Yak milk–derived exosomes alleviate lipopolysaccharide-induced intestinal inflammation by inhibiting PI3K/AKT/C3 pathway activation

摘要

Intestinal epithelial cells (IEC) are important partsof the mucosal barrier, whose function can be impairedupon various injury factors such as lipopolysaccharide.Although food-derived exosomes are preventableagainst intestinal barrier injuries, there have been fewstudies on the effect of yak milk–derived exosomesand the underlying mechanism that remains poorlyunderstood. This study aimed to characterize the effectof exosomal proteins derived from yak and cowmilk on the barrier function of IEC-6 treated with lipopolysaccharideand the relevant mechanism involved.Proteomics study revealed 392 differentially expressedproteins, with 58 higher expressed and 334 lower expressedin yak milk–derived exosomes than those incow exosomes. Additionally, the top 20 proteins witha relatively consistent higher expression in yak milkexosomes than cow milk exosomes were identified. ProteinCD46 was found to be a regulator for alleviatinginflammatory injury of IEC-6. In vitro assay of the roleof yak milk exosomes on survival of IEC-6 in inflammationby 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay confirmed the effectivenessof yak milk exosomes to increase IEC-6 survival up to18% for 12 h compared with cow milk exosomes (upto 12%), indicating a therapeutic effect of yak milkexosomes in the prevention of intestinal inflammation.Furthermore, yak and cow milk exosomes were shownto activate the PI3K/AKT/C3 signaling pathway, thuspromoting IEC-6 survival. Our findings demonstratedan important relationship between yak and cow milkexosomes and intestinal inflammation, facilitating furtherunderstanding of the mechanisms of inflammationdrivenepithelial homeostasis. Interestingly, comparedwith cow milk exosomes, yak milk exosomes activatedthe PI3K/AKT/C3 signaling pathway more to lowerthe incidence and severity of intestine inflammation,which might represent a potential innovative therapeuticoption for intestinal inflammation.