Hemp seed oil ameliorates DSS-induced ulcerative colitis in mice by altering transcriptomics and metabolomics

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with complex pathogenesis and limited treatments. Hemp seed oil, with its unique ω-6/ω-3 polyunsaturated fatty acid ratio and phenolic antioxidants, exhibits anti-inflammatory and gut barrier-enhancing properties, though its mechanisms in UC are not fully understood. Here, we applied an integrated transcriptomics and metabolomics approach to investigate the effects of hemp seed oil in dextran sulfate sodium (DSS)-induced UC mice. Treatment with hemp seed oil (1 g/kg) significantly alleviated disease activity, suppressed proinflammatory cytokine levels (interleukin (IL)-6, IL-1β, and IL-17), and improved colonic histopathology. Metabolomic profiling via ultrahigh-performance liquid chromatography-quadrupole-orbitrap tandem mass spectrometry (UPLC-Q-Orbitrap MS/MS) identified 19 significantly altered colonic metabolites, predominantly involved in amino acid metabolism, energy homeostasis, and lipid signalling pathways. Transcriptomic analysis suggested that hemp seed oil treatment was associated with inhibition of the IL-17 and tumor necrosis factor (TNF) signalling pathways while upregulating genes involved in barrier function (e.g., zonula occludens-1 (ZO-1) and Occludin). Integrative analysis revealed strong inverse correlations between key metabolites (e.g., docosahexaenoic acid ethyl ester, adenosine diphosphate (ADP)) and IL-17 pathway activation (IL17A, C-X-C motif chemokine ligand 10 (CXCL10)), suggesting that hemp seed oil may attenuate UC through reprogramming the "metabolism‒inflammation" axis. These findings suggest potential multitarget therapeutic mechanisms of hemp seed oil against UC, indicate critical links between metabolic reprogramming and the immune‒inflammatory axis, and offer novel insights for the development of phytomedicine for the treatment of inflammatory bowel disease.