Intestinal Bacteria Restricts Fat Absorption

Researchers from the UT Southwestern Medical Center reveal that intestinal bacteria suppress a chemical that regulates the amount of fat absorbed, leading to an increase in weight gain in mice fed a high-sugar, high-fat diet. The research, which was reported in Science, may someday help develop novel treatments for obesity, diabetes, and malnutrition, which affect hundreds of millions of people globally.

“We know that there are big differences in the composition of the gut microbiome between lean and obese mice, as well as lean and obese people. The question we’ve been grappling with is, does our microbiome cause metabolic changes that promote obesity, and if so, what are the molecular causes? This study paints part of that picture,” said Lora Hooper, Ph.D., Professor and Chair of Immunology, Professor of Microbiology, a member of the Center for the Genetics of Host Defense at UT Southwestern, and a Howard Hughes Medical Institute Investigator. Dr. Hooper co-led the study with Yuhao Wang, Ph.D., a former UTSW graduate student and postdoctoral researcher in the Hooper lab who is now a faculty member at Zhejiang University in Hangzhou, China.

It has long been recognized by scientists that “germ-free” mice, which lack a gut microbiome and are kept in sterile colonies, tend to be thinner than mice with them, particularly when fed a Western-style high-sugar, high-fat diet. Drs. Hooper and Wang, together with their colleagues, employed RNA sequencing to compare gene expression in the small intestines of germ-free mice versus “conventional” animals that had usual gut flora in an effort to determine why.

The group focused on the Snhg9 gene, which generates a lengthy, noncoding RNA with an unidentified function. The RNA molecule made by Snhg9 links to a protein known as CCAR2, causing a chemical cascade that stops dietary fats from being absorbed by the cells lining the intestine. This was demonstrated through a series of tests. Further research revealed that the immune system-controlled feedback loop alerted the intestinal cells that made this RNA to the presence of gut microorganisms, which resulted in a decrease in its synthesis.

Even on a Western-style diet, the process sparked by this molecule prevented obesity in germ-free mice and animals genetically modified to produce additional Snhg9 RNA. Additional experiments revealed that compared to wild-type mice, these animals weren’t absorbing as much dietary fat. On the other hand, Snhg9-deficient animals put on extra weight when fed a high-sugar, high-fat diet, even when their gut microorganisms were eradicated with antibiotics.

Together, the results assist to unravel the puzzle of how the microbiome controls metabolism in host organisms. These results follow a 2017 publication headed by Drs. Hooper and Wang that found a molecular “accelerator” for lipid absorption and metabolism. The finding might someday help researchers figure out how to control this relationship to prevent or treat metabolic illnesses. For instance, Snhg9 inhibition or pharmaceutical mimicry of Snhg9 activity could one day be used to treat obesity, according to Dr. Hooper.

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