Gut microbiota-derived metabolites and IL-22 signaling in inflammatory bowel disease: context-dependent regulation of mucosal repair and inflammation
TL;DR
It is proposed that the duration and magnitude of IL-22 exposure, its cellular source, the IL-22/IL-22BP balance, epithelial target-cell state, concurrent inflammatory signals, and disease context collectively determine whether IL-22 promotes mucosal repair or contributes to inflammatory amplification.
Abstract
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), arises from complex interactions among host susceptibility, microbial dysbiosis, altered metabolite profiles, and dysregulated mucosal immune responses. Interleukin-22 (IL-22), a cytokine that acts primarily on non-hematopoietic cells, contributes to epithelial antimicrobial defense, survival, and tissue repair, but may also amplify inflammation under specific chronic or co-inflammatory conditions. This review evaluates the evidence linking major microbiota-associated metabolites—including short-chain fatty acids (SCFAs), bile acids (BAs), tryptophan (Trp) -derived metabolites, and the trimethylamine (TMA)/trimethylamine N-oxide (TMAO) pathway—to IL-22 production, bioavailability, and function in IBD. Relatively direct mechanistic support is available for SCFA-mediated and Trp-Aryl hydrocarbon receptor (AhR) -dependent regulation of IL-22, whereas bile acid effects appear metabolite-, receptor-, and context-dependent. In contrast, the proposed relationship between TMA/TMAO and IL-22 is currently supported mainly by indirect evidence and should be considered an emerging hypothesis. We further incorporate IL-22-binding protein (IL-22BP) as a determinant of local IL-22 bioavailability and distinguish upstream regulation of IL-22 production from downstream signaling initiated through the epithelial IL-22R1/IL-10R2 receptor complex. Particular attention is given to canonical JAK1/TYK2-STAT3 signaling and its context-dependent interactions with NF-κB, PI3K-AKT-mTOR, and MAPK pathways. We propose that the duration and magnitude of IL-22 exposure, its cellular source, the IL-22/IL-22BP balance, epithelial target-cell state, concurrent inflammatory signals, and disease context collectively determine whether IL-22 promotes mucosal repair or contributes to inflammatory amplification. By separating established mechanisms from associative, extrapolated, and hypothesis-generating evidence, this review provides a more evidence-calibrated framework for investigating the microbiota-metabolite-IL-22 network in UC and CD.