PFAS and microbiota dysbiosis: An emerging link to respiratory toxicity

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants of increasing concern because of their widespread use, environmental mobility, bioaccumulation, and multisystem toxicity, including immunotoxicity, hepatotoxicity, neurotoxicity, reproductive toxicity, and endocrine disruption. Regulatory restrictions on legacy PFAS have accelerated the use of short-chain, ether-containing, and other replacement compounds, including GenX/HFPO derivatives, 6:2 Cl-PFESA, OBS, and ultrashort-chain PFAS; however, their respiratory and toxicological profiles remain incompletely characterized. Although ingestion through food and drinking water is the major exposure route for the general population, inhalation through indoor dust, aerosols, occupational emissions, and firefighting-related sources may be relevant in high-exposure settings, while the actual dose reaching human lung tissue remains poorly defined. Emerging evidence indicates that PFAS-induced toxicity may also involve disruption of host-microbiota interactions. The lung microbiome, despite its low biomass, contributes to mucosal immunity, epithelial homeostasis, and respiratory defense, while the gut-lung axis enables intestinal microbial signals to influence pulmonary inflammation. PFAS-associated gut dysbiosis can alter short-chain fatty acids, bile-acid metabolism, tryptophan-derived metabolites, and microbial products such as lipopolysaccharide, thereby providing plausible mechanistic links between intestinal disturbance and pulmonary immune responses. However, direct evidence that PFAS causally remodel the lung microbiota or that microbiota-derived signals mediate PFAS-induced lung injury remains limited. This review integrates current evidence from epidemiological, in vitro, and in vivo studies to evaluate PFAS-associated respiratory toxicity, with particular emphasis on emerging PFAS, exposure relevance, pulmonary inflammation and injury, and microbiota-mediated mechanisms along the gut-lung axis. By distinguishing established pulmonary effects from emerging microbiota-related hypotheses, this review identifies critical knowledge gaps and highlights priorities for future exposure assessment, mechanistic research, and risk evaluation.