Evidence of Human Milk Oligosaccharides in Cord Blood and Maternal-to-Fetal Transport across the Placenta
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Overview
2.2. Serum Samples
2.3. Human Milk Oligosaccharide Standards
2.4. HMO Isolation and Analysis by HPLC
2.5. Analysis of Human Milk Oligosaccharides by Enzymatic Digest
2.6. Determination of Oligosaccharides by LC-MS/MS
2.7. Ex-Vivo Perfusion of a Single Human Placental Cotyledon
2.8. Statistical Analysis
3. Results
3.1. HMO Profiles in Cord Blood Serum Resemble Peripartal HMO Profiles in Maternal Serum
3.2. HMO Concentration and Composition in Mother–Infant Dyads
3.3. HMOs in Venous Cord Blood Associate with Maternal HMOs
3.4. Maternal to Fetal 2′FL Transport across the Placenta
4. Discussion
4.1. HMO Concentration and Composition in the Maternal and Fetal Circuits
4.2. Biological Roles of Fetal HMOs
4.3. HMO Transport across the Placenta
4.4. Modifiers of Fetal HMOs: Maternal and Fetal Factors
4.5. Gestational Age
4.6. Infant Factors
4.7. Secretor Status
5. Conclusions and Significance
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
HMO | Human Milk Oligosaccharide |
2′FL | 2′-fucosyllactose |
3FL | 3-fucosyllactose |
LNT | lacto-N-tetraose |
LNnT | lacto-N-neo-tetraose |
LNFP | lacto-N-fucopentaose |
LNDFH | lacto-N-difucohexaose |
LNH | lacto-N-hexaose |
LDFT | lactodifucotetraose |
3′SL | 3′-sialyllactose |
6′SL | 6′-sialyllactose |
3′SLN | 3′-siallyllactosamine |
6′SLN | 6′-siallyllactosamine |
LST | sialyllacto-N-tetraose |
DSLNT | disialyllacto-N-tetraose |
SAT | subcutaneous adipose tissue |
FUT2 | fucosyltransferase-2 |
FUT3 | fucosyltransferase-3 |
References
- Bode, L. Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology 2012, 22, 1147–1162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Donovan, S.M.; Comstock, S.S. Human Milk Oligosaccharides Influence Neonatal Mucosal and Systemic Immunity. Ann. Nutr. Metab. 2016, 69 (Suppl. 2), 42–51. [Google Scholar] [CrossRef]
- Eiwegger, T.; Stahl, B.; Haidl, P.; Schmitt, J.; Boehm, G.; Dehlink, E.; Urbanek, R.; Szepfalusi, Z. Prebiotic oligosaccharides: In vitro evidence for gastrointestinal epithelial transfer and immunomodulatory properties. Pediatr Allergy Immunol. 2010, 21, 1179–1188. [Google Scholar] [CrossRef] [PubMed]
- Eiwegger, T.; Stahl, B.; Schmitt, J.; Boehm, G.; Gerstmayr, M.; Pichler, J.; Dehlink, E.; Loibichler, C.; Urbanek, R.; Szepfalusi, Z. Human milk—Derived oligosaccharides and plant-derived oligosaccharides stimulate cytokine production of cord blood T-cells in vitro. Pediatr. Res. 2004, 56, 536–540. [Google Scholar] [CrossRef] [PubMed]
- He, Y.; Liu, S.; Kling, D.E.; Leone, S.; Lawlor, N.T.; Huang, Y.; Feinberg, S.B.; Hill, D.R.; Newburg, D.S. The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 2016, 65, 33–46. [Google Scholar] [CrossRef] [PubMed]
