Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development
Abstract
:1. Introduction
2. Exosomal miRNAs and Intestinal Maturation
2.1. Intestinal Epithelial Cells
2.2. Intestinal Stem Cells
2.3. Intestinal Epithelial Barrier Function
2.3.1. Tight Junctions
2.3.2. Goblet Cells and Mucus Layer
2.3.3. Gut Microbiome
2.4. Lamina Propria Regulatory T Cells
2.4.1. Epigenetic Regulation of FOXP3 Expression
2.4.2. Transforming Growth Factor β and FOXP3 Expression
2.5. Anti-Inflammatory Action of Milk Exosomes
2.6. Adaptive Maternal Responses of Milk Exosomes in Preterm Infants
3. Necrotizing Enterocolitis
3.1. Pathogenesis
3.2. Milk Exosomes in Experimental Necrotizing Enterocolitis
3.3. Anti-Inflammatory Action of miRNA-148a, miRNA-22 and miRNA-30b
3.4. Hormonal Regulation of MiRNA-148a Expression
3.5. MEX-Mediated Up-Regulation of TNF-α-Induced Protein 3
3.6. Milk Exosome Lipidomics and NEC Prevention
3.7. Improvement of Malnutrition-Induced Intestinal Barrier Dysfunction
4. Systemic Bioavailability of Milk Exosomes for Epigenetic Regulation
4.1. Milk Exosomes, Thymic T-Cell Maturation and Atopy Prevention
4.2. Milk Exosomes and Hepatic Metabolism
4.3. Milk Exosomes and Neurodevelopment
4.4. Milk Exosomes and Potential Impact on Pancreatic β-Cell Proliferation
4.5. Milk Exosomes and Their Potential Impact on Beige/Brown Adipogenesis
4.6. Milk Exosomes and Their Potential Impact on White Adipogenesis
4.7. Milk Exosomes and Bone Homeostasis
5. Milk Processing and Exosome Bioavailability
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
List of Abbreviations (in Alphabetical Order)
AD | atopic dermatitis |
AMPK | adenosine monophosphate-activated protein kinase |
α-syn | α-synuclein |
BAT | brown adipose tissue |
BCAA | branched-chain amino acid |
BCKD | branched-chain α-ketoacid dehydrogenase |
BET | beige adipose tissue |
BLG | β-lactoglobulin |
BMI | body mass index |
BMMF | bovine meat and milk factor |
CAV3 | caveolin 3 |
CaMKIIα | calcium/calmodulin-dependent protein kinase IIα |
CARMA1 | CARD-containing MAGUK protein 1 |
CCK | cholecystokinin |
CCKR | cholecystokinin receptor |
CCR | chemokine, CC motif, receptor |
CDX2 | caudal-type homeobox transcription factor 2 |
CEBP | CCAAT/enhancer-binding protein |
CIDEA | death-inducing DFFA-like effector A |
circRNA | circular RNA |
CLDN1 | claudin 1 |
CMA | cow milk alllergy |
CRC | colorectal cancer |
CYR61 | cystein-rich protein 61 |
DBT | dihydrolipoamide branched-chain transacylase |
DC | dendritic cell |
DMBT1 | deleted in malignant brain tumors 1 |
DNMT1 | DNA methyltransferase 1 |
DON | deoxynivalenol |
DSS | dextran sodium sulfate |
ERRα | estrogen-related receptor-α |
ER | endoplasmic reticulum |
EV | extracellular vesicle |
FcRn | neonatal crystallizable fragment receptor |
FOXP3 | forkhead box transcription factor P3 |
GATA4 | GATA-binding protein 4 |
GI | gastrointestinal tract |
GP130 | interleukin 6 signal transducer |
GRP94 | glucose-regulated protein 94 |
GSIS | glucose-stimulated insulin secretion |
GSK3 | glycogen synthase kinase 3 |
HM | human milk |
HDAC4 | histone deacetylase 4 |
hMSC | human mesenchymal stem cell |
HoP | Holder pasteurization |
HSP | heat shock protein |
IBD | inflammatory bowel disease |
IEC | intestinal epithelial cell |
IFN | interferon |
IgA | immunoglobulin A |
IgG | immunoglobulin G |
IGF-1 | insulin-like growth factor 1 |
IGF1R | IGF-1 receptor |
IκB | inhibitor of κB |
IKK | IκB kinase |
IL-1 | interleukin 1 |
IL-2 | interleukin 2 |
IL-6 | interleukin 6 |
IL-8 | interleukin 8 |
IL-10 | interleukin 10 |
IL-17 | interleukin 17 |
ISC | intestinal stem cell |
iTreg | inducible regulatory T cell |
