Per-and polyfluoroalkyl substances (PFAS) driven reorganization of brain metabolism is impacted by resident microbiota

Emerging evidence indicates PFAS can cross the blood-brain barrier and cause neurotoxicity, and that these pollutants also accumulate in gut microbiota. However, how gut microbes shape PFAS-driven brain metabolic disruption was poorly understood. To address this, researchers exposed specific pathogen-free (SPF) and germ-free (GF) mice to an obesogenic diet plus a PFAS mixture (PFHxS, GenX, PFOA, PFOS, FTOH) for 8 weeks, then performed untargeted lipidomic and metabolomic analyses on plasma and five brain regions using high-resolution LC-MS/MS.

PFAS were detected in all brain regions tested, with PFOS being the most enriched. Pathway analysis revealed nicotinate and nicotinamide metabolism as the most consistently altered pathway in both SPF and GF mice. The effects were region-specific: gut microbiota differentially modulated PFAS responses in the cortex, cerebellum, and brainstem, while the olfactory bulb responded largely independently of microbiota. Plasma-brain correlation analyses further suggested systemic metabolic crosstalk, with association strengths varying by region and microbiome status.

Gut microbiota also shaped PFAS-induced lipid dysregulation in the brain, and metabolites such as methylnicotinamide and delta-valerobetaine were among the most responsive. The authors conclude this is the first demonstration that resident microbiota impact PFAS-associated metabolic remodeling across the gut-plasma-brain axis, highlighting a new avenue for understanding PFAS neurotoxicity.