Integrated multi-omics reveals correlational links between gut microbiota alterations and glycerophospholipid dysregulation upon TBPH exposure

TBPH correlated with altered glycerophospholipid profiles in serum and intestine. • Compositional shifts in the gut microbiota were observed following TBPH exposure. • Elevated thyroid hormones and serum PLA2 activity co-occurred with TBPH exposure. • Systemic PC remodeling had a statistical association with gut microbiota changes. Bis(2-ethylhexyl) tetrabromophthalate (TBPH), a replacement for polybrominated diphenyl ethers, poses health concerns due to environmental ubiquity and potential endocrine disruption. Here, we investigated TBPH‑induced metabolic dysregulation mechanisms focusing on glycerophospholipid homeostasis and gut microbiota. Male Sprague‑Dawley (SD) rats were orally exposed to TBPH (0, 5, 50, 500 mg/kg) for 28 days; only control and 500 mg/kg groups underwent untargeted metabolomics (serum and intestinal) and 16S rRNA sequencing. At the highest dose, TBPH was significantly associated with disruption of the glycerophospholipid metabolism pathway, with marked alterations in phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) in both serum and intestinal contents. This exposure was also associated with compositional shifts in the gut microbiota, characterized by a reduction in potentially beneficial genera (e.g., Akkermansia and Parabacteroides ), an enrichment of genera associated with dysbiosis (e.g., Desulfovibrio and Mucispirillum ), and a rewiring of microbial co‑occurrence networks. At the highest dose tested, TBPH was associated with increased serum phospholipase A2 (PLA2) activity. Partial least squares path modeling (PLS‑PM) identified statistical associations consistent with the hypothesis that TBPH may be indirectly associated with serum PLA2 activity through pathways involving the gut microbiota and its associated PC metabolites, as well as through elevated thyroid hormones. All findings were correlational and hypothesis‑generating; direct extrapolation to human health risk was not possible from this high‑dose animal study. Collectively, our findings generated the hypothesis that TBPH exposure was associated with host lipid homeostasis alterations through coordinated associations with the gut microbial ecosystem and endocrine signaling, warranting further investigation into its metabolic toxicity. Download: Download high-res image (288KB) Download: Download full-size image