Risk of chronic low-dose pesticide cocktail exposure: Increased inflammatory bowel disease susceptibility through...

Human exposure to concurrent multiple pesticide residues is inevitable given the application of pesticides in modern agricultural, yet the associated health risks remain insufficiently characterized. A mixture of ten frequently detected pesticides was incorporated into the diet of male ICR mice at three dose levels (ADI, 100 ×ADI, and 10 ×NOAEL) for 17 weeks to evaluate intestinal risks. ADI exposure caused no significant colonic inflammation or injury, whereas 100 ×ADI and 10 ×NOAEL caused IBD, characterized by shortened colon length, epithelial injury, upregulated pro-inflammatory cytokines (IL-1β, IL-6, IL-22), and downregulated tight junIction proteins (ZO-1, occludin). In DSS-induced model, even ADI group developed evident IBD, and those at 100 ×ADI and 10 ×NOAEL group exhibited more exacerbated intestinal inflammatory responses and tissue injury, indicating that chronic ADI dose pesticide cocktail exposure markedly increased susceptibility to IBD. At 10 ×NOAEL dose, the relative abundances of Lactobacillus, Streptococcus, and Candidatus_Saccharimonas were significantly reduced, whereas Faecalibaculum and Akkermansia were significantly enriched, which was closely associated with increased pro-inflammatory cytokines (IL-6, IL-22) and upregulation of RORγt and IL-17a alongside reduced Foxp3 and IL-10, indicating a disrupted Th17/Treg balance linked to colonic inflammation and barrier dysfunction. FMT confirmed the critical role of the gut microbiota in mediating both pesticide-induced colonic inflammation and aggravation of DSS-induced colitis. Collectively, these findings demonstrate that chronic low-dose pesticide cocktail exposure disrupts gut microbial homeostasis, alters the Th17/Treg balance, upregulates pro-inflammatory cytokines, and compromises intestinal barrier integrity, thereby triggering colonic inflammation and exacerbating DSS-induced IBD. This work highlights the necessity of the evaluation of mixed pesticide residue.