Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota

作者：Lingjun Tong, Haining Hao, Zhe Zhang, Youyou Lv, Xi Liang, Qiqi Liu, Tongjie Liu, Pimin Gong, Lanwei Zhang, Fangfang Cao, Giorgia Pastorin, Chuen Neng Lee, Xiaoyuan Chen, Jiong‐Wei Wang, Huaxi Yi · 发表于：Theranostics · 年份：2021 · DOI：10.7150/thno.62046 · 被引用次数：340 · 研究领域：Extracellular vesicles in disease、IL-33, ST2, and ILC Pathways、Infant Nutrition and Health

Rationale: Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients.We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice.Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease.Methods: MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation.Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium.Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing.Results: We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model.Mechanistically, mEVs attenuated inflammatory response via inhibiting TLR4-NF-κB signaling pathway and NLRP3 inflammasome activation.Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10 + Foxp3 + regulatory T (Treg) cells in the inflamed colon.The disturbed gut...