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

Abstract

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 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. Conclusions: 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.

Lactobacillus rhamnosus GG Derived Extracellular Vesicles Modulate Gut Microbiota and Attenuate Inflammatory in DSS-Induced Colitis Mice

“…Teng et al showed that plant-derived EVs regulated gut microbiota composition and localization, and enhanced the gut barrier function to alleviate colitis [44]. It was documented in our previous research that milk-derived EVs could alleviate colitis via modulating gut microbiota [45]. Here, we found that LGG-EVs restored the disorders of αand β-diversity induced by DSS.…”

Effect of Extracellular Vesicles Derived From Lactobacillus plantarum Q7 on Gut Microbiota and Ulcerative Colitis in Mice

“…Mice were housed in an animal care facility and provided with sufficient food (Beijing Keao Xieli Feed Co., Ltd., Beijing, China) and water. Colitis was induced by 3.5% dextran sulfate sodium (DSS, Yeasen Biotech, Shanghai, CN) administration in the drinking water ( 23 ) and the mice were treated Q7-EVs by gavage ( 23 , 24 ). The mice were acclimated for a week and randomly divided into four groups: control group (PBS, daily), DSS+PBS group (PBS, daily), DSS+10 μg Q7-EVs group (0.5 mg/kg body weight Q7-EVs, daily), DSS+20 μg Q7-EVs group (1 mg/kg body weight Q7-EVs, daily).…”

Beneficial Effects of Bovine Milk Exosomes in Metabolic Interorgan Cross-Talk

“…These results were replicated in vivo in a mouse model of ulcerative colitis. Moreover, the administration of bovine milk exosomes improved wide aspects of cytokine homeostasis, immune response, and modestly improved gut microbiota profile [ 139 ]. Thus, bovine milk exosomes constitute a promising therapeutic tool in managing intestinal inflammatory disorders.…”