UVA Discovery Could Ease Jet Lag, Improve Chemotherapy, Among Other Benefits

Using “three-dimensional gut organoids,” Sean Moore’s and Jason Papin’s research team studied how gut microbes manufacture certain types of fatty acids. (Photos by Dan Addison, University Communications)

A team of researchers found a link between circadian timekeeping and specific gut components by narrowing down “a daunting list of hundreds of bacterial metabolites to a short list of three of four prime suspects responsible for the dramatic resetting of the intestinal clock we observed when cells were exposed to metabolites from certain bacteria,” said Moore, a pediatric gastroenterologist at UVA Children’s. Researchers then were able to establish “a chain of causality between specific microbes, their metabolites and their effects on the clock.”

Biological Clockwork

The UVA scientists found that gut microbes regulate our intestinal cells by manufacturing what are called short-chain fatty acids. These particular fatty acids are only made by gut bacteria and switch certain mammalian genes on and off as needed over 24-hour periods. That makes them a critical timekeeper for important biological processes. 

The scientists were able to study this in the lab using “three-dimensional gut organoids,” essentially tiny guts in a dish. The researchers began using mouse organoids, but then were able to reproduce their findings using human cells.

Determining where to start, though, was quite a challenge. The interactions between gut microbes and our bodies are terribly complex. The microbes, for example, make many “metabolites,” including different varieties of fatty acids.

That’s where Papin’s expertise in computer modeling was critical. The models allowed the research team to quickly determine which metabolites might be the most important for biological timekeeping. That provided vital direction for the work and offers a valuable tool for future research.

“Biology is increasingly a data-rich science and computational methods are becoming necessary to understand what the data tell us about microbial and human physiological systems,” said Papin, who is part of UVA’s Department of Biomedical Engineering, a collaboration of UVA’s School of Medicine and School of Engineering. “Systems modeling can help us embrace the complexity of these biological systems to answer questions we have and to help us frame new questions we didn’t even know to ask.”

By better understanding the function of various metabolites, doctors will be positioned to manipulate them to benefit good health and improve quality of life. Tweaking the body’s biological clock might benefit night-shift workers, for example, or might be used to help patients fend off salmonella infections that cause food poisoning, as salmonella’s ability to invade the body is determined, in part, by the circadian clock.

“Timing is everything,” Moore said. “Understanding how the microbes within us shape biological rhythms in the gut will ultimately help us choose the right treatment, for the right patient, at the right time.”

Findings Published

The researchers have published their findings in the journal Gastroenterology. The team consisted of Jibraan Fawad, Deborah Luzader, Gabe Hanson, Tom Moutinho, Dr. Craig McKinney, Paul G. Mitchell, Kathleen Brown-Steinke, Ajay Kumar, Miri Park, Suengwon Lee, David T. Bolick, Greg Medlock, Jesse Y. Zhao, Andrew E. Rosselot, C. James Chou, Emily Eshleman, Theresa Alenghat, Christian I. Hong, Papin and Moore. 

The work was supported by the National Institutes of Health, grants R01 DK117005, U19 AI116491 and R01 AT010253; UVA’s TransUniversity Microbiome Initiative; and the National Research Foundation of Korea, grant 2020R1A6A3A03038405.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.