Milk-Derived Extracellular Vesicles Carrying ssc-let-7c Alleviate Early Intestinal Inflammation and Regulate Macrophage Polarization via Targeting the PTEN-Mediated PI3K/Akt Pathway

Milk-derived extracellular vesicles (mEVs) are beneficial to the health of infants. However, the effect of mEVs on early intestinal inflammation is not well established. Herein, weaned colitic mice were used to explore the potential effects and underlying mechanisms of porcine mEVs (pmEVs) on intestinal inflammation during early life. We found that pmEVs administration attenuated early life intestinal inflammation and promoted colonic barrier integrity in mice. The anti-inflammatory effect of pmEVs was achieved by shifting a proinflammatory macrophage (M1) toward an anti-inflammatory macrophage (M2). Moreover, pmEVs can be absorbed by macrophages and reduce proinflammatory polarization (stimulated by LPS) in vitro. Noteworthily, ssc-let-7c was found to be highly expressed in pmEVs that can regulate the polarization of macrophages by targeting the tensin homologue deleted on chromosome ten (PTEN), thereby activating the PI3K/Akt pathway. Collectively, our findings revealed a crucial role of mEVs in early intestinal immunity and its underlying mechanism.