Table 1 Milk-derived extracellular vesicles alleviate intestinal related diseases

Cow milk

DSS-induced UC Mice

Alleviates colitis by regulating the intestinal immune homeostasis via inhibiting NLRP3 and TLR4-NF-κB signaling pathways, restoring the α-diversity of the gut microbiota effectively and Treg/Th17 cell balance.

IL-1β, TNF-α, IL-6, IL-2, and IL-22↓; IL-17 A, L-23R, MPO↓; TLR4, Myd88, iNOS, COX2, p-IκBα, p65↓; ASC, NLRP3, and pro-caspase-1↓; IL-10↑; Akkermansia↑

[136]

Cow milk

DSS-induced UC Mice

Modulates the inflammatory response through the interplay between the NFκB and A20, and restore a normal gut microbiota profile.

TNFAIP3, Zo-1↑; NFκB, COX2, and miR-125b↓; pro-inflammatory cytokines↓; anti-inflammatory cytokines↑

[137]

Cow and human milk

DSS-induced UC Mice

Attenuates the severity of colitis and reduce colon shortening, reduce the expression of pro-inflammatory cytokine.

TNF-α, IL-6, DNMT1/3↓; TGF-β, miR-320/375, and Let-7↑

[138]

Cow milk

DSS-induced UC Mice

Alleviates the severity of acute colitis, reduce the expression of pro-inflammatory cytokines, chemokine ligands and chemokine receptors.

CXCL2/3/5, CCL3/4/11↓; PTGS2, IL-1a, IL-1β, IL-33, IL-6 and IL-17 A↓

[139]

Cow milk

DSS-induced UC Mice

Attenuates colitis through optimizing gut microbiota abundance and by regulating the expression of the intestinal genes.

IL-6 and TNF-α↓; Dubosiella, Bifidobacterium, UCG-007, Lachnoclostridium, Lachnospiraceae↑; butyrate and acetate↑

[140]

Cow milk

DSS-induced UC Mice

Regulates the concentrations of lipids and amino acids in both fecal samples and colonic tissues, recover the metabolic abnormalities caused by inflammation.

Acetate, butyrate, L-arginine↑;

C13:0, C15:1, C20:1, C20:2, C20:5, C22:6↓; L-valine, L-serine and L-glutamate↓

[141]

Goat milk

LPS-induced IPEC-J2 cells

Increases the antimicrobial peptides, defensins and toll like receptors, induce the preferential expression of the anti-inflammatory, improve intestinal homeostasis.

IL18, IL12p40, MMP9, NOS2↓; MUC2, EBI3, IL-6, IL-8↑

[142]

Human breast milk

LPS-induced NEC mice (intestinal epithelial cells, IEC-6 cells)

Protects against NEC and attenuate TLR4 signaling via EGF/EGFR activation, inhibit enterocyte apoptosis and restore enterocyte proliferation

TLR4, NF-κB, IL-6, IL-1β, GSK3β, iNOS↓; EGFR, PCNA↑

[150]

Human breast milk

hypoxia and gavage-induced NEC rat and human normal intestinal epithelial cell line (FHC)

Protects against NEC by promoting intestinal cell proliferation and migration

Ileum injury area↓; villous integrity, proliferation and migration↑

[152]

Human breast milk

H₂O₂-induced NEC (intestinal stem cells, ISCs)

Increases ISC viability, protect ISCs from oxidative stress injury via the Wnt/β-catenin signaling pathway

Axin2, c-Myc, and Cyclin D1↑

[153]

Human breast milk

LPS-induced NEC rat (intestinal epithelial cells, IEC-6 cells)

Decreases the incidence and severity of experimental NEC, increase IEC proliferation and decrease apoptosis, protect IEC from injury in vitro

Cell proliferation rate↑;

Late apoptotic cells↓; intestinal damage↓; NEC incidence↓

[154]

Human breast milk

H₂O₂-induced NEC (intestinal epithelial cells, IECs)

Increases IEC viability, protects IECs from oxidative stress and cell toxicity induced by H₂O₂

cell viability↑

[155]

Human breast milk

hypoxia and gavage-induced NEC rat

reduce ischemic necrosis and epithelial damage, increase the number of BrdU-positive cells in the intestinal mucosa, decrease the severities of NEC

intestine length, number of BrdU-positive cells↑; NEC score↓

[95]

Human breast milk

LPS-induced NEC mice and human normal intestinal epithelial cell line (FHC)

Enhances epithelial cell proliferation and migration, and ameliorate the severity of LPS-induced NEC via ERK/MAPK pathway

gut damage and necrosis↓; NEC score↓; proliferation and migration↑; p-ERK↓

[156]

Human breast milk

Hypoxia, LPS-induced NEC mouse and intestinal epithelial cells (IEC)

Attenuates NEC damage by reducing the intestinal epithelial injury and inflammation, restoring the intestinal mucous production, and increasing goblet cells

