Yak whey protein peptides alleviate DSS-induced colitis by modulating the NLRP3 inflammasome and gut barrier

Yak whey protein and its peptides possess excellent anti-inflammatory and antioxidant properties. However, their effects against colitis have rarely been investigated. Therefore, in this study, yak whey protein was hydrolyzed using alkaline protease, and the preventive effects of the resulting yak whey protein peptides (YWP) were evaluated in a dextran sulfate sodium (DSS)-induced murine colitis model, while peptidomic analysis was further employed to screen potential bioactive peptides. The results showed that YWP attenuated DSS-induced body weight loss, colon shortening, splenomegaly, increased disease activity, and histological damage in mice. YWP administration was also associated with reduced oxidative stress and inflammatory responses, preservation of intestinal barrier-related proteins, altered gut microbiota composition, increased short-chain fatty acid levels, and lower expression of NLRP3/ASC/Caspase-1 inflammasome-related proteins. Peptidomic profiling identified 5,821 peptides in YWP, and molecular docking indicated that KGPWFW, GGWGW, WFGY, and FYYY exhibited favorable predicted binding to myeloperoxidase. Collectively, these findings demonstrate that prophylactic YWP administration attenuates the development and severity of DSS-induced colitis in mice and support its potential as a food-derived ingredient for maintaining intestinal health.