Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate Triggers IBD-like Pathology through the Gut Microbiota–Arachidonic Acid Axis: Protective Role of <i>Akkermansia muciniphila</i>

Environmental pollutants are increasingly recognized as modulators of gut microbiota and metabolic pathways, contributing to the rising global incidence of inflammatory bowel disease (IBD). The novel brominated flame retardant bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is increasingly detected in ecosystems and human tissues, yet its impact on intestinal health remains unclear. Here, we combined shotgun metagenomics, untargeted metabolomics, and targeted biochemical assays in a murine model to reveal how TBPH drives IBD-like pathology. TBPH exposure resulted in shortened colons, disrupted epithelial barriers, and elevated systemic pro-inflammatory cytokines, accompanied by gut microbiota dysbiosis marked by depletion of Akkermansia muciniphila ( AKK ). Decreased abundance of AKK correlated with arachidonic acid (AA) accumulation and hyperactivation of the phospholipase A2 (PLA2)-cyclooxygenase 2 (COX2)-prostaglandin E2 (PGE2) inflammatory cascade, leading to NF-κB activation and mucosal injury. Supplementation with viable AKK restored AA homeostasis, suppressed inflammatory signaling, and preserved the barrier integrity. These results demonstrate a microbiota-dependent mechanism linking TBPH exposure to AA-driven intestinal inflammation and identify AKK as a critical protective species, which highlights the gut microbiota–AA metabolic axis as a potential mechanism for pollutant-induced intestinal disorders.