Time of Lactation and Maternal Fucosyltransferase Genetic Polymorphisms Determine the Variability in Human Milk Oligosaccharides.

Mandy Vogel,Sean Austin,Gregory Lefebvre,Toralf Kirsten,Maya Shevlyakova,Norbert Sprenger,Aline Charpagne,Aristea Binia,Wieland Kiess,Julien Marquis

doi:10.3389/fnut.2020.574459

Abstract

Rationale: Human milk oligosaccharides (HMOs) vary among mothers and genetic factors contribute to this variability. We assessed changes in HMO concentrations during the first year of lactation and the relationship with FUT2 Secretor group and FUT3 Lewis group defining genetic polymorphisms.Methods: Milk samples were collected from lactating mothers participating in the LIFE Child cohort in Leipzig, Germany. The concentrations of 24 HMOs in milk samples collected at 3 months (N = 156), 6 months (N = 122), and 12 months (N = 28) were measured using liquid chromatography. Concentrations of HMOs were compared at all time-points and were tested for their associations with FUT2 and FUT3 genetic variations by sPLS regression.Results: FUT2 SNP rs601338 was found to predominantly define the Secretor status Se-: 11.8% and it was highly correlated with 2′-fucosyllactose (2′FL, p < 0.001) and lacto-N-fucosylpentaose-I (LNFP-I, p < 0.001). FUT3 SNPs rs28362459 and rs812936 were found to define Lewis status (Le-: 5.9%) and correlated with lacto-N-fucosylpentaose-II (LNFP-II, p < 0.001). A polygenic score predicted the abundance of 2′FL levels within Secretors' milk (adj. R2 = 0.58, p < 0.001). Mean concentrations of most of the individual HMOs, as well as the sums of the measured HMOs, the fucosylated HMOs, and the neutral HMOs were lower at 6 and 12 months compared to 3 months (p < 0.001).Conclusions: Secretor and Lewis status defined by specific FUT2 and FUT3 SNPs are confirmed to be good proxies for specific individual HMOs and milk group variabilities. The polygenic score developed here is an opportunity for clinicians to predict 2′FL levels in milk of future mothers. These results show opportunities to strengthen our understanding of factors controlling FUT2 and FUT3 functionality, the temporal changes and variability of HMO composition during lactation and eventually their significance for infant development.

Highlights

Human milk oligosaccharides (HMOs) are unconjugated glycans found in human milk and they are composed of the monosaccharides glucose, galactose, fucose, Nacetylglucosamine and N-acetylneuraminic acid, the main form of sialic acid in humans
HMO concentrations have been measured in breast milk during the first year of lactation at 3, 6 and 12 months of infant age
This remained true for most individual HMOs regardless of the milk group of the mother (Supplementary Table 2)

Summary

Introduction

Human milk oligosaccharides (HMOs) are unconjugated glycans found in human milk and they are composed of the monosaccharides glucose, galactose, fucose, Nacetylglucosamine and N-acetylneuraminic acid, the main form of sialic acid in humans. They represent the third most abundant solid component of the human milk (5 to 20 g/L) after lactose and lipids [1,2,3,4]. The concentration of HMOs decreases during lactation, only few studies have gone beyond the first 6 months of lactation [9,10,11]. Some HMOs have a specific concentration trajectory over time [1] with most decreasing and few increasing in concentration suggesting the presence of regulatory mechanisms that control their temporal variation

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