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BackgroundConventional therapies for inflammatory bowel disease (IBD) are associated with significant adverse effects, highlighting the need for safer and effective alternatives. Krill oil (KO), a rich source of long-chain omega-3 polyunsaturated fatty acids (PUFAs) and astaxanthin, has shown therapeutic potential in several disorders but remains understudied in chronic colitis. This study evaluates the potential therapeutic efficacy of KO, alone or in combination with dexamethasone (DEX), in a spontaneous chronic colitis mouse model that closely mimics human IBD. The molecular mechanisms underlying the health benefits of KO were also explored.MethodsFour groups of homozygous Winnie mice (Win/Win) received 10% KO, 20 ng/g DEX, KO + DEX, or saline (sham) for 28 days. Heterozygous littermates (Win/Wt) were used as controls (n = 10 per group). Disease activity, colonic histopathological changes, epithelial barrier integrity, and underlying molecular mechanisms were evaluated.ResultsTreatments with KO, DEX, and KO + DEX significantly reduced disease severity and mucosal injury. Restoration of colonic permeability was observed across all treatment groups, with KO + DEX and DEX treatments notably enhancing the expression of tight junction proteins. Transcriptomic profiling identified changes in epithelial barrier-related and cell adhesion molecules (CAM)-related genes following KO treatment, including higher expression of Cldn1, Cldn4, Galnt3 and lower expression of Icam1, Selp, Sele, Ptprc. Combination therapy with KO and DEX was associated with gene expression patterns related to epithelial polarity and extracellular matrix anchoring (Ctnnb1, Dsg2, Muc4, Itga8), as well as lower expression of CAM-related genes implicated in immune cell recruitment.ConclusionKO treatment showed promising therapeutic benefits, with some being comparable to DEX, and enhanced efficacy when combined with DEX, in a mouse model of spontaneous chronic colitis by restoring epithelial barrier integrity and suppressing CAM-mediated immune cell recruitment.