Increased intestinal permeability and bile acid accumulation via inhibition of the FXR-SHP pathway contribute to coumarin-induced systemic inflammation.

Abstract

Coumarin causes severe poisoning in animals, affecting the development of agriculture and animal husbandry. Coumarin induces hepatotoxicity, but the inflammatory mechanism of coumarin is unclear. Here, we explored the effects of coumarin on systemic and hepatic inflammation. Our study found that coumarin reduced the abundance of Akkermansia muciniphila. The number of colonic goblet cells and the expression of Claudin 1 and ZO-1 were decreased in coumarin-treated groups, increasing intestinal permeability. Coumarin elevated the expression of lipopolysaccharide (LPS) biosynthesis genes and serum LPS. These changes increased oxidative stress indicators and total BA (TBA) in the liver. Coumarin inhibited Fxr and Shp expressions in the liver, thereby promoting cholesterol 7-alpha hydroxylase (Cyp7a1) transcription and upregulating TBA level. Collectively, coumarin induced systemic and hepatic inflammation by decreasing tight junction protein and colonic goblet cells, increasing LPS biosynthesis genes of gut microbiota and serum LPS, and elevating TBA level via the Fxr-Shp pathway.IMPORTANCECoumarin, a compound found in Melilotus officinalis, a high-quality forage plant crucial to animal husbandry, has raised safety concerns due to its potential for severe animal poisoning and liver toxicity. It is not clear about the mechanism of coumarin-induced systemic inflammation and liver inflammation. This research aims to elucidate the mechanisms of coumarin-induced systemic and hepatic inflammation, which is of significant importance for the development of agriculture and animal husbandry. In agriculture, understanding how coumarin affects the gut microbiota and intestinal barrier function could lead to the development of new varieties of Melilotus officinalis with lower coumarin concentrations, thus improving its safety as a forage crop.