Bile acids and apical sodium-dependent bile acid transporter impact per- and polyfluoroalkyl substances absorption: Evidence from in vivo and cross-sectional studies.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals with worldwide contamination and human exposure. Epidemiological studies have linked high PFAS levels to various diseases, highlighting their potential health risks. However, current studies often overlook the possibility that diseases may influence PFAS levels in patients, potentially overestimating or underestimating their true public health impacts. Here, we found that a high-fat diet, which increases bile acids secretion, decreased the area under the curve (AUC) of nearly all target PFAS in rats, with about 50 % of these decreases statistically significant. Bile acid supplementation further significantly reduced the AUC of approximately 80 % of target PFAS. Subsequent molecular docking and in vitro PFAS binding assays with the apical sodium-dependent bile acid transporter (ASBT) showed that bile acids can compete with PFAS for ASBT's binding pocket. Follow-up ASBT-specific inhibitor experiments revealed the inhibitor decreased the AUC of nearly half of the target PFAS by over 40 %, confirming ASBT's critical role in PFAS absorption. Analysis of the 2017-2018 National Health and Nutrition Examination Survey case-control data revealed that gallbladder surgery (1464 participants), gallstones (1460 participants), and hypertriglyceridemia (715 participants), conditions that increase bile acid secretion and/or inhibit ASBT expression, showed negative correlations with all target PFAS, with more than 75 % of these results being statistically significant. Together, our findings confirm the essential role of bile acids and ASBT in PFAS absorption, which should be incorporated into future PFAS research to improve the accuracy of exposure risk assessments.