The molecular component of caffeine may play a role in gut health

Summary: Xanthine, a purine metabolite found in caffeinated products like coffee and tea, as well as chocolate, appears to play a role in TH17 cell differentiation in the gut. The results could lead to a better understanding of gut health and shed new light on the development of inflammatory diseases such as IBD.

Source: Brigham and Women’s Hospital

The gut is home to a number of microbes that affect health and disease. It is believed that some types of microorganisms contribute to the development of inflammatory diseases, such as: B. inflammatory bowel disease (IBD), but the exact cascade of events leading from microbes to immune cells to disease remains mysterious.

A new study by researchers at Brigham and Women’s Hospital, a founding member of Mass General Brigham’s health system, examines exactly what leads to the formation of Th17 cells – a key subtype of cells in the gut – and uncovers some of the underappreciated molecular actors and events , which lead to cell differentiation in the intestine.

One of these players is the purine metabolite xanthine, found in high concentrations in caffeinated foods like coffee, tea, and chocolate.

The results of the study are published in immunity.

“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 author Jinzhi Duan, PhD, from the Department of Gastroenterology, Hepatology and endoscopy in the medical faculty of the BWH.

“We investigated the underlying mechanisms of Th17 cell formation in the gut and found some surprising results that could help us better understand how and why diseases like IBD can develop.”

While shedding light on the steps leading to Th17 cell differentiation, the researchers unexpectedly discovered a role for xanthine in the gut.

“Sometimes in research we make these accidental discoveries — it’s not necessarily something you’ve been looking for, but it’s an interesting finding that opens up more areas of investigation,” said senior author Richard Blumberg, MD, of the Department of Gastroenterology, and Hepatology Endoscopy in the medical department.

“It’s too early to speculate on whether the amount of xanthine in a cup of coffee leads to beneficial or harmful effects in a person’s gut, but it gives us interesting leads to follow as we look for ways to to create a protective response and a stronger barrier in the gut.”

Interleukin-17-producing helper T cells (Th17) are thought to play a key role in the gut. The cells can help build a protective barrier in the gut, and when a bacterial or fungal infection occurs, these cells can release signals that prompt the body to produce more Th17 cells. But the cells have also been linked to diseases like multiple sclerosis, rheumatoid arthritis, psoriasis and IBD.

This shows a woman drinking coffee
While shedding light on the steps leading to Th17 cell differentiation, the researchers unexpectedly discovered a role for xanthine in the gut. The image is in the public domain

Duan, co-lead author Juan Matute, MD, Blumberg and colleagues used multiple mouse models to study the molecular events that lead to Th17 cell development. Surprisingly, they found that even in germ-free mice or mice that had been given antibiotics, Th17 cells could proliferate to eradicate bacteria.

The team found that endoplasmic reticulum stress in gut epithelial cells drives Th17 cell differentiation by purine metabolites such as xanthine, even in mice that did not carry microbes and whose genetic signatures indicated cells with protective properties.

The authors note that their study was limited to cells in the gut – it’s possible that the interaction between cells in the gut and other organs like the skin and lungs may have an important impact on the results.

They also note that their study does not identify what triggers Th17 cells to become pathogenic β€” that is, play a role in disease. They note that more research is needed, including studies that focus on human IBD-Th17 cells.

“Although we don’t yet know what causes the pathogenesis, the tools developed here could bring us a step closer to understanding what causes disease and what might help resolve or prevent it,” Blumberg said.

Financing: This work was supported by the National Institutes of Health (Grants DK044319, DK051362, DK053056, DK088199, DK117565, DK110559, DK015070), the Harvard Digestive Diseases Center (DK034854), the CCF Research Fellowship Award (#707702), and the Pediatric Scientist Development Program supported (K12HD000850), Austrian Science Fund (FWF J 4396), Wellcome Trust (Senior Investigator Award 106260/Z/14/Z and 222497/Z/21/Z), European Research Council (HORIZON2020/ERC Grant Agreement No. 648889) . ), the DFG individual grant (SO1141/10-1); DFG research group FOR5042 “miTarget – The microbiome as a target for inflammatory bowel diseases” (Project P5); the DFG Cluster of Excellence 2167 Precision Medicine in Chronic Inflammation, the BMBF project iTREAT (SP5); and the EU H2020 grant SYSCID (Contract No. 733100).

About this caffeine and gut health research news

Author: Serena Bronda
Source: Brigham and Women’s Hospital
Contact: Serena Bronda – Brigham and Women’s Hospital
Picture: The image is in the public domain

Original research: Closed access.
“Stress of endoplasmic reticulum in gut epithelium initiates synthesis of purine metabolites and promotes Th17 cell differentiation in gut” by Jinzhi Duan et al. immunity


Stress of the endoplasmic reticulum in the gut epithelium initiates the synthesis of purine metabolites and promotes the differentiation of Th17 cells in the gut


  • ER stress in intestinal epithelial cells (IEC) drives gut Th17 differentiation
  • Th17 cells induced by IEC-ER stress require H2O2 generated by DUOX2/DUOXA2
  • IEC-ROS induce Th17 differentiation through purine metabolites including xanthine
  • IEC-ER stress promotes microbial Th17 induction even under aseptic conditions


Gut IL-17-producing helper T cells (Th17) rely on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains a mystery.

Here we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused UPR and increased Th17 cells, even under antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs increased their production of both reactive oxygen species (ROS) and purine metabolites.

Treating mice with N-acetyl-cysteine ​​or allopurinol to reduce ROS production or xanthine, respectively, decreased Th17 cells, which were associated with increased UPR. Th17-related genes also correlated with ER stress and UPR in people with inflammatory bowel disease.

Overall, we identify a mechanism of intestinal Th17 cell differentiation arising from an IEC-associated UPR.

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