Glyphosate induces lipid metabolism imbalance in liver of zebrafish ( Danio rerio ) under different dietary conditions: Unexpected discovery from the perspective of the gut-liver axis

Glyphosate (GLY) is a widely used herbicide worldwide, whose environmental risks cannot be ignored. In this study, the adverse effects of GLY on the liver function of zebrafish were systematically investigated from the perspective of the gut-liver axis under normal diet (6% crude fat) and high-fat diet conditions (HFD, 24% crude fat). Combined histopathological and physiological biochemical analysis revealed that GLY exposure caused structural damage and an inflammatory response in the liver of zebrafish, accompanied by significant lipid accumulation. Analysis of the expression of metabolic phenotypes and lipid homeostasis-related genes in the liver of zebrafish revealed that GLY caused a disorder of the liver metabolic profiles. This disorder led to significant changes in the contents of metabolites associated with lipid and amino acid metabolism under normal diet and high-fat diet conditions. GLY exposure also promoted the expression of genes associated with fatty acid synthesis and inhibited the expression of genes associated with fatty acid oxidation in the liver of zebrafish. Analysis of intestinal function revealed that GLY exposure led to intestinal dysfunction and ecological imbalances of gut microbiota in zebrafish. Correlation analysis revealed close relationships between changes in the composition of gut microbiota and changes in liver function under GLY exposure. The combined exposure of GLY and HFD caused more severe toxicity effects, including liver damage, intestinal barrier damage, and dysbiosis of the gut microbiota in zebrafish. These results reveal the effects of GLY exposure on liver function, intestinal barrier function, and gut microbiota composition of zebrafish under different dietary conditions and provide new insights into the mechanism of regulating GLY-induced hepatotoxicity via the gut-liver axis. The findings of this study deepen our understanding of the environmental risks of GLY and underscore the influence of different dietary conditions on the toxicity effects of pesticides.