- Kulinich, A.; Liu, L. Human milk oligosaccharides: The role in the fine-tuning of innate immune responses. Carbohydr. Res. 2016, 432, 62–70. [Google Scholar] [CrossRef] [PubMed]
- Kurakevich, E.; Hennet, T.; Hausmann, M.; Rogler, G.; Borsig, L. Milk oligosaccharide sialyl(alpha2,3)lactose activates intestinal CD11c+ cells through TLR4. Proc. Natl. Acad. Sci. USA 2013, 110, 17444–17449. [Google Scholar] [CrossRef]
- Jantscher-Krenn, E.; Zherebtsov, M.; Nissan, C.; Goth, K.; Guner, Y.S.; Naidu, N.; Choudhury, B.; Grishin, A.V.; Ford, H.R.; Bode, L. The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut 2012, 61, 1417–1425. [Google Scholar] [CrossRef]
- Lin, A.E.; Autran, C.A.; Espanola, S.D.; Bode, L.; Nizet, V. Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J. Infect. Dis. 2014, 209, 389–398. [Google Scholar] [CrossRef]
- Lin, A.E.; Autran, C.A.; Szyszka, A.; Escajadillo, T.; Huang, M.; Godula, K.; Prudden, A.R.; Boons, G.J.; Lewis, A.L.; Doran, K.S.; et al. Human milk oligosaccharides inhibit growth of group B Streptococcus. J. Biol. Chem. 2017, 292, 11243–11249. [Google Scholar] [CrossRef] [Green Version]
- Goehring, K.C.; Kennedy, A.D.; Prieto, P.A.; Buck, R.H. Direct evidence for the presence of human milk oligosaccharides in the circulation of breastfed infants. PLoS ONE 2014, 9, e101692. [Google Scholar] [CrossRef] [PubMed]
- Ruhaak, L.R.; Stroble, C.; Underwood, M.A.; Lebrilla, C.B. Detection of milk oligosaccharides in plasma of infants. Anal. Bioanal. Chem. 2014, 406, 5775–5784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dotz, V.; Rudloff, S.; Blank, D.; Lochnit, G.; Geyer, R.; Kunz, C. 13C-labeled oligosaccharides in breastfed infants’ urine: Individual-, structure- and time-dependent differences in the excretion. Glycobiology 2014, 24, 185–194. [Google Scholar] [CrossRef] [PubMed]
- Dotz, V.; Rudloff, S.; Meyer, C.; Lochnit, G.; Kunz, C. Metabolic fate of neutral human milk oligosaccharides in exclusively breast-fed infants. Mol. Nutr. Food Res. 2015, 59, 355–364. [Google Scholar] [CrossRef]
- Rudloff, S.; Pohlentz, G.; Borsch, C.; Lentze, M.J.; Kunz, C. Urinary excretion of in vivo 13C-labelled milk oligosaccharides in breastfed infants. Br. J. Nutr. 2012, 107, 957–963. [Google Scholar] [CrossRef]
- Rudloff, S.; Pohlentz, G.; Diekmann, L.; Egge, H.; Kunz, C. Urinary excretion of lactose and oligosaccharides in preterm infants fed human milk or infant formula. Acta Paediatr. 1996, 85, 598–603. [Google Scholar] [CrossRef]
- Bode, L.; Kunz, C.; Muhly-Reinholz, M.; Mayer, K.; Seeger, W.; Rudloff, S. Inhibition of monocyte, lymphocyte, and neutrophil adhesion to endothelial cells by human milk oligosaccharides. Thromb Haemost. 2004, 92, 1402–1410. [Google Scholar] [CrossRef]
- Bode, L.; Rudloff, S.; Kunz, C.; Strobel, S.; Klein, N. Human milk oligosaccharides reduce platelet-neutrophil complex formation leading to a decrease in neutrophil beta 2 integrin expression. J. Leukoc. Biol. 2004, 76, 820–826. [Google Scholar] [CrossRef]
