Project description:Background & Aims: Environmental toxicants (ETs) associate with various adverse health outcomes. Here, we hypothesized that exposures to ETs are associated with obesity and insulin resistance via a dysbiotic gut microbiota and derived alterations in microbiome-mediated bile acid (BA) synthesis. Methods: Serum BAs, per- and polyfluoroalkyl substances (PFAS) and additional twenty-seven ETs were measured by mass spectrometry in 264 Danes (121 women and 143 men, age 56.6 ± 7.3 years, BMI 29.7 ± 6.0 kg/m2). Bacterial species were identified based on whole-genome shotgun (WGS) sequencing of DNA extracted from purified stool samples. Personalized genome-scale metabolic models (GEMs) of gut microbial communities were developed to elucidate regulation of BA pathways. Subsequently, we compared findings in the human study with metabolic implications of perfluorooctanoic acid (PFOA) exposure in a PPAR-humanized murine model. Results: Fasting serum concentrations of twelve ETs associated directly with measures of obesity and insulin resistance. Several bacterial species including Dorea longicatena, Dorea formicigenerans, Subdoligranulum spp., Veillonella spp., and Roseburia intestinalis associated positively and in a sex-dimorphic manner, particularly in women, with high exposure to ETs. Moreover, high serum concentrations of ETs were linked with higher fasting serum levels of microbiome-synthesized secondary BAs such as lithocholic acid (LCA) and ursodeoxycholic acid (UDCA). These findings were substantiated by the outcome of a murine exposure study. Conclusion: Serum concentrations of ETs, particularly in women, were associated with an altered gut microbiome-mediated secondary BA biosynthesis, linked with obesity and insulin resistance.
