Researchers discover microbes that influence how the gut uses its genes

The gastrointestinal microbiota plays a role in host physiology, metabolism and nutrition. An altered gut microbial community is linked to a number of gut conditions, including cancer, obesity, and various gut disorders. Researchers at Duke University report that their new study in mice demonstrates that microbes are able to influence which genes in the gut are turned on. Their findings open a door to understanding microbes and could lead to new therapies for gastrointestinal and related diseases.

The results are published in the journal Cellular and Molecular Gastroenterology and Hepatology in a paper titled “Transcriptional Integration of Distinct Microbial and Nutritional Signals by the Small Intestinal Epithelium”.

“The gut constantly interprets and adapts to complex combinations of food and microbial stimuli,” the researchers wrote. “However, the transcriptional strategies by which the intestinal epithelium integrates these coincident information sources remain unresolved. We recently discovered that microbiota colonization suppresses epithelial activity of HNF4 nuclear receptor transcription factors, but their integrative was unknown.

“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, PhD, professor of molecular genomics. and microbiology at Duke and director of the Duke Microbiome Center.

The researchers first 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 researchers observed 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.

“It’s a relatively consistent finding across multiple studies, from our lab and others, that microbes actually promote lipid absorption,” explained Colin Lickwar, PhD, senior research associate in Rawls’s lab 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 explained. “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.”

“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. Most of us don’t understand it, but some of them are cleared up by this article.

The researchers focused on a transcription factor called HNF4-Alpha, which is known to regulate genes involved in lipid metabolism and genes that respond to microbes.

The researchers found that HNF4-Alpha is important for simultaneously integrating multiple signals in the gut.

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

“This identifies potential transcriptional mechanisms for intestinal adaptation to multiple cues and how microbiota can modulate intestinal lipid absorption, epithelial cell turnover, and systemic energy balance,” the researchers noted.