Gastrointestinal microbiota play a role in host physiology, metabolism, and nutrition. An alteration in the gut microbial community is linked to a number of intestinal conditions, including cancer, obesity, and a variety of bowel disorders. Researchers at Duke University report their new study in mice demonstrates microbes are able to influence which of the gut’s genes are being called into action. Their findings open a door of understanding for microbes and may lead to new therapies for gastrointestinal and related diseases.
The findings 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 intestine constantly interprets and adapts to complex combinations of dietary and microbial stimuli,” wrote the researchers. “However, the transcriptional strategies by which the intestinal epithelium integrates these coincident sources of information remain unresolved. We recently found that microbiota colonization suppresses epithelial activity of HNF4 nuclear receptor transcription factors, but their integrative regulation was unknown.”
“The gut is a fascinating interface between an animal and the world it lives in, and it receives information from both the diet and the microbes it harbors,” said John Rawls, PhD, a 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 to RNA—and the proteins that turn this copying process on or off in the small intestine, where most uptake of fat and other nutrients occurs.
While both the germ-free and normal mice were able to metabolize fatty acids in a high-fat diet, the researchers observed the germ-free animals used a very different set of genes to deal with a high-fat meal.
“We were surprised to find that the gene playbook that the gut epithelium uses to respond to dietary fat is different depending on whether or not microbes are there,” 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, a senior research associate in Rawls’ lab and first author on the paper. “And that, at some level, also impacts systemic processes like weight gain.”
The germ-free mice saw an increase in activity of the genes involved in fatty acid oxidation, literally burning of fatty acids, to provide fuel for the gut’s cells.
“Typically we think about the gut just doing its job absorbing dietary nutrients across the epithelium to share with the rest of the body, but the gut has to eat too,” Rawls explained. “So what we think is going on in germ-free animals, is that the gut is consuming more of the fat than it would if the microbes were there.“
“There are a bunch of recent papers showing that there is a substantial capacity to change the larger architecture of the intestine as well as in the individual gene programs,” Lickwar said. “There is a remarkable amount of plasticity in the intestine. We largely don’t understand it, but some of it is elucidated by this paper.”
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 in simultaneously integrating multiple signals within the intestine.
“For every way that germ-free animals seem unusual, that teaches us something about the large impact of the microbiome on what we consider to be ‘normal’ animal biology,” Rawls concluded.
“This identifies potential transcriptional mechanisms for intestinal adaptation to multiple signals and how microbiota may modulate intestinal lipid absorption, epithelial cell renewal, and systemic energy balance,” noted the researchers.