LDLR | low density-lipoprotein receptor |
LGR5 | leucine-rich-repeat-containing G-protein-coupled receptor 5 |
lncRNA | long non-coding RNA |
LRP6 | low-density lipoprotein receptor-related protein 6 |
MesD | mesoderm development |
MEV | milk extracellular vesicle |
MEX | milk exosome |
MFG | milk fat globule |
MFG-E8 | MFG epidermal growth factor 8 |
MGEC | mammary gland epithelial cell |
MHC | major histocompatibility complex |
miRNA | micro-ribonucleic acid |
MPO | myeloperoxidase |
mTORC1 | mechanistic target of rapamycin complex 1 |
MUC1 MUC2 | mucin 1 mucin 2 |
MyD88 | MyD88 innate immune signal transduction adaptor |
NCOA1 | nuclear receptor co-activator 1 |
NEC | necrotizing enterocolitis |
NF-κB | RELA protooncogene, NFKB subunit |
NK | natural killer |
OCLN | occludin |
OTU | operational taxonomic unit |
PBMC | peripheral blood mononuclear cell |
PCNA | proliferating cell nuclear antigen |
PGC-1α | peroxisome proliferator-activated receptor-γ co-activator 1α |
PGC-1β | peroxisome proliferator-activated receptor-γ co-activator 1β |
PI3K | phosphatidylinositol 3-kinase |
PPAR | peroxisome proliferator-activated receptor |
PPARGC1A | peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) |
PRKAA1 | catalytic subunit α1 of AMPK |
PRKAG2 | regulatory subunit γ2 of AMPK |
PTEN | phosphatase and tensin homolog |
PURB | purine-rich element binding protein B |
RIP140 | receptor interacting protein 140 |
RegIIIγ | regenerating islet-derived 3γ |
ROR | RAR-related orphan receptor |
SIRT1 | sirtuin 1 |
SNARE | soluble N-ethylmaleimide-sensitive factor attachment protein receptor |
SOCS1 | signal transducer and activator of transcription 1 |
SNCA | α-synuclein |
STAT | signal transducer and activator of transcription |
TCR | T cell receptor |
TGFβ | transforming growth factor-β |
TJ | tight junction |
TLR | toll-like receptor |
TNFα | tumor necrosis factor-α |
TNFAIP3 | TNFα-induced protein 3 |
TFF3 | trefoil factor 3 |
T2DM | type 2 diabetes mellitus |
Treg | FOXP3+ regulatory T cell |
TSDR | Treg-specific demethylated region |
TSG101 | tumor susceptibility gene 101 |
UCP1 | uncoupling protein 1 |
UCP2 | uncoupling protein 2 |
UCP3 | uncoupling protein 3 |
UHT | ultraheat-treated |
3′UTR | 3′-untranslated region |
VEGF | vascular endothelial growth factor |
WAT | white adipose tissue |
WNT | wingless |
ZO-1 | zonula occludens 1 |
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Model | MEX Source | Insulting Agents | Biological Effects | References |
---|---|---|---|---|
IEC-6 cells | Human | H2O2 | Increased cell viability; protection from oxidative stress | [231] |
IEC-6 | Yak, Cow | Hypoxia | Yak-MEX increased survival of IEC-6 cells compared with bovine-MEX; yak-MEX promote oxygen-sensitive prolyl hydroxylase (PHD)-1 expression and decrease HIF-α, VEGF and p53 | [72] |
IEC | Porcine | LPS | Decreased LPS-induced TLR4/NF-κB signaling pathway activation; reduced LPS-induced apoptosis via the p53 pathway | [162] |
IEC murine intestine | Porcine | Deoxynivalenol | Up-regulation of miRNA-181a, miRNA-30c, miRNA-365-5p and miRNA-769-3p in IPEC-J2 cells; suppression of p53 pathway; increased proliferation and TJs; inhibition of apoptosis | [85] |
Premature Sprague–Dawley rat pups; IEC-6 cells | Human | Asphyxia, hypothermia, hypercaloric feed, hypoxia | Decrease in histological NEC grade; increased IEC cell proliferation; decreased apoptosis of IEC | [232] |
Prominin-1+ ISCs of small intestines of neonatal rat | Human | H2O2 | Increase in ISC viability; increased expression of LRG5, axin2, c-myc, cyclin D1, HES1, DII1, DII4 | [77] |
