Gastrointestinal Epithelial Autophagy: A Critical Regulator of Intestinal Mucosal Homeostasis and Pathogenesis in Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic gastrointestinal disorder driven by intestinal barrier dysfunction and mucosal immune dysregulation.Multiple pathological pathways disrupt intestinal mucosal immunity to initiate IBD progression, including aberrant innate immune receptor activation, imbalance between pro- and anti-inflammatory lymphocyte subsets, defective mucosal antimicrobial secretion, and dysregulated interaction between epithelium and gut commensals. Gastrointestinal epithelial cells (IECs) form the critical frontline barrier, and their functional impairment is central to IBD pathogenesis. Autophagy, a conserved lysosomal catabolic process essential for cellular homeostasis, is a key regulator of IEC function. Mounting evidence links impaired autophagic flux in IECs to disrupted barrier integrity, exacerbated inflammation, and gut microbial dysbiosis, thereby promoting IBD onset and progression.This review systematically summarizes the molecular mechanisms governing autophagy in IECs, focusing on core ATG genes and key signaling pathways (PI3K/Akt/mTOR, AMPK, NF-κB). It further dissects autophagy’s multifaceted roles in maintaining mucosal homeostasis, including barrier preservation, modulation of cell fate, and crosstalk with the microbiota and immune system. Additionally, the review highlights the clinical relevance of autophagy-related genetic polymorphisms (e.g., ATG16L1, IRGM) in IBD susceptibility and the pathological evidence of defective autophagy in patient tissues. Finally, it discusses the therapeutic potential of autophagy modulators and outlines key unanswered questions and future research directions for developing precision IBD therapies.