A new discovery from the School of Medicine about how the microbes in our guts regulate the body’s biological clock could help us battle sleep disorders, combat jet lag, fight off foodborne illness and even improve chemotherapy outcomes.
A research team led by UVA’s Sean Moore, MD, MS, and Jason Papin, PhD, used miniature “guts in a dish” and advanced computer modeling to reveal how microscopic organisms that naturally live in our guts direct the timing of daily activities of the cells lining our intestines. These activities, such as absorbing nutrients from food, are essential to good health; disruptions of the intestinal cells’ “circadian rhythms” have been linked to obesity, ulcers, diarrhea, inflammatory bowel disease and other health problems.
The new research, from UVA’s TransUniversity Microbiome Initiative and collaborators, sheds light on how unique byproducts produced by our gut bacteria reset the internal clock that sets the schedule for when intestinal cells carry out their vital jobs. With this information, doctors may be able to target our gut microbes to improve patients’ health, battle disease and possibly even reset our internal clocks when we travel to reduce jet lag.
“UVA post-doctoral scientist Dr. Deborah Luzader, research assistant Dr. Jibraan Fawad and pediatric gastroenterology fellow Dr. Craig McKinney found that organoids or ‘miniguts’ – derived from either the small intestine or colon of mice and patients – provide a new platform for exploring circadian timekeeping between intestinal epithelial cells and a simplified, but complete, gut microbiome,” said Moore, a pediatric gastroenterologist at UVA Children’s. “Data scientists in the Papin and Moore Labs – Gabe Hanson, Dr. Greg Medlock and Dr. Tom Moutinho – applied powerful tools from systems biology and machine learning to narrow 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 intestinal clock we observed when cells were exposed to metabolites from certain bacteria . By combining organoid, microbiome, metabolomic and machine -learning approaches, we established a chain of causality between specific microbes, their metabolites and their effects on the clock.”
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. 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,” said Papin, who is part of UVA’s Department of Biomedical Engineering, a collaboration of UVA’s School of Medicine and School of Engineering. “The future is very bright in biomedical research as we take advantage of the data science and computational methods being developed.”
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.”
The researchers have published their findings in the journal Gastroenterology. The team consisted of Jibraan A. Fawad, Deborah H. Luzader, Gabriel F. Hanson, Thomas J. Moutinho Jr., Craig A. McKinney, Paul G. Mitchell, Kathleen Brown-Steinke, Ajay Kumar, Miri Park, Suengwon Lee, David T. Bolick, Greg L. 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.
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