Microbes help orchestrate how the gut uses its genes

DURHAM, NC — Microbes that help break down food actually tell the gut how to do its job better, according to a new mouse study at Duke.

The researchers said it appears that the microbes are able to influence which gut genes are turned on, and in turn this interaction could lead to remodeling of the epithelial cells that line the gut so that ‘they match the diet.

“The gut is a fascinating interface between an animal and the world it lives in, and it receives information from both diet and the microbes it harbors,” said John Rawls, Ph.D., professor of Molecular Genomics and Microbiology at Duke. and director of the Duke Microbiome Center.

The study was published May 6 in the open-access journal Cellular and Molecular Gastroenterology and Hepatology.

To begin analyzing messages from microbes to cells in the gut, the Duke researchers compared mice raised without any gut microbes and those with a normal gut microbiome. The researchers focused on the crosstalk between RNA transcription – DNA being copied onto RNA – and the proteins that turn this copying process on or off in the small intestine, where most of the absorption of fats and other nutrients.

While the germ-free and normal mice were able to metabolize fatty acids in a high-fat diet, the striking finding was that the germ-free animals used a very different set of genes to cope with a high-fat meal.

“We were surprised to find that the genetic manual used by the intestinal epithelium to respond to dietary fat is different depending on whether or not microbes are present,” Rawls said.

Researchers have also found that microbes can help the gut absorb fat.

“It’s a relatively consistent finding across multiple studies, from our lab and others, that microbes actually promote lipid absorption,” said Colin Lickwar, Ph.D., senior research associate in the lab of Rawls and first author of the article. “And that, on some level, also impacts systemic processes like weight gain.”

The germ-free mice saw an increase in the activity of genes involved in fatty acid oxidation, literally the burning of fatty acids, to provide fuel to gut cells.

“Generally, we think the gut is just doing its job of absorbing food nutrients through the epithelium to share with the rest of the body, but the gut also has to eat,” Rawls said. “So what we think is happening in germ-free animals is that the gut is consuming more fat than it would if the microbes were there.”

And this may reflect differences in the composition of gut epithelial cells.

“There are a bunch of recent papers showing that there is substantial ability to alter the broader gut architecture as well as within individual genetic programs,” Lickwar said. “There is a remarkable amount of plasticity in the gut. We don’t understand much of it, but some of them are elucidated by this article.

The researchers focused their efforts on a transcription factor called HNF4-Alpha, which is known to regulate genes involved in lipid metabolism and genes that respond to microbes. “We thought this might represent an interface or crossroads between interpreting information from microbial sources or dietary fats,” Lickwar said.

“It’s certainly complicated, but we seem to identify that HNF4-Alpha is important for integrating multiple signals in the gut simultaneously,” Lickwar said.

“For every way germ-free animals look unusual, it teaches us something about the important impact the microbiome has on what we consider ‘normal’ animal biology,” Rawls said.

This research was supported by the National Institutes of Health (R01-DK093399, P01-DK094779, R01-DK113123, R01-DK111857, R01-DK081426, P01-HL020948), as well as the Nuclear Receptor Signaling Atlas consortium (NURSA, U24- 693 DK09774).

CITATION: “Transcriptional integration of distinct microbial and nutritional signals by the small intestine epithelium”, Colin Lickwar, James Davison, Cecelia Kelly, Gilberto Padilla Mercado, Briana Davis, Matthew Tillman, Ivana Semova, Sarah Andres, Goncalo Vale, Jeffrey McDonald and John Rawls. Cellular and Molecular Gastroenterology and Hepatology, online May 2, 2022. DOI: 10.1016/j.jcmgh.2022.04.013