Metabolomics‐Based Investigation Elucidates the Anti‐Ulcerative Colitis Effect of Kaempferol

ABSTRACTKaempferol is a natural flavonoid with low bioavailability, but it demonstrates significant anti‐inflammatory properties. In a DSS‐induced colitis model, oral administration of kaempferol effectively alleviated characteristic symptoms of ulcerative colitis (UC) in mice. However, its regulatory effects on metabolism within the circulatory system, colon, and gut microenvironment remain insufficiently explored. Pharmacokinetic properties and metabolomics analysis revealed that the much higher level of kaempferol in the gut contents may contribute to its more pronounced metabolic regulatory effects on gut contents compared to those observed in the serum and colon. In detail, kaempferol significantly reversed 102 metabolites in gut contents, involving metabolic pathways comprising amino acid, bile acid, fatty acid, and nucleotide metabolism. Conversely, kaempferol modulated only 10 metabolites in serum and 17 in colon. The systemic effects of kaempferol mediated via gut‐host crosstalk were evidenced by the regulation of shared metabolic pathways. These included tryptophan metabolism and primary bile acid biosynthesis in both serum and gut contents, as well as linoleic acid metabolism and biosynthesis of unsaturated fatty acids in both colon and gut contents. These insights provide a mechanistic basis for the anti‐colitic effects of kaempferol and identify potential metabolic targets for therapeutic intervention in UC within the intestinal ecosystem.