Per- and polyfluoroalkyl substances mixture impairs intestinal barrier function through microbiota-derived...

Per- and polyfluoroalkyl substances (PFASs) are persistent environmental pollutants linked to various health risks, including intestinal disorders. However, the effect of real-world PFASs mixture on intestinal health remains unclear. Therefore, this study aimed to investigate the effects of a PFASs mixture by mimicking the exposure composition in a population on intestinal homeostasis in rats. Although the colon showed no significant morphological alterations, transcriptomic analysis revealed dose-dependent changes in gene expression levels related to cell-cell and tight junctions. Immunofluorescence and immunohistochemistry further confirmed these findings, demonstrating a dose-dependent decrease in key tight junction proteins, occludin and claudin-1, in the colonic epithelium. Integrative analysis revealed that PFASs mixture exposure disrupted the growth and metabolism of gut bacteria, such as Ruminococcus, leading to increased production of 21-deoxycortisol (21-DF). 21-DF inhibited cortisol to cortisone conversion, elevating cortisol levels in intestinal epithelial cells. Consequently, the increased cortisol levels suppressed the expression of tight junction proteins and disrupted the intestinal barrier function. Our findings provide novel insights into the underlying mechanisms by which real-world PFASs mixture disrupt intestinal barrier function through the gut microbiome-metabolome-epithelial cell axis, highlighting the need to consider the complex interplay between environmental pollutants, gut microbiota, and host health in risk assessment and development of intervention strategies.