A1 Refereed original research article in a scientific journal
Exposure to environmental toxicants is associated with gut microbiome dysbiosis, insulin resistance and obesity
Authors: Sen Partho, Fan Yong, Schlezinger Jennifer J., Ehrlich Stanislav D., Webster Thomas F., Hyötyläinen Tuulia, Pedersen Oluf, Orešič Matej
Publisher: Pergamon Press
Publication year: 2024
Journal: Environment International
Journal name in source: Environment International
Article number: 108569
Volume: 186
ISSN: 0160-4120
eISSN: 1873-6750
DOI: https://doi.org/10.1016/j.envint.2024.108569
Web address : https://doi.org/10.1016/j.envint.2024.108569
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/387402734
Environmental toxicants (ETs) are associated with adverse health outcomes. Here we hypothesized that exposures to ETs are linked with obesity and insulin resistance partly through a dysbiotic gut microbiota and changes in the serum levels of secondary bile acids (BAs). Serum BAs, per- and polyfluoroalkyl substances (PFAS) and additional twenty-seven ETs were measured by mass spectrometry in 264 Danes (121 men and 143 women, aged 56.6 ± 7.3 years, BMI 29.7 ± 6.0 kg/m2) using a combination of targeted and suspect screening approaches. Bacterial species were identified based on whole-genome shotgun sequencing (WGS) of DNA extracted from stool samples. Personalized genome-scale metabolic models (GEMs) of gut microbial communities were developed to elucidate regulation of BA pathways. Subsequently, we compared findings from the human study with metabolic implications of exposure to perfluorooctanoic acid (PFOA) in PPARα-humanized mice. Serum levels of twelve ETs were associated with obesity and insulin resistance. High chemical exposure was associated with increased abundance of several bacterial species (spp.) of genus (Anaerotruncus, Alistipes, Bacteroides, Bifidobacterium, Clostridium, Dorea, Eubacterium, Escherichia, Prevotella, Ruminococcus, Roseburia, Subdoligranulum, and Veillonella), particularly in men. Conversely, females in the higher exposure group, showed a decrease abundance of Prevotella Copri. High concentrations of ETs were correlated with increased levels of secondary BAs including lithocholic acid (LCA) and ursodeoxycholic acid (UDCA). In silico causal inference analyses suggested that microbiome-derived secondary BAs may act as mediators between ETs and obesity or insulin resistance. Furthermore, these findings were substantiated by the outcome of the murine exposure study. Our combined epidemiological and mechanistic studies suggest that multiple ETs may play a role in the etiology of obesity and insulin resistance. These effects may arise from disruptions in the microbial biosynthesis of secondary BAs.
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