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.

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.

Two Bifidobacterium bifidum strains could exert their anti-inflammatory and intestinal barrier protecting effects both in vitro and in vivo, upregulate the expression of the aryl hydrocarbon receptor (AhR) in mice with DSS-induced colitis.