Environment shapes gut microbiome and determines susceptibility to DSS-colitis in Adamdec1-/- mice.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by marked clinical heterogeneity, reflecting complex interactions between host genetics, environmental exposures, and the gut microbiome. Although over 300 genetic risk loci have been identified, these account for only a fraction of disease variance, highlighting the importance of gene-environment interactions. ADAM-like Decysin-1 (ADAMDEC1) is a gastrointestinal-restricted metalloprotease implicated in mucosal repair and immune regulation, with reduced expression reported in IBD. While Adamdec1-deficient mice exhibit increased susceptibility to colitis, the mechanisms underlying phenotypic variability remain poorly understood. METHODS: To dissect genetic and environmental contributions to colitis severity, C57BL/6J wild-type (WT) and Adamdec1-/- mice were co-housed in two distinct environments and subjected to dextran sodium sulfate (DSS)-induced colitis. Disease severity was assessed by weight loss, immune cell infiltration, and transcriptional profiling of inflammatory and epithelial repair markers using flow cytometry and qPCR. Gut microbiome composition was analyzed from fecal samples collected following extended co-housing to evaluate environment-driven microbial differences. RESULTS: Environmental factors exerted a stronger influence than genotype on gut microbiome composition. WT mice displayed consistent inflammatory and transcriptional responses to DSS across environments, whereas Adamdec1 -/- mice exhibited marked cage-dependent variability, ranging from severe colitis to a mild, WT-like phenotype. Severe disease in Adamdec1 -/- mice was associated with enhanced neutrophil recruitment, increased CD11b expression, altered monocyte/macrophage activation, impaired epithelial proliferation, and disrupted stem cell-associated gene expression. These phenotypic differences correlated with distinct microbiome profiles indicating genotype-dependent microbial pathogenicity. CONCLUSION: These findings demonstrate that loss of Adamdec1 creates a state of heightened sensitivity to environmental and microbiome related factors, in which gut microbial composition correlates with differences in inflammatory and epithelial outcomes during colitis. This study identifies a gene-environment-microbiome axis associated with phenotypic variability in intestinal inflammation and provides mechanistic insight into the heterogeneity of IBD. Targeting environmentally driven microbial modifiers may represent a promising strategy for personalized intervention in genetically susceptible individuals.