A Link Between Cellular Stress and Gut Inflammation

Scientists determined how a state of cellular stress in the inner lining of the gut promotes production of a type of immune cell linked to chronic inflammatory diseases. The inner lining of the gastrointestinal tract, called the intestinal epithelium, absorbs nutrients into the body and acts as a barrier restricting entry of harmful factors. Damage to the intestinal epithelium plays a role in chronic inflammation and development of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. Understanding how a healthy intestinal epithelium is maintained and what leads to damage is critical to broadening knowledge about inflammatory bowel diseases and developing prevention and treatment strategies.

In this study, scientists explored how the intestinal epithelium promotes production of Th17 cells—immune system cells that produce a protein called IL-17 and contribute to both the protective barrier of the intestinal epithelium and to chronic inflammatory conditions. Th17 cell production is triggered by microbes adhering to the epithelium, but it is unclear how the epithelium orchestrates this response. Knowing that epithelial cells are susceptible to a cellular state known as endoplasmic reticulum (ER) stress, where the capacity of a cell to properly shape newly generated proteins becomes overwhelmed, they sought to determine if ER stress in the intestinal epithelium influenced production of Th17 cells. To do so, they utilized two mouse models of ER stress and found an increased number of Th17 cells in both models. Interestingly, this increase in Th17 cells occurred in the mouse model even in the absence of gut microbes. This suggests that ER stress is a key player in Th17 production, and that, in wild-type mice, microbes may boost Th17 cell production by invoking ER stress in the epithelium. Additional experiments revealed that this response required production of a family of molecules called purine metabolites, most notably the small molecule xanthine.

To explore whether ER stress was linked to Th17 cell production in humans, the researchers looked at genes with increased activity in biosamples from people with ulcerative colitis and people with Crohn’s disease. They noted that Th17-, ER stress-, and purine metabolism-associated genes were increased in the samples, suggesting that the response observed in mice is also associated with inflammatory bowel diseases in humans. These studies revealed how ER stress in the mouse intestinal epithelium leads to increased production of Th17 cells, generating new knowledge of intestinal epithelium biology. Additional research will be needed to elucidate what causes Th17 cells to promote chronic inflammation and lead to the development of inflammatory bowel diseases.