LS174T human colonic cells; C57BL/6 mice | Bovine | Hypoxia, hyperosmolar formula, LPS | Increased goblet cell numbers and mucin production; Increased expression trefoil factor 3 (TFF3) and mucin 2 (MUC2). Enhanced the expression of glucose-regulated protein 94 (GRP94) | [47] |
C57BL/6J mice | Bovine | Dextran sulfate sodium | Decreased inflammation through the down-regulation of colitis-associated miRNAs, especially miRNA-125b, associated with a higher expression of the NF-κB inhibitor TNFAIP3 | [84] |
Newborn Sprague–Dawley rat pups; human intestinal epithelial FHC | Human, term/preterm | Hypoxia formula | Preterm MEX significantly enhanced proliferation and migration of IECs compared with term MEX | [233] |
Intestinal organoids; C57BL/6 mice pups | Human | LPS | Decreased expression of TNF-α and TLR4 | [163] |
Balb/c mice | Human | Dextran sulfate sodium | MEX attenuated the severity of colitis induced by DSS and statistically reduced the histopathological scoring grade and shortening of the colon; reduced expression of IL-6, TNF-α, DNMT1 and DNMT3; up-regulation of TGF-β | [148] |
Mdr1a−/− mice (5 weeks old) | Bovine | 60% MEX-deficient diet | Higher degree of intestinal lesions; deficiency of miRNA-200a-3p targeting Cxcl9 mRNA | [234] |
Intestine of kindlin 2 knockout mice | Bovine | Kindlin 2 knockout | Decrease in macroscopic colitis score in MEX-treated mice compared with untreated mice | [235] |
Intestinal organoids of C57BL/6 mouse pups | Human | Hypoxia formula, LPS | Decreased IL-6 mRNA expression; decreased injury score and MPO activity; increase in goblet cell number and MUC2 mRNA expression | [92] |
miRNA-148a 3p Target Genes | Potential Functional Outcomes During Breastfeeding |
---|---|
PRKAA1 | Inhibition of AMPK; suppression of pancreatic β-cell activation; increased IEC-and β-cell mTORC1 activity with IEC and β-cell proliferation |
PRKAG2 | Inhibition of AMPK; suppression of β-cell activation; increased IEC and β-cell mTORC1 activity with IEC- and βcell proliferation |
PPARGC1B | Inhibition of PCG-1β; Reduced mitochondrial function |
UCP3 | Reduced fatty acid β-oxidation and energy expenditure |
CCK2R | Reduced satiety signals increasing milk/food intake |
MAFB | Increased osteoclastogenesis |
LDLR | Reduced hepatic LDL cholesterol uptake |
ABCA1 | Reduced HDL-mediated reverse cholesterol transport |
COL1A1 | Reduced collagen I synthesis |
IL6ST (GP130) | Reduced expression of GP130 resulting in attenuated IL-6 signaling, increased cortical bone maturation |
IKBKA | Inhibition of IκB kinase α and NF-κB signaling, suppression of inflammation |
IKBKB | Inhibition of IκB kinase β and NF-κB signaling, suppression of inflammation |
CAMK2A | Inhibition of calcium/calmodulin-dependent protein kinase IIα and downstream TLR4 signaling |
DNMT1 | Inhibition of DNA methyltransferase 1 increasing epigenetic expression of developmental genes (INS, IGF1; SNCA, FOXP3) and suppression of RIP140 expression and RIP140-dependent nuclear receptors and transcription factors such as PGC-1α |
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Melnik, B.C.; Stremmel, W.; Weiskirchen, R.; John, S.M.; Schmitz, G. Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development. Biomolecules 2021, 11, 851. https://doi.org/10.3390/biom11060851
Melnik BC, Stremmel W, Weiskirchen R, John SM, Schmitz G. Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development. Biomolecules. 2021; 11(6):851. https://doi.org/10.3390/biom11060851
Chicago/Turabian StyleMelnik, Bodo C., Wolfgang Stremmel, Ralf Weiskirchen, Swen Malte John, and Gerd Schmitz. 2021. "Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development" Biomolecules 11, no. 6: 851. https://doi.org/10.3390/biom11060851