Donkey Milk Improves Dextran Sulfate Sodium-Induced Ulcerative Colitis by Protecting Gut Barrier Function, Inhibiting the TLR4/MyD88/NF-κB Signaling Pathway, and Modulating Gut Microbiota.

Donkey milk (DM) demonstrates promising bioactive properties, including anti-inflammatory and microbiota-modulating effects with therapeutic potential for ulcerative colitis (UC)-though mechanistic research remains limited. To bridge this research gap, a standardized DSS-induced murine UC model was established. Results indicated that daily DM administration markedly attenuated clinical manifestations of UC, such as reduced body weight, intestinal mucosal injury, and increased Disease Activity Index (DAI). Mechanistically, DM enhanced gut barrier integrity through transcriptional upregulation of key genes (MUC2, Reg3α, Reg3g, Occludin, Alpi, ZO-1) while suppressing inflammation via TLR4/MyD88/NF-κB cascade inhibition and concomitant reduction of proinflammatory cytokines (TNF-α, IL-1β, IL-18). Cecal 16S rDNA sequencing further confirmed DM-mediated microbial restoration, characterized by significant enrichment of beneficial genera (Enterorhabdus, Lachnoclostridium, Parvibacter) and reduction of inflammation-associated taxa (Bacteroides, norank_Muribaculaceae, Eubacterium fissicatena group). In conclusion, our integrated analysis validates DM as a nutraceutical intervention capable of simultaneously targeting mucosal healing, inflammation resolution, and microbiome restoration-positioning it as a promising therapeutic and prophylactic approach for IBD spectrum disorders.