Imbalance Between Gut Microorganisms, Immune Cells Could Set Stage for Autoimmune Disease

An imbalance in the reciprocal relationship between common gut bacteria and certain immune cells can set the stage for the development of autoimmune inflammation, according to a study conducted by researchers at Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, who described their findings recently in Immunity.

Scientists have known bacteria and other microorganisms, or microbiota, drive the development of the immune system in the intestine, said senior investigator Jay Kolls, M.D., director of the Richard King Mellon Foundation Institute for Pediatric Research at Children’s Hospital and professor of pediatrics at Pitt School of Medicine.

In particular, segmented filamentous bacteria (SFB) play a critical role in the production of T-helper (Th) immune cells that make interleukin-17, which is a signaling molecule that promotes inflammation. According to the researchers, these Th17 immune responses have been implicated in many human autoimmune diseases, including arthritis, multiple sclerosis and inflammatory bowel diseases.

“Because many infectious agents are introduced into the body through the intestine and certain bacteria are essential for proper intestinal function, there is intense interest in understanding the role of the gut microbiome in health and disease,” Dr. Kolls said. “Our study demonstrated these Th17 cells in turn control the gut’s SFB burden, and disruptions in the balance between them can have important consequences.”

For the study, the team engineered mice lacking the receptor for IL-17 in cells of the gastrointestinal tract, preventing the molecule from binding to the cells and blocking IL-17 signaling. That led to an overgrowth of SFB in the gut. Further testing showed that the absence of IL-17 signaling triggered other intestinal immune defects, creating an environment in which IL-17 could cause intestinal inflammation.

“These results show us the yin-yang relationship between SFB and Th17 cells. As SFB goes up, more Th17 cells are produced to hold the bacteria in check. Without the influence of IL-17 signaling, SFB overgrows,” Dr. Kolls explained. “These findings could have a tremendous impact on our understanding of how intestinal and autoimmune disorders develop, and also could point us to new ways to treat these diseases.”

The team included Pawan Kumar, Ph.D., Leticia Monin, Ph.D., Patricia Castillo, B.S., Waleed Elsegeiny, Ph.D., William Horne, M.S., Taylor Eddens, B.S., Amit Vikram, Ph.D., Misty Good, M.D., Kyle Bibby, Ph.D., and Ronald C. Montelaro, Ph.D., all of the University of Pittsburgh; Alexi A. Schoenborn, B.S., and Ajay S. Gulati, M.D., both of the University of North Carolina at Chapel Hill; and Dennis W. Metzger, Ph.D., of Albany Medical College.

The project was funded by National Institutes of Health grants GM008208, AI114146, DK101608; and Children’s Hospital of Pittsburgh of UPMC.