- Bhargava, P.; Li, C.; Stanya, K.J.; Jacobi, D.; Dai, L.; Liu, S.; Gangl, M.R.; Harn, D.A.; Lee, C.H. Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways. Nat. Med. 2012, 18, 1665–1672. [Google Scholar] [CrossRef] [Green Version]
- Urashima, T.H.J.; Sato, S.; Kobata, A. Human Milk Oligosaccharides as Essential Tools for Basic and Application Studies on Galectins. Trends Glycoscie. Glycotechnol. 2018, 30, SE51–SE65. [Google Scholar] [CrossRef] [Green Version]
- Bode, L.; Jantscher-Krenn, E. Structure-function relationships of human milk oligosaccharides. Adv. Nutr. 2012, 3, 383S–391S. [Google Scholar] [CrossRef] [PubMed]
- Chaturvedi, P.; Warren, C.D.; Altaye, M.; Morrow, A.L.; Ruiz-Palacios, G.; Pickering, L.K.; Newburg, D.S. Fucosylated human milk oligosaccharides vary between individuals and over the course of lactation. Glycobiology 2001, 11, 365–372. [Google Scholar] [CrossRef] [PubMed]
- Coppa, G.V.; Pierani, P.; Zampini, L.; Carloni, I.; Carlucci, A.; Gabrielli, O. Oligosaccharides in human milk during different phases of lactation. Acta Paediatr. Suppl. 1999, 88, 89–94. [Google Scholar] [CrossRef] [PubMed]
- Sprenger, N.; Lee, L.Y.; De Castro, C.A.; Steenhout, P.; Thakkar, S.K. Longitudinal change of selected human milk oligosaccharides and association to infants’ growth, an observatory, single center, longitudinal cohort study. PLoS ONE 2017, 12, e0171814. [Google Scholar] [CrossRef] [PubMed]
- Xu, G.; Davis, J.C.; Goonatilleke, E.; Smilowitz, J.T.; German, J.B.; Lebrilla, C.B. Absolute Quantitation of Human Milk Oligosaccharides Reveals Phenotypic Variations during Lactation. J. Nutr. 2017, 147, 117–124. [Google Scholar] [CrossRef]
- Gabrielli, O.; Zampini, L.; Galeazzi, T.; Padella, L.; Santoro, L.; Peila, C.; Giuliani, F.; Bertino, E.; Fabris, C.; Coppa, G.V. Preterm milk oligosaccharides during the first month of lactation. Pediatrics 2011, 128, e1520–e1531. [Google Scholar] [CrossRef]
- Stahl, B.; Thurl, S.; Henker, J.; Siegel, M.; Finke, B.; Sawatzki, G. Detection of four human milk groups with respect to Lewis-blood-group-dependent oligosaccharides by serologic and chromatographic analysis. Adv. Exp. Med. Biol. 2001, 501, 299–306. [Google Scholar]
- Thurl, S.; Henker, J.; Siegel, M.; Tovar, K.; Sawatzki, G. Detection of four human milk groups with respect to Lewis blood group dependent oligosaccharides. Glycoconj. J. 1997, 14, 795–799. [Google Scholar] [CrossRef]
- Thurl, S.; Munzert, M.; Henker, J.; Boehm, G.; Muller-Werner, B.; Jelinek, J.; Stahl, B. Variation of human milk oligosaccharides in relation to milk groups and lactational periods. Br. J. Nutr. 2010, 104, 1261–1271. [Google Scholar] [CrossRef] [Green Version]
- Erney, R.M.; Malone, W.T.; Skelding, M.B.; Marcon, A.A.; Kleman-Leyer, K.M.; O’Ryan, M.L.; Ruiz-Palacios, G.; Hilty, M.D.; Pickering, L.K.; Prieto, P.A. Variability of human milk neutral oligosaccharides in a diverse population. J. Pediatr. Gastroenterol. Nutr. 2000, 30, 181–192. [Google Scholar] [CrossRef]
