cells, the researchers said, act as intermediaries between bacteria that aid in the digestion of food, and proteins that play a role in absorption of nutrients.

The experiments, performed in mice, revealed that HDAC3 activates genes that are involved in the absorption of fat.

They found that HDAC3 interacts with the biological clock related processes in the gut to refine the rhythmic flow of proteins involved in fat absorption.

According to the researchers, this regulation happens in the daytime in humans -- who eat during the day -- and at night in mice, which eat at night. "The microbiome actually communicates with our metabolic machinery to make fat absorption more efficient," said lead author Zheng Kuang of UT Southwestern.

Kuang added that when fat is overabundant, the communication could result in obesity. "Whether the same thing is going on in other mammals, including humans, is the subject of future studies," he said.

The researchers said that histone modifications - a chemical change made by enzymes like HDAC3 - control the expression of genes, which regulates the protein making machinery within cells. Researchers at Lora Hooper's lab in UT Southwestern decided to perform a study in mice on histone modifications that seemed to rise and fall along with the circadian rhythms.

They compared normal, bacteria-laden mice with ones free of the microbes, and discovered that some histone modifications - including those made by HDAC3 - were rhythmic depending on the time of the day in normal mice, but held steady at a flat level in germ-free mice. The researchers developed a mouse lacking HDAC3 only in the gut lining -- which they said was "unremarkable while eating a normal chow diet."

When the same mouse was fed a high fat, high sugar diet -- similar to one commonly consumed in the United States -- the researchers found something very different. "We call it the junk food diet. I describe it as like driving through a fast food restaurant for a burger and fries and then stopping off at the donut shop," Hooper said.

She added that most mice on that diet become obese. "To our surprise, those that had no HDAC3 in their intestinal lining were able to eat a high fat, high sugar diet, and stay lean," Hooper said.

When the researchers compared the HDAC3-deficient mice to the germ-free mice, they found that both groups of mice showed the same flat, nonrhythmic histone modifications, confirming that HDAC3 was important in circadian rhythms. According to the researchers, HDAC3 attached to the clock machinery -- present in every cell of the body -- to ensure that fat absorption was highest when mammals were awake and eating.

"Our results suggest that the microbiome and the circadian clock have evolved to work together to regulate metabolism," Hooper said. According to Hooper, the mechanism could have evolved to enable mammals to use energy efficiently in order to boost immunity in an environment with food scarcity.