From Exposure to Dysfunction: The Intestinal Toxicity of Per- and Polyfluoroalkyl Substances

Per- and Polyfluoroalkyl substances (PFAS) are highly persistent synthetic chemicals increasingly associated with adverse health outcomes. The gastrointestinal tract represents both a major route of exposure and a key target of PFAS toxicity. This review integrates updated evidence on how PFAS compromise intestinal homeostasis through interrelated structural, metabolic, and immunological mechanisms. PFAS disrupt epithelial integrity by down-regulating tight-junction proteins, inducing oxidative stress, and activating inflammasome signaling. Concurrently, metabolic reprogramming and PFAS-driven microbial dysbiosis contribute to barrier dysfunction and altered production of signal/metabolic molecules. These alterations may link environmental exposure to chronic intestinal inflammation and increase susceptibility to inflammatory bowel disease and related metabolic disorders. By synthesizing recent findings, key mechanistic gaps were highlighted also emphasizing the need for integrative experimental and translational studies to refine risk assessment in humans and develop preventive and therapeutic strategies.