- McGuire, M.K.; Meehan, C.L.; McGuire, M.A.; Williams, J.E.; Foster, J.; Sellen, D.W.; Kamau-Mbuthia, E.W.; Kamundia, E.W.; Mbugua, S.; Moore, S.E.; et al. What’s normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically. Am. J. Clin. Nutr. 2017, 105, 1086–1100. [Google Scholar] [CrossRef] [PubMed]
- Jantscher-Krenn, E.; Aigner, J.; Reiter, B.; Kofeler, H.; Csapo, B.; Desoye, G.; Bode, L.; Van Poppel, M.N.M. Evidence of Human Milk Oligosaccharides in maternal circulation already during pregnancy—A pilot study. Am. J. Physiol. Endocrinol. Metab. 2018, 316, E347–E357. [Google Scholar] [CrossRef] [PubMed]
- Jantscher-Krenn, E.; Treichler, C.; Brandl, W.; Schönbacher, L.; Köfeler, H.; van Poppel, M. The association of Human Milk Oligosaccharides (HMO) with glucose metabolism in overweight and obese pregnant women. Am. J. Clin. Nutr. 2019, in press. [Google Scholar] [CrossRef] [PubMed]
- Perazzolo, S.; Hirschmugl, B.; Wadsack, C.; Desoye, G.; Lewis, R.M.; Sengers, B.G. The influence of placental metabolism on fatty acid transfer to the fetus. J. Lipid Res. 2017, 58, 443–454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pausan, M.-R.; Kolovetsiou-Kreiner, V.; Richter, G.L.; Madl, T.; Giselbrecht, E.; Weiss, E.-C.; Jantscher-Krenn, E.; Moissl-Eichinger, C. Human Milk Oligosaccharides modulate the risk for preterm birth in a microbiome dependent and independent manner. bioRxiv 2019. [Google Scholar] [CrossRef]
- Wise, A.; Robertson, B.; Choudhury, B.; Rautava, S.; Isolauri, E.; Salminen, S.; Bode, L. Infants Are Exposed to Human Milk Oligosaccharides Already in utero. Front. Pediatr. 2018, 6, 270. [Google Scholar] [CrossRef] [Green Version]
- Jost, T.; Lacroix, C.; Braegger, C.; Chassard, C. Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health. Nutr. Rev. 2015, 73, 426–437. [Google Scholar] [CrossRef]
- Zivkovic, A.M.; Lewis, Z.T.; German, J.B.; Mills, D.A. Establishment of a Milk-Oriented Microbiota (MOM) in Early Life: How Babies Meet Their MOMs. Funct. Food Rev. 2013, 5, 3–12. [Google Scholar]
- Coppa, G.V.; Zampini, L.; Galeazzi, T.; Facinelli, B.; Ferrante, L.; Capretti, R.; Orazio, G. Human milk oligosaccharides inhibit the adhesion to Caco-2 cells of diarrheal pathogens: Escherichia coli, Vibrio cholerae, and Salmonella fyris. Pediatr. Res. 2006, 59, 377–382. [Google Scholar] [CrossRef]
- Jantscher-Krenn, E.; Lauwaet, T.; Bliss, L.A.; Reed, S.L.; Gillin, F.D.; Bode, L. Human milk oligosaccharides reduce Entamoeba histolytica attachment and cytotoxicity in vitro. Br. J. Nutr. 2012, 108, 1839–1846. [Google Scholar] [CrossRef]
- Morrow, A.L.; Ruiz-Palacios, G.M.; Jiang, X.; Newburg, D.S. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. J. Nutr. 2005, 135, 1304–1307. [Google Scholar] [CrossRef] [PubMed]
