Intestinal diseases have always posed a serious threat to human health, with inflammatory bowel disease (IBD) being one of them. IBD is an autoimmune disease characterized by chronic inflammation, including ulcerative colitis (UC) and Crohn’s disease (CD). The “alarm” cytokine IL-33, which is intimately associated with Th2 immunity, is a highly potent inflammatory factor that is considered to have dual functions—operating as both a pro-inflammatory cytokine and a transcriptional regulator. IL-33 has been shown to play a crucial role in both the onset and development of IBD. Therefore, this review focuses on the pathogenesis of IBD, the major receptor cell types, and the activities of IL-33 in innate and adaptive immunity, as well as its underlying mechanisms and conflicting conclusions in IBD. We have also summarized different medicines targeted to IL-33-associated diseases. Furthermore, we have emphasized the role of IL-33 in gastrointestinal cancer and parasitic infections, giving novel prospective therapeutic utility in the future application of IL-33.

Mast cells have vital functions in allergic responses and parasite ejection, while the underlying mechanisms remain unclear. Meanwhile, MCs are essential for the maintenance of GI barrier function, and their interactions with neurons, immune cells, and epithelial cells have been related to various gastrointestinal (GI) disorders. An increasing number of investigations are being disclosed, with a lack of inner connections among them. This review aims to highlight their properties and categorization and further delve into their participation in GI diseases via interplay with neurons and immune cells. We also discuss their roles in diseases like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Based on the evidence, we advocated for their potential application in clinical practices and advocated future research prospects.

Intestinal homeostasis requires immune tolerance, barrier integrity, tissue repair, and microbiota mutualism. Interleukin-10 (IL-10) is essential, but not merely as an immunosuppressant. Although IL-10 signals via the IL-10R—JAK1/TYK2—STAT3 axis, its outputs are cell-type and context dependent. In macrophages, IL-10 restrains IL-23 production, inflammasome activation, IL-1β release, and metabolic reprogramming. In T cells, it limits pathogenic T helper 17 cell (Th17) responses while stabilizing regulatory cells and promoting metabolically driven IL-10 production. In the epithelium, IL-10 maintains barrier integrity by limiting apoptosis, endoplasmic reticulum (ER) stress, and mucus defects. IL-10 and the gut microbiota engage in reciprocal regulation: microbial metabolites and structural components enhance IL-10 production and receptor responsiveness, whereas IL-10 signaling preserves microbial diversity and ecological resilience. This may help to explain why systemic recombinant IL-10 failed in Crohn’s disease (CD)—increasing ligand abundance alone is unlikely to recapitulate endogenous localization or restore refractory target cells. Emerging strategies aim to tune IL-10 signaling through gut-selective delivery, engineered cytokines, conditionally activated prodrugs, regulatory cell approaches, and microbiome or metabolic interventions. Clinical translation requires biomarkers of IL-10R expression, STAT3 responsiveness, macrophage metabolic state, microbial signatures, and acquired IL-10 hyporesponsiveness. Despite the established role of IL-10 in intestinal homeostasis, systemic IL-10 therapy has failed in clinical trials, and there is a lack of effective strategies to restore IL-10 signaling in a spatially and cell-specific manner. The spatially organized, metabolically conditioned homeostatic IL-10 signaling—largely inferred from model systems and awaiting direct spatial validation in human intestine—offers a roadmap for more precise therapy in inflammatory bowel disease and related intestinal disorders.