Xanthine, which is found in coffee, tea and chocolate, may play a role in the generation of interleukin-17-producing T helper (Th17) cells, an important subtype of cells in the intestine.
Duan et al. identified a mechanism of intestinal Th17 cell differentiation that emerges from an intestinal epithelial cell-associated an unfolded protein response. Image credit: Duan et al., doi: 10.1016/j.immuni.2023.02.018.
“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 Dr. Jinzhi Duan, a researcher at Brigham and Women’s Hospital.
“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 inflammatory bowel disease (IBD) may develop.”
While illuminating the steps leading to Th17 cell differentiation, the researchers unexpectedly discovered a role for xanthine in the gut.
“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,” said Dr. Richard Blumberg, also from Brigham and Women’s Hospital.
“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.”
Th17 cells are thought to play a key role in the intestine. They can help to build a protective barrier in the gut, and when a bacterial or fungal infection occurs, these cells may release signals that cause the body to produce more Th17 cells. But the cells have also been implicated in diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, and IBD.
The scientists used several mouse models to study the molecular events that lead to the development of Th17 cells.
Surprisingly, they found that Th17 cells could proliferate even in germ-free mice or mice that had been giving antibiotics wiping out bacteria.
They found that endoplasmic reticulum stress in intestinal epithelial cells drove Th17 cell differentiation through purine metabolites, such as xanthine, even in mice that did not carry microbes and with genetic signatures that suggested cells with protective properties.
“Our study was limited to cells in the intestine — it’s possible that crosstalk between cells in the gut and other organs, such as the skin and lung, may have an important influence on outcomes,” the authors said.
“The study does not identify what causes Th17 cells to become pathogenic — that is, play a role in disease.”
“Further exploration is needed, including studies that focus on human-IBD Th17 cells.”
“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,” Dr. Blumberg said.
The study was published in the journal Immunity.
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Jinzhi Duan et al. Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut. Immunity, published online March 13, 2023; doi: 10.1016/j.immuni.2023.02.018
