Milk‐Derived Small Extracellular Vesicles Promote Recovery of Intestinal Damage by Accelerating Intestinal Stem Cell‐Mediated Epithelial Regeneration

Abstract

Scope: Milk-derived small extracellular vesicles (M-sEVs) are critical bioactive components in milk. They are considered to be regulators in milk that may have promising applications. Understanding their biological effects would be important in nutrition. Intestinal organoids and mice are used to explore the effects of M-sEVs on intestinal regeneration. Methods and results: M-sEVs could be absorbed by intestinal epithelia and upregulate expression of the microRNAs (miRNAs) expressed in milk: miR-148a, miR-22, miR-30, and miR-29a. Interestingly, M-sEVs promote proliferation of intestinal epithelia and repairs the epithelial damage that is caused by tumor necrosis factor-𝜶 in intestinal organoids. M-sEVs ameliorate intestinal mucosa damage in mice caused by treatment with dextran sulfate sodium, as well as increasing expression of the intestinal stem cells (ISC) markers leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5), olfactomedin 4 (Olfm4), and Achaete-Scute Family BHLH Transcription Factor 2 (Ascl2) and stimulating intestinal epithelial proliferation to repair epithelial damage. Furthermore, miR-29 is more abundant in M-sEVs-treated mice, and miR-29 could upregulate expression of ISC marker genes and accelerates intestinal regeneration to recover damaged intestinal epithelia. Conclusions: We reveal that M-sEVs and miR-29 can accelerate intestinal stem cell-mediated epithelial regeneration and repair epithelial damage.

Advances in the protection of intestinal mucosal barrier function by milk-derived miRNAs

“…116 In contrast, Lin et al (2022), based on demonstrating that human milk exosomes promote intestinal stem cell proliferation, found that this efficacy was associated with its carrying miR-29a-targeted regulation of g protein-coupled receptor 5, Olfm4 and achaet-sccute family BHLH transcription factor 2 expression. 117 Similarly, Guo et al (2022), while exploring the mechanism by which human milk exosomes alleviate NEC symptoms in mice, found that miR-148a-3p could target the expression of the P53 signaling pathway to enhance the proliferation of IEC-6 cells. 118 Gao et al (2021) also found that yak milk exosomes increased the survival of mouse intestinal crypt epithelial cells under hypoxia and confirmed that this was associated with the targeting of the carried miR-34a to inhibit hypoxia-inducible factor HIF-α expression, which in turn promoted intestinal epithelial cell proliferation and differentiation.…”

Dietary Epigenetic Modulators: Unravelling the Still-Controversial Benefits of miRNAs in Nutrition and Disease

“…Another miRNA characterized from milk exosomal vesicles is miR-29, capable of targeting IL-23, a cytokine involved in intestinal damage. To this aim, treatment with milk vesicles containing miR-29 stimulated intestinal stem cell proliferation and gut recovery under several pathological conditions [ 40 ], while incubation with miR-31-5p from milk-derived exosomes improved in vitro endothelial function and promoted angiogenesis and diabetic wound healing in vivo [ 41 ]. Recent studies reported that oral administration of exosomal vesicles prevented colon shortening, intestinal epithelium disruption, infiltration of inflammatory cells, and tissue fibrosis in a mouse ulcerative colitis model via inhibition of the TLR4-NF-κB signaling pathway and nucleotide-binding oligomerization domain, the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation [ 30 ].…”

Extracellular Vesicles from Animal Milk: Great Potentialities and Critical Issues

“…Moreover, decreased levels of miRNA-200a-3p, which is highly abundant in mEVs [ 112 ], were associated with bovine milk EV depletion in the mouse diet and exacerbated the inflammatory bowel disease (IBD) symptoms through chemokine (C-X-C motif) ligand 9 (CXCL9) production [ 171 ]. In particular, a recent study on intestinal organoids and DSS mice showed the upregulation of three mEV miRNAs in the intestinal epithelia after vesicle absorption and the increased expression of intestinal stem cell markers, which led to cell proliferation and mucosal damage repair [ 172 ].…”