IL4I1 and LAO1 deficiency triggers colonic inflammation in mice via metabolic dysregulation and gut microbiota dysbiosis

Inflammatory bowel disease (IBD) is a chronic non-specific intestinal inflammatory disease whose etiology is not yet fully understood, and genetic factors play an important role in the pathogenesis of inflammatory bowel disease. Here, a comprehensive comparative analysis of four genetically distinct mouse strains was conducted, namely the wild type (WT), LAO1 knockout (LAO1 KO), IL4I1 knockout (IL4I1 KO), and double knockout (DKO) mice. Unexpectedly, a higher incidence of spontaneous diarrhea was observed in DKO mice compared to the other three genotypes. We sought to clarify the mechanisms by which IL4I1 and LAO1 deficiency induces colonic inflammation in mice through metabolomic analysis and gut microbiota profiling. The results showed that IL4I1 and LAO1 deficiency suppressed L-amino acid metabolism, leading to reduced hydrogen peroxide production, which subsequently up-regulated the indoleamine 2,3-dioxygenase 1 (IDO1)-Kynurenine (Kyn) metabolic pathway. The Kyn accumulation might promote excessive secretion of pro-inflammatory cytokines in the colon, establishing an inflammatory microenvironment. In addition, IL4I1 and LAO1 deficiency altered the gut microbiota composition and reduced the level of pentanoate. As critical anti-inflammatory metabolites, decreased pentanoate levels might further exacerbate conic inflammation. Notably, the observed microbial alterations might also modulate the IDO1-Kyn metabolic pathway. Taken together, these findings demonstrate that IL4I1 and LAO1 are key regulators of normal colon health, suggesting that restoring LAO adapter protein activity may provide novel therapeutic avenues.