Mechanisms of Casein-Derived Immunomodulatory Peptides Maintaining Immune Homeostasis via Regulating Gut Microbiota in a Cyclophosphamide-Induced Mouse Model

Two immunomodulatory signature peptides (PFPEVFG and SPAQILQW) were obtained from casein hydrolysates produced by <i>Kluyveromyces marxianus</i> JY-1 in our previous studies with the aid of virtual screening. However, their mechanisms for improving the composition of the gut microbiota in immunosuppressed mice remain unknown. The aim of this study was to reveal the mechanisms of immunomodulation and improvement of gut microbiota composition mediated by the casein peptides PFPEVFG and SPAQILQW through a cyclophosphamide (Cy)-induced immunosuppression and intestinal mucosal injury mouse model. The casein peptides PFPEVFG and SPAQILQW reversed Cy-induced intestinal structural damage and could correct for Cy-induced intestinal flora disorders. Importantly, fecal microbiota transplantation (FMT) confirmed that the casein peptides PFPEVFG and SPAQILQW attenuate immunosuppression by targeting participation in the dynamic balance of the gut microbiota. These results indicated that the casein peptides PFPEVFG and SPAQILQW have the potential to be used as natural medicines for the treatment of immunosuppression.