IL-6↓; injury condition↓; injury score↓; MPO activity, MUC2↓; goblet cells↑

[103]

Human breast milk

LPS-induced NEC mice (Caco-2 and NCM460 cell lines)

Prevents NEC by reducing inflammation and injury in the intestinal epithelium as well as restores the intestinal tight-junction proteins

ZO-1, Claudin 1, and OCLN↑

[157]

Human breast milk

LPS-induced NEC mice (intestinal epithelial IEC6 cells)

Exerts significant protective effect on NEC mice, including inhibiting inflammation and cell apoptosis, and improving intercellular tight junctions

miR-148a-3p, SIRT1↑;

p53, NF-κB↓

[94]

Human breast milk

asphyxia and cold stress-induced NEC mice and LPS-induced intestinal epithelial IEC-6 and IEC-18 Cell Lines

Attenuates the severity of experimental NEC and intestinal damage through reducing NEC score and ileal inflammation, restoring the number of damaged ileal crypts

Lgr5, MBP↑; IL-6, Iba1↓; NEC score↓; ileum crypts number↑; cell migration rate↑

[96]

Human breast milk

LPS-induced NEC C57BL/6 mice

Attenuates NEC-induced epithelial injury by reducing inflammation through inhibiting TNFα and TLR4 expression, and stimulating intestinal regeneration

TNF-α, TLR4, Ki67 and Lgr5↓;

[158]

Porcine milk

DON-induced NEC mice and porcine jejunum intestinal enterocytes IPEC-J2 cells

Protects the intestine against DON-induced damage by promoting cell proliferation and TJs and by inhibiting cell apoptosis

β-catenin, cyclin D1, p-Akt↑; ZO-1, OCLN, and CLDN1↑; p53, p21, Caspase 3, Caspase 9, Fas, and SERPINE1↓; miR-181a, miR-365-5p, miR-30c, and miR-769-3p↑

[112]

Porcine milk

LPS-induced NEC mice

Protects against the LPS-induced intestine epithelial cell injury by inhibiting cell apoptosis and inflammation through the p53 and TLR4/NF-κB pathway via the action of exosome miRNAs

IL-1β, IL-6, and TNF-α↓;

p53, FAS, and Caspase-3↓; TLR4, Myd88, p-IκBα and p-NF-κB↓; miR-4334, miR-219, and miR-338↑

[113]

Bovine milk

LPS, hypoxia, and hyperosmolar formula feeding induced NEC mouse and human colonic LS174T cells

Prevents NEC-induced mouse intestinal injury by increasing goblet cell production and ER function

MUC2, TFF3, and GRP94↑; mucin production and goblets cell↑; MPO↓

[159]

Rat milk

Intestinal epithelial cells (IEC-18)

Prevents NEC by promoting IEC viability and proliferation, and stimulating intestinal stem cell activity

PCNA, Lgr5, and cell viability↑

[119]

Bovine milk

Human colon cancer (HCT116) cell lines

Inhibits colon cancer cell growth and survival, and anti-inflammatory activity, providing an effective alternative for oral delivery

cell growth and survival↓

[170]

Human breast milk

Colon epithelial cell line (CRL 1831)

Reduces risk of colon cancer by elevating the expression of miR-148a and decreasing DNA methyltransferase1

miRNA-148a↑; DNMT1↓

[171]

Human breast milk

Colonic epithelial cells (CCD 841) and colonic tumor cells (LS123)

Alter the miRNA expression profile of the colon epithelial cells and promote the proliferation of healthy colon epithelial cells without affecting the growth of the colon cancer cells

miR-148a↑; collagen-type I, PTEN, and DNMT↓

[173]

Bovine milk

Colorectal cancer cells (LIM1215, SW620)

Attenuates tumor burden through decreasing the number of colonies and increasing cell death in the colorectal cancer cells

Number of colonies↓; percentage of cell death↑; tumor volume↓

[117]

Goat milk

Mouse colon cancer cell line (MC38)

Enhances the antitumor effect of the photothermal therapy and reduce the inflammatory response after treatment

Ki67, TNF-α, IL-6, and IL-1β↓; tumor weights↓; CD3⁺CD4⁺ and CD3⁺CD8⁺↑;

[174]

Buffalo milk

Colorectal cancer cells HCT116, and HT-29

High expression of miR-27b induce higher cytotoxic effects, CRC cell apoptosis, ROS and lysosome accumulation via PERK/IRE1/XBP1 and CHOP protein modulation

ROS, PERK, IRE1, XBP1, ATF6, CHOP, Bax/Bcl-2, p-ERK/ERK, procaspase-12, p-p38/p38, and p-JNK/JNK↑; apoptosis, lysosome, ER-tracker↑

[175]

Human breast milk

Intestinal IR injury rats

Protects the intestine against damage from IR injury by decreasing the intestinal inflammation and enhancing epithelial proliferation

TNFα↓; Ki67↑; Intestinal IR injury score↓

[190]