Concentrates of two subsets of extracellular vesicles from cow’s milk modulate symptoms and inflammation in experimental colitis

Abstract

Extracellular vesicles (EVs) are involved in cell-to-cell communication and modulation of numerous physiological and pathological processes. EVs are found in large quantities in milk and contain several inflammation- and immunity-modulating proteins and microRNAs, through which they exert beneficial effects in several inflammatory disease models. Here, we investigated the effects of two EV subsets, concentrated from commercial cow’s milk, on a murine model of colitis induced with dextran sodium sulfate (DSS). P35K EVs, isolated by ultracentrifugation at 35,000 g, and P100K EVs, isolated at 100,000 g, were previously characterized and administered by gavage to healthy and DSS-treated mice. P35K EVs and, to a lesser extent, P100K EVs improved several outcomes associated to DSS-induced colitis, modulated the gut microbiota, restored intestinal impermeability and replenished mucin secretion. Also, P35K EVs modulated innate immunity, while P100K EVs decreased inflammation through the downregulation of colitis-associated microRNAs, especially miR-125b, associated with a higher expression of the NFκB inhibitor TNFAIP3 (A20). These results suggest that different milk EV subsets may improve colitis outcomes through different, and possibly complementary, mechanisms. Further unveiling of these mechanisms might offer new opportunities for improving the life of patients with colitis and be of importance for milk processing, infant milk formulation and general public health.

Oral Administration of Bovine Milk‐Derived Extracellular Vesicles Alters the Gut Microbiota and Enhances Intestinal Immunity in Mice

“…It had been reported that mEVs were bioavailable, biologically active compounds that played a key role in the regulation of intestinal immune homeostasis, intestinal barrier protection, and DSS‐induced colitis. [ 41,52,53 ] In our study, the results indicated that the expression level of Muc2, RegIIIγ, Myd88, and GATA4 genes in the intestinal epithelium of mice by oral administration mEVs was increased significantly. MUC2 could be up‐regulated by butyrate and provide a protective barrier between the epithelial surfaces and the gut lumen.…”

“…It was reported in the recent study that the abundance of Lachnospiraceae and Ruminococaccae were significantly increased in mice rich in milk EVs diet. [ 40,41 ] It could be due to changes in the gut microbial community caused by fraction of milk EVs that escape absorption. [ 42 ] Lachnospiraceae and Ruminococcaceae were two of the most abundant families from the Order Clostridiales and had been associated with the maintenance of gut health.…”

“…showed that supraphysiological P100K milk EVs (≈430 mg kg −1 body weight) had no significative effect on the protection of DSS‐induced colitis compared with the P35K EVs. [ 41 ] However, the exact mechanism of mEVs affecting intestinal immunity remained to be determined in future study.…”

Milk-Derived Extracellular Vesicles in Inter-Organism, Cross-Species Communication and Drug Delivery

“…Furthermore, the study also reported the uptake of bovine milk EVs by murine macrophages [ 81 ]. Whilst the protein cargo in milk EVs from humans, cows and pigs are known to be contributed majorly by mammary epithelial cells, numerous other proteins expressed and/or associated with immune cells have been discovered too [ 66 , 108 , 147 ].…”

Circulating microRNAs in Breast Milk and Their Potential Impact on the Infant

“…Another study [ 69 ] assessed the effect of exosomes from commercial cow’s milk in dextran sulfate sodium–induced colitis in a murine model. They noticed an improvement in several features of the dextran sulfate sodium–induced colitis, a modulation of the gut microbiota as well as a restored intestinal permeability and replenished mucin secretion.…”