A Common Indoor Pollutant, 1,4-Dichlorobenzene, Induces Colonic Inflammation via Vitamin D Receptor-Reg3γ-Gut Microbiota Axis

1,4-Dichlorobenzene (1,4-DCB), a widely used household insect repellent and fungicide, has been epidemiologically linked to ulcerative colitis, yet its potential mechanisms remain poorly understood. In this study, juvenile male mice developed colonic inflammation following exposure to 1,4-DCB at doses of 0.03-3 mg/kg/day, a range corresponding to the human estimated daily intake (EDI) and relevant internal exposure levels in adolescents. This was evidenced by increased fecal moisture (by 12.22%-18.21%) and colon weight (17.57%-38.33%), shortened colon length (13.51%-24.88%), crypt expansion, and connective tissue hyperplasia. 1,4-DCB exposure upregulated the colonic expression of regenerating family member 3 gamma (Reg3γ), a key antimicrobial peptide that targets Gram-positive bacteria. This upregulation was accompanied by gut microbiota dysbiosis, elevated colonic levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines, as well as decreased levels of tight junction proteins. Microbiota depletion alleviated these colitis symptoms induced by 1,4-DCB. In human colonic cells, we further validated LPS-induced inflammation and impaired permeability as well as identified vitamin D receptor (VDR) as a potential primary molecular target for 1,4-DCB. Overall, this study provides the first evidence that environmentally relevant levels of 1,4-DCB induce colonic inflammation through the VDR-Reg3γ-gut microbiota axis. These findings highlight the potential colonic health risk posed by this prevalent indoor pollutant.