Docosahexaenoic acid alleviates DSS-induced colitis by regulating the gut microbiota and restoring the gut barrier.

Docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid, has well-recognized anti-inflammatory activity; however, the mechanisms underlying its protective effects in inflammatory bowel disease (IBD) remain incompletely understood. In this study, we investigated the effects of DHA in a dextran sulfate sodium (DSS)-induced mouse model of colitis and examined whether these effects were mediated by the gut microbiota. DHA administration markedly alleviated DSS-induced colitis, as indicated by reduced body weight loss, disease activity, mortality, colon shortening, histological injury, intestinal barrier disruption, and colonic inflammatory responses. 16 S rRNA gene sequencing showed that DHA reshaped the gut microbial community and increased the abundance of beneficial taxa, including Bifidobacterium. Antibiotic cocktail (ABX)-mediated microbiota depletion largely abolished the protective effects of DHA, whereas fecal microbiota transplantation (FMT) from DHA-treated donors transferred resistance to DSS-induced colitis to recipient mice. DHA also restored tight junction protein expression and increased the frequency of colonic regulatory T cells in a microbiota-dependent manner. These findings indicate that DHA alleviates experimental colitis by modulating the gut microbiota, restoring intestinal barrier integrity, and regulating mucosal immune homeostasis. DHA may therefore represent a promising dietary strategy for the prevention or adjunctive treatment of ulcerative colitis (UC).