Microbial tryptophan-IPA axis mediates 6:2 chlorinated polyfluorinated ether sulfonate (6:2Cl-PFESA)-induced...

Chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs) are widely used substitutes for perfluorooctane sulfonate (PFOS) and are increasingly detected in environmental and human matrices, yet their neurobehavioral risks during early life remain poorly defined. Here, male C57BL/6J mice were orally exposed to F-53B (6:2Cl-PFESA; 0.1 or 1 mg/kg/day) during juvenility for four weeks. F-53B selectively impaired recognition memory and social novelty preference, whereas locomotor activity, anxiety-like behavior, and Y-maze working memory were largely preserved. Mechanistically, F-53B compromised intestinal barrier integrity, as evidenced by reduced occludin expression and disrupted ZO-1 continuity, accompanied by elevated circulating lipopolysaccharide (LPS) and a systemic pro-inflammatory cytokine shift. In parallel, the hippocampus exhibited microglial activation, enhanced inflammatory signaling, and reduced PSD95 expression, consistent with neuroinflammatory stress and synaptic vulnerability. Shotgun metagenomics revealed pronounced microbiome restructuring and network rewiring, while widely targeted metabolomics converged on a marked disruption of tryptophan metabolism, characterized by depletion of microbiota-derived indole metabolites, including indole-3-propionic acid (IPA), together with altered serotonin-related signatures. Notably, oral IPA supplementation rescued behavioral deficits and attenuated gut-brain inflammatory alterations, restoring intestinal aryl hydrocarbon receptor (AhR) nuclear translocation, reducing LPS and cytokine levels, and ameliorating hippocampal inflammatory phenotypes. Collectively, these findings provide mechanistic evidence that a microbiota-tryptophan metabolite-gut barrier-inflammation axis links exposure to substitute PFAS with selective neurobehavioral dysfunction, highlighting microbiota-derived metabolites as potential modulators of PFAS-associated neurotoxicity.