- Jantscher-Krenn, E.; Bode, L. Human milk oligosaccharides and their potential benefits for the breast-fed neonate. Minerva Pediatr. 2012, 64, 83–99. [Google Scholar] [PubMed]
- Plaza-Diaz, J.; Fontana, L.; Gil, A. Human Milk Oligosaccharides and Immune System Development. Nutrients 2018, 10, 1038. [Google Scholar] [CrossRef] [PubMed]
- Isganaitis, E.; Venditti, S.; Matthews, T.J.; Lerin, C.; Demerath, E.W.; Fields, D.A. Maternal obesity and the human milk metabolome: Associations with infant body composition and postnatal weight gain. Am. J. Clin. Nutr. 2019. [Google Scholar] [CrossRef] [PubMed]
Maternal and Infant Characteristics | Total n = 22 | |
---|---|---|
Mean | ± SD | |
Maternal Age (years) | 34.6 | 4.5 |
BMI (kg/m2) pre-pregnancy | 21.9 | 2.8 |
BMI delivery (kg/m2) | 27.9 | 3.2 |
Weight gain (kg) | 16.3 | 5.8 |
Parity primiparous (n, %) | 14 (63.6) | |
Mode of delivery, vaginal (n, %) | 15 (68.2) | |
Gestational age at delivery (d) | 278 | 7.8 |
Infant sex (male n, %) | 11 (50) | |
Ponderal index | 2.45 | 0.22 |
Infant Birth weight (g) | 3324 | 297 |
Placental weight (g) | 496.3 | 149.0 |
Maternal Serum (n = 22) | Fetal Serum (n = 22) | p Value (Wilcoxon Test) | |
---|---|---|---|
HMO | Median (IQR) | Median (IQR) | |
2′FL | 124.7 (43.3–236.6) | 111.41 (40.0–286.4) | 0.485 |
3′SLN | 41.4 (30.9–59.6) | 69.4 (26.5–97.1) | 0.178 |
LDFT | 66.4 (30.4–95.7) | 39.8 (7.1–91.1) | 0.260 |
3′SL | 215.1 (163.8–279.2) | 244.9 (95.6–309.8) | 0.961 |
6′SLN | 39.2 (30.7–47.1) | 101.7 (27.4–196.1) | 0.001 |
6′SL | 33.2 (23.8–45.9) | 70.0 (21.9–97.4) | 0.006 |
LNT | n.q. | n.q. | |
LNnT | n.q. | n.q. | |
LNFP1 | 12.0 (0.0–24.6) | 15.6 (10.1–26.9) | 0.615 |
LNFP2/3 | 9.6 (3.8–17.0) | 7.3 (1.5–23.2) | 0.858 |
LSTc | 38.4 (24.8–57.2) | 42.8 (19.1–56.2) | 0.758 |
LNDFH | 5.9 (0.0–11.9) | 2.33 (0.0–12.6) | 0.723 |
DSLNT | 9.5 (1.8–16.4) | n.q. | |
fucosylated | 212.6 (94.5–375.3) | 181.4 (86.6–435.0) | 0.615 |
sialylated | 409.3 (283.1–532.3) | 657.7 (175.5–756.6) | 0.178 |
Total HMO | 611.0 (480.5–911.3) | 870.9 (360–1225.3) | 0.322 |
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Hirschmugl, B.; Brandl, W.; Csapo, B.; van Poppel, M.; Köfeler, H.; Desoye, G.; Wadsack, C.; Jantscher-Krenn, E. Evidence of Human Milk Oligosaccharides in Cord Blood and Maternal-to-Fetal Transport across the Placenta. Nutrients 2019, 11, 2640. https://doi.org/10.3390/nu11112640
Hirschmugl B, Brandl W, Csapo B, van Poppel M, Köfeler H, Desoye G, Wadsack C, Jantscher-Krenn E. Evidence of Human Milk Oligosaccharides in Cord Blood and Maternal-to-Fetal Transport across the Placenta. Nutrients. 2019; 11(11):2640. https://doi.org/10.3390/nu11112640
Chicago/Turabian StyleHirschmugl, Birgit, Waltraud Brandl, Bence Csapo, Mireille van Poppel, Harald Köfeler, Gernot Desoye, Christian Wadsack, and Evelyn Jantscher-Krenn. 2019. "Evidence of Human Milk Oligosaccharides in Cord Blood and Maternal-to-Fetal Transport across the Placenta" Nutrients 11, no. 11: 2640. https://doi.org/10.3390/nu11112640