The gut is home to a vast array of microorganims that can influence both health and disease. While some of them are known to contribute to the development of inflammatory conditions, such as the inflammatory bowel disease (IBD), the precise sequence of events that lead from these microbes to immune cells to disease remains a mystery.
Now, a team of researchers led by the Brigham and Women’s Hospital (BWH) has explored what drives the generation of Th17 (Interleukin-17-producing T helper) cells – a type of cells which, on the one hand, play a crucial role by helping to build a protective barrier in the gut that, when encountering a bacterial or fungal infection, releases signals causing the body to produce more Th17 cells, but on the other hand, are also implicated in diseases such as multiple sclerosis, rheumatoid arthritis, and IBD. The scientists were surprised to discover that the purine metabolite xanthine, which is found in coffee, tea, and chocolate, may have a fundamental role in Th17 differentiation.
“One of the concepts in our field is that microbes are required for Th17 cell differentiation, but our study suggests that there may be exceptions,” said co-lead auhor Jinzhi Duan, an expert in Gastroenterology, Hepatology, and Endoscopy at BWH. “We studied the underlying mechanisms of Th17 cell generation in the gut and found some surprising results that may help us to better understand how and why diseases like IBD may develop.”
“Sometimes in research, we make these serendipitous discoveries—it’s not necessarily something you sought out, but it’s an interesting finding that opens up further areas of inquiry,” added senior author Richard Blumberg, a gastroenterologist at the same institution. “It’s too soon to speculate on whether the amount of xanthine in a cup of coffee leads to helpful or harmful effects in a person’s gut, but it gives us interesting leads to follow up on as we pursue ways to generate a protective response and stronger barrier in the intestine.”
By using several mouse models to examine the molecular events which trigger the development of Th17 cells, the researchers were surprised to find that Th17 cells could proliferate even in germ-free mice, with endoplasmic reticulum stress in intestinal epithelial cells driving Th17 cell differentiation through purine metabolites like xanthine, even in animals which did not carry microbes. Moreover, these cells’ genetic signatures suggested they might have protective properties.
Since this study was limited to cells in the intestine, further research is needed to examine the relation between these cells and other organs, such as the skin or the lungs, which may have a critical influence on disease outcomes. More investigations are also necessary to determine what causes Th17 cells to sometimes become pathogenic.
“While we don’t yet know what’s causing pathogenesis, the tools we have developed here may take us a step closer to understanding what causes disease and what could help resolve or prevent it,” Blumberg concluded.
The study is published in the journal Immunity.
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