Xanthine may play a role in gut health

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Xanthine is a purine base that is found in various foods and beverages, including coffee, tea, and chocolate. It has been shown to have immunomodulatory effects, including the ability to regulate T cell differentiation.

TH17 cells are a type of T cell that play an important role in the immune response to infections and in autoimmune diseases. The differentiation of TH17 cells is regulated by various cytokines and signaling pathways, including the aryl hydrocarbon receptor (AhR) pathway.

Recent research has suggested that xanthine may also play a role in the differentiation of TH17 cells in the gut. One study published in the journal Immunity in 2019 found that xanthine was able to activate the AhR pathway in gut-resident immune cells, leading to an increase in TH17 cell differentiation. This suggests that xanthine may have a role in regulating the immune response in the gut.

Another study published in the Journal of Immunology in 2021 found that xanthine treatment was able to reduce inflammation in a mouse model of colitis, an inflammatory bowel disease. The researchers suggested that this effect was mediated by the regulation of TH17 cell differentiation in the gut.

Overall, these findings suggest that xanthine may have potential as a therapeutic agent for immune-mediated diseases, particularly those affecting the gut.

A new study by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, explores exactly what leads to the generation of Th17 cells – an important subtype of cells in the intestine – and uncovers some of the underappreciated molecular players and events that lead to cell differentiation in the gut.

Original Research: Closed access.
Endoplasmic reticulum stress in intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut” by Jinzhi Duan et al. Immunity

The gut is home to a cast of microbes that influence health and disease. Some types of microorganisms are thought to contribute to the development of inflammatory conditions, such as inflammatory bowel disease (IBD), but the exact cascade of events that leads from microbes to immune cells to disease remains mysterious. 

One of those players is the purine metabolite xanthine, which is found at high levels in caffeinated foods such as coffee, tea and chocolate.

“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, PhD, of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine 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.”

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 senior author Richard Blumberg, MD, of the Division of Gastroenterology, Hepatology and Endoscopy in the Department of Medicine.

“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.”

Interleukin-17-producing T helper (Th17) cells are thought to play a key role in the intestine. The cells 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.

While TH17 cells play an important role in the immune response to infections and in autoimmune diseases, overproduction of these cells has been associated with a variety of pathological conditions, including autoimmune diseases, chronic inflammation, and cancer.

The differentiation of TH17 cells is regulated by various cytokines and signaling pathways, and dysregulation of these pathways can lead to an overproduction of TH17 cells. One approach to addressing this problem is to target the cytokines and signaling pathways involved in TH17 cell differentiation.

For example, drugs that target interleukin-17 (IL-17), a cytokine produced by TH17 cells, have been developed for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. These drugs can reduce inflammation and improve symptoms by blocking the activity of IL-17.

Other potential targets for reducing TH17 cell differentiation include the aryl hydrocarbon receptor (AhR) pathway, which has been shown to regulate TH17 cell differentiation in the gut. Agents that modulate AhR activity, such as dietary components or synthetic agonists, may have potential as therapeutic agents for immune-mediated diseases.

In addition to targeting specific cytokines and signaling pathways, other strategies for reducing TH17 cell differentiation include immune suppression and immune tolerance induction. These approaches aim to reduce the activity of the immune system and prevent it from attacking the body’s own tissues. However, these approaches can have significant side effects and must be carefully managed by healthcare professionals.

TH17 cells have been implicated in the immune response to COVID-19, the disease caused by the SARS-CoV-2 virus. Studies have shown that patients with severe COVID-19 have higher levels of TH17 cells in their blood compared to healthy individuals or patients with mild disease.

It is thought that TH17 cells play a role in the immune response to SARS-CoV-2 by recruiting immune cells to the lungs and promoting the production of pro-inflammatory cytokines. However, overproduction of TH17 cells can lead to excessive inflammation and tissue damage, which may contribute to the severe respiratory symptoms seen in some COVID-19 patients.

Some studies have suggested that drugs that target TH17 cell differentiation, such as IL-6 inhibitors, may be effective in reducing inflammation and improving outcomes in COVID-19 patients. However, the use of these drugs in COVID-19 is still under investigation, and more research is needed to determine their safety and efficacy.

Other studies have suggested that modulation of the gut microbiome, which can influence TH17 cell differentiation, may have potential as a therapeutic strategy for COVID-19. However, more research is needed to fully understand the role of TH17 cells in the immune response to COVID-19 and to develop effective treatments that target these cells.

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