Chlorothalonil Induces Metabolic Syndrome in Mice by Regulating Host Gut Microbiota and Bile Acids Metabolism Via Fxr Pathways

Background：The most commonly used organochlorine pesticide, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet.Results: This study found that the low-dose CHI based on acceptable daily intake (ADI) level could induce metabolic syndrome (MetS) in mice, including obesity, hepatic steatosis, dyslipidemia, and insulin resistance. In addition, exposure to low-dose CHI could induce an imbalance in the gut microbiota of mice, resulting in a significant increase in the ratio of Firmicutes to Bacteroidetes. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the low-dose CHI could induce MetS in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, the low-dose CHI could disturb the serum metabolism of bile acids (BAs) in mice, causing the inhibition of the signal response of BAs receptor farnesol X receptor (FXR) and leading to glycolipid metabolism disorders in liver tissue and epididymal white adipose tissue (epiWAT) of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the low-dose CHI-induced MetS in mice.Conclusions: In conclusion, the low-dose CHI was found to induce MetS in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of MetS, demonstrating the key role of gut microbiota in the toxic effects of pesticides.