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.

Scope Milk‐derived extracellular vesicles (mEVs) as nanoparticles are being developed as novel drug vehicles due to their pivotal role in cell–cell communication. As an important bioactive component in milk, little is known about their effect on the gut microbiota and intestinal immunity. Therefore, the effects of mEVs on gut microbiota and intestinal immunity in mice are investigated. Methods and results First, a new method to obtain high‐yield mEVs is developed. Afterward, the colonic contents from C57BL/6 mice fed different doses of mEVs (8 weeks) are collected and the microbial composition via 16S rRNA gene sequencing is analyzed. It is found that mEVs could alter the gut microbiota composition and modulate their metabolites—short‐chain fatty acids (SCFAs). Furthermore, the effects of mEVs on intestinal immunity are evaluated. It is observed that the expression levels of Muc2, RegIIIγ, Myd88, GATA4 genes, and IgA, sIgA are increased in the intestine, which are significant for the integrity of the mucus layer. Conclusion These findings reveal that the genes with critical importance for intestinal barrier function and immune regulation are modified in mice by oral administration mEVs, which also result in the changes of the relative composition of gut microbiome and SCFAs.

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Probiotics plays an important role in regulating gut microbiota and maintaining intestinal homeostasis. Extracellular vesicles (EVs) derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect. However, the anti-inflammatory effect and mechanism of probiotics derived EVs on inflammatory bowel disease (IBD) remains unclear. In this study, the effect of Lactobacillus plantarum Q7-derived extracellular vesicles (Q7-EVs) on gut microbiota and intestinal inflammation was investigated in C57BL/6J mice. The results showed that Q7-EVs alleviated DSS-induced colitis symptoms, including colon shortening, bleeding, and body weight loss. Consumption of Q7-EVs reduced the degree of histological damage. DSS-upregulated proinflammatory cytokine levels including IL-6, IL-1β, IL-2 and TNF-α were reduced significantly by Q7-EVs (p < 0.05). 16S rRNA sequencing results showed that Q7-EVs improved the dysregulation of gut microbiota and promoted the diversity of gut microbiota. It was observed that the pro-inflammatory bacteria (Proteobacteria) were reduced and the anti-inflammatory bacteria (Bifidobacteria and Muribaculaceae) were increased. These findings indicated that Q7-EVs might alleviate DSS-induced ulcerative colitis by regulating the gut microbiota.

Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease. Probiotics have a potential beneficial effect on the prevention of UC onset and relapse in clinical trials. Lactobacillus rhamnosus GG (L. rhamnosus GG) have shown clinical benefits on UC patients, however, the precise mechanisms are unknown. The aim of this study is to explore the effect of extracellular vesicles released from L. rhamnosus GG (LGG-EVs) on dextran sulfate sodium (DSS)-induced colitis and propose the underlying mechanism of LGG-EVs for protecting against colitis. The results showed that LGG-EVs could prevent colonic tissue damage and shortening of the colon (p < 0.01), and ameliorate intestinal inflammation by inhibiting TLR4-NF-κB-NLRP3 axis activation. Consistently, the pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-2) were suppressed effectively upon LGG-EVs treatment (p < 0.05). The 16S rRNA sequencing showed that LGG-EVs administration could reshape the gut microbiota in DSS-induced colitis mice, which further alters the metabolism pathways of gut microbiota. These findings propose a novel perspective of L. rhamnosus GG in attenuating inflammation mediated by extracellular vesicles and offer consideration for developing oral gavage of LGG-EVs for colitis therapies.

Milk-derived extracellular vesicles (mEVs) have been proposed as a potential nanomedicine for intestinal disorders; however, their impact on intestinal barrier integrity in gut inflammation and associated metabolic diseases has not been explored yet. Here, mEVs derived from bovine and human breast milk exert similar protective effects on epithelial tight junction functionality in vitro, survive harsh gastrointestinal conditions ex vivo, and reach the colon in vivo. Oral administration of mEVs restores gut barrier integrity at multiple levels, including mucus, epithelial, and immune barriers, and prevents endotoxin translocation into the liver in chemical-induced experimental colitis and diet-induced nonalcoholic steatohepatitis (NASH), thereby alleviating gut disorders, their associated liver inflammation, and NASH. Oral administration of mEVs has potential in the treatment of gut inflammation and gut-liver axis–associated metabolic diseases via protection of intestinal barrier integrity.

Probiotics effectively regulated lipid metabolism and improve hyperlipidemia. The purpose of this study was to further evaluate the functions of lipid-lowering strains in vivo and elucidate the mechanism. The hyperlipidemia...

It is well known that the flavor of skim milk is inferior to whole milk due to the lack of fat. With the popularity of low-fat dairy products, improving the flavor of skim milk is a main focus for food scientists. During the production of skim milk, preheating treatments have a significant effect for the flavor of skim milk. In this study, to explore the optimal processing conditions, milk was preheated at 30 °C, 40 °C, 50 °C, 60 °C for 30 min prior to defatting. When the optimal temperature was determined, milk was then preheated at the optimal temperature for 10 min, 20 min, 30 min, 40 min and 50 min, respectively, to obtain the best preheating time. Distinctions between skim milk samples with different processing conditions were studied by sensory evaluation, e-tongue and HS-SPME-GC-MS analysis. Principle components analysis (PCA) and cluster analysis (CA) were selected to associate with e-tongue results and compare the similarities and differences among the skim milks. Sensory and e-tongue results matched and both showed that a preheating temperature of 50 °C and 30 min time might be the optimal combination of processing conditions. Thirteen volatiles, including ketones, acids, aldehydes, alcohols, alkanes and sulfur compounds, were analyzed to evaluate flavor of the skim milks produced by different preheating treatments. Combined with previous studies, the results indicated that most volatile compounds were decreased by reducing the fat concentration and the typical compound 2-heptanone was not detected in our skim milk samples.