Fish gut microbiota mediate pollutant-induced lipid toxicity via bidirectional biotransformation and dysbiosis

Abstract The gut microbiota acts simultaneously as a target of environmental pollutants and as a driver of their biotransformation, but how these two roles jointly determine host toxicity remains insufficiently defined. Using zebrafish as a One Health model, we show that dietary exposure to environmentally relevant levels of triphenyl phosphate (TPHP), an organophosphate flame retardant, causes intestinal lipid accumulation, barrier disruption, and PPAR pathway dysregulation. By combining antibiotic-treated zebrafish models, stable isotope-assisted metabolomics, and multiomics profiling, we found that the gut microbiota transforms TPHP through a bidirectional network. It reactivates host-derived glucuronidated metabolites via deconjugation and ferments TPHP carbon skeletons into small-molecule metabolites, including L-phenylalanine and N-acetyltyramine, that are integrated into host lipid and energy metabolism. The functional disruption of the microbiota abolishes these metabolite signals, supporting a key role of the gut microbiota in TPHP biotransformation. Metagenomics identifies specific bacterial taxa (such as Acinetobacter, Pseudomonas, and Aeromonas) and hydrolytic enzyme families responsible for these transformations. Our findings suggest that the gut microbiota functions beyond a passive target of pollutant exposure: it expands the metabolic fate of TPHP and generates pollutant-derived metabolic signals that intersect with host lipid homeostasis, collectively mediating the observed lipotoxicity through host–microbe interactions. This work provides a mechanistic framework for incorporating gut microbiome dynamics into chemical risk assessment under the One Health paradigm.