Regulation of intestinal regulatory T cells via stress response pathways in inflammatory bowel disease

Cell stress, including endoplasmic reticulum (ER) stress, heat shock, and hypoxia, plays a pivotal role in cellular homeostasis and immune regulation, particularly in the intestine. ER stress, a key aspect of cell stress, triggers the unfolded protein response (UPR) to restore balance by managing misfolded proteins or inducing apoptosis if unresolved. The activation of these stress responses has emerged as a critical contributor to intestinal inflammation in conditions like inflammatory bowel disease (IBD). Regulatory T cells (Tregs), vital for maintaining mucosal immune tolerance, are strongly influenced by cellular stress, with the UPR shaping their stability, metabolic programming, and function. Microbial dysbiosis and reduced short-chain fatty acids (SCFAs) disrupt these adaptive pathways, further impairing Treg function. In this review, we explore how UPR signaling shapes Treg metabolism and intestinal inflammation. Identifying gaps in UPR-mediated adaptation and stress thresholds, we thus propose microbiome- and ER-stress-based therapeutic strategies as putative strategies for restoring immune balance in IBD.