Gut microbiome-mediated mechanisms of per- and polyfluoroalkyl substances (PFAS) biotransformation and their implications for human health

Per- and polyfluoroalkyl substances (PFAS) represent a diverse group of synthetic chemicals widely utilized in industrial processes, consumer goods, food-contact materials, and plastics due to their exceptional chemical stability and resistance to degradation. However, their pervasive presence in the environment, persistence, and ability to bioaccumulate have raised increasing concerns about human exposure and associated health risks. Dietary intake, through contaminated food, drinking water, and food packaging materials, serves as a primary route of exposure, placing the gastrointestinal tract at the center of PFAS–host interactions. Recent research suggests that the gut microbiome plays a significant role in modifying PFAS toxicokinetics, bioavailability, and biological effects. This review consolidates current insights into the complex relationship between PFAS and the gut microbiome, detailing mechanisms such as microbial uptake, bioaccumulation, enzymatic defluorination, β-oxidation-like biotransformation processes, and alterations in bile acid and short-chain fatty acid metabolism. Conversely, exposure to PFAS can disrupt microbial diversity, compromise intestinal barrier integrity, and affect various host functions, including immune response, metabolism, liver and kidney health, and neuroendocrine regulation. Experimental studies, data from human cohorts, and findings from multi-omics approaches reveal that microbiome-driven changes contribute to chronic health issues like inflammation, metabolic disorders, insulin resistance, and immune system dysregulation. Additionally, advancements in metagenomics, metabolomics, and transcriptomics are shedding light on the intricate mechanisms underlying PFAS–microbiome interactions. These developments underscore the potential for microbiome-targeted interventions to mitigate the adverse health effects of these enduring environmental pollutants.