UF researchers discover molecular address system that may aid gut health

Building on previous findings that show a specific protein is associated with gut health, University of Florida researchers have discovered an intricate molecular mechanism that encodes a unique address system, identifying the route a certain type of immune cell takes to reach its final destination: the large intestine.

The findings shed light on the way the protein works to deliver cells associated with suppressing inflammation to the gut in mice and in humans, which may prove useful in combating inflammatory bowel disease, or IBD, and other intestinal disorders, in humans as well as in animals, said Liang Zhou, M.D., Ph.D. a professor in the UF College of Veterinary Medicine’s department of infectious diseases and immunology. Zhou is the corresponding author on the study, which was published in June in Science Immunology.

Zhou has studied the protein, an intracellular molecule known as aryl hydrocarbon receptor, or AHR, for years, intrigued by its potential for controlling complex cellular relationships within the body that affect disease. Although best known as a sensor for detecting environmental contaminants inside the body, AHR has unique aspects that have not been widely explored scientifically. For example, it has remained relatively unchanged genetically  over time across many different species, including nematodes, or worms, Zhou said.

“This means it should not have evolved to detect only man-made pollutants, as it appeared even before man appeared on the planet,” said Zhou, also a member of the UF Health Cancer Center. “We have long been interested in the receptor’s physiological function and how it responds to other stimuli, such as dietary compounds.”

Previously, it was not known how AHR modulates regulatory T cells, a subtype of white blood cells that play a key role in suppressing cell-mediated inflammation in the gut.

“But now we’ve found an address — a location mark,” Zhou said. “And more importantly, we have found potential ways to modify that address to deliver the cells to that location so they can act to suppress inflammation in the gut.”

The direct target of AHR is another protein, known as GPR15, also known as the HIV or simian immunodeficiency virus co-receptor. This protein is critical in the intestinal homing of regulatory T cells in mice and in humans, further suggesting a physiological role for AHR in intestinal tissue stability, the researchers said. Zhou’s longtime postdoctoral associate, Lifeng Xiong, Ph.D., first author on the paper, made that discovery.

“It is quite fascinating to discover how our immune system has evolved such an intricate address system that is regulated by AHR,” Xiong said.

Joseph Dean, M.S., a doctoral student in Zhou’s laboratory and a co-author on the paper, expanded on the practical significance of the finding.

“It’s what tells the T cells to go to the intestine, instead of to the spleen, or someplace else,” he said. “Using next-generation sequencing technology, we’ve found that AHR is directly responsible for regulating GPR15.”

Elaborating on the analogy of the address system, Zhou said that if GPR15 is the location mark, the envelope it is written on is the regulatory T cell, and AHR is the person who writes the address.

“This address system we’ve discovered is mediated by AHR and GPR15,” he said. “If you write that address on the envelope, the letter will be delivered to the right location — the large intestine.”