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./nMethods: 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./nResults: 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 microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity via influencing the gut microbiota./nConclusions: These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis via inhibiting TLR4-NF-κB and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota.

中文翻译：

---

乳源性细胞外囊泡通过调节肠道免疫力和重塑肠道菌群来缓解溃疡性结肠炎

理由：牛奶是人类饮食的重要组成部分，尤其是对儿童而言，因为它富含各种营养成分。我们最近开发了一种从牛奶中分离细胞外囊泡 (mEV) 的有效方案，并发现 mEV 含有大量免疫活性蛋白并调节健康小鼠的肠道免疫和微生物群。在这里，我们旨在探索 mEVs 对炎症性肠病的治疗效果。/n方法：分别通过 RNA 测序和蛋白质组学分析 mEVs 中的 microRNA 和蛋白质含量，然后进行功能注释。溃疡性结肠炎 (UC) 通过给小鼠喂食葡聚糖硫酸钠来诱导。通过流式细胞仪对肠道免疫细胞群进行表型分析，并分析肠道微生物群通过16S rRNA 测序。/n结果：我们发现 mEVs 中丰富的蛋白质和 microRNAs 参与了免疫和炎症通路的调节，并且口服 mEVs 可防止结肠缩短、减少肠上皮破坏、抑制炎症细胞和组织的浸润小鼠 UC 模型中的纤维化。从机制上讲，mEVs通过抑制 TLR4-NF-κB 信号通路和 NLRP3 炎性体激活来减弱炎症反应。此外，mEVs 能够纠正细胞因子产生障碍并恢复 T 辅助 17 型 (Th17) 细胞与白介素 10 ⁺ Foxp3 ^{+之间的平衡}炎症结肠中的调节性 T (Treg) 细胞。在使用 mEV 治疗后，UC 中受干扰的肠道微生物群也部分恢复。肠道菌群与细胞因子之间的相关性表明，mEVs 可能通过影响肠道菌群来调节肠道免疫。/n结论：这些发现表明，mEVs通过抑制 TLR4-NF-κB 和 NLRP3 信号通路调节肠道免疫稳态来缓解结肠炎，恢复Treg/Th17 细胞平衡，重塑肠道菌群。