Research notes impact of season and infant gender on HMO composition in breast milk

By Nikki Hancocks

- Last updated on GMT

getty | nataliaderiabina
getty | nataliaderiabina

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New research reveals differences in breast milk HMO levels in secretor and non secretor Israeli mothers to male and female babies, as well as revealing how composition changes with the seasons.

Breast milk (BM) is highly variable among mothers and it evolves as the infant grows older. One of the most important components in BM are the HMOs, a highly abundant group of indigestible oligosaccharides that stimulate the growth of gut commensals, prevent the adhesion of enteropathogens and modulate host immunity​.

BM contains 12~13 g/L of HMOs​, of which more than 250 varieties have been separated and more than 200 chemical structures have been characterised to date.

The concentrations of the representing HMOs have been determined in secretor and non-secretor donor’s milk​ at several lactation periods. HMO levels have additionally been determined in several regions of the world.

Since little is known about the HMO content and variation in HM in the Israeli region, the recent study, funded by he The Israeli Dairy Council, sought to conduct a longitudinal analysis to assess the HMO profile across lactation stages in lactating Israeli women.

This study is the first report on the variability of the HMO profile in lactating Israeli women from the Tel Aviv area and the researchers demonstrate that the HMO profile depends upon maternal (secretor status) and infant factors (infant sex) as well as environmental factors (season).

The researchers say future studies are warranted to confirm the findings in larger cohorts that include diverse Israeli communities.

What we know about HMO's

The average values of the concentrations of 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), lacto-N-tetraose (LNT), 3′-sialyllactose (3′-SL) and 6′-sialyllactose (6′-SL) have been calculated from the published data​.

The HMOs are synthesized in the mammary gland and are classified into three major types depending on the expression and activity of the enzymes sialyltransferases and fucosyltransferases (FUT), resulting in neutral fucosylated HMO (e.g., 2′-FL), neutral N-containing HMOs (e.g., LNT) and acidic (sialylated) HMOs (e.g., 6′-SL, disialyllacto-N-tetraose: DSLNT).

The mother’s genetic makeup determines the activity of the α1-2-fucosyltransferase (FUT2) encoded by the secretor (Se) gene and the α1-3/4-fucosyltransferase (FUT3) encoded by the Lewis (Le) genes, resulting in four milk phenotypes (secretors: Se+Le+, non-secretors: Se+Le−, Se−Le+, and Se−Le−).

The four major milk groups are determined by the presence or absence of fucosylated oligosaccharides (OS) in BM and are regulated by the activity of two fucosyltransferases (FUT) enzymes; the Se gene encodes FUT2 for the generation of α1,2-fucosylated OS, and the FUT3 enzyme is encoded by the Le gene, for the generation of α1, α1,3/4-fucosylated OS, and based on the Lewis blood group system.

Women with an active Se locus are classified as secretors (Se+), whereas women with an active Le locus are classified as Lewis-positive (Le+). Women lacking FUT2 or FUT3 activity are classified as non-secretors (Se−) or Lewis negative (Le−), missing α1,2-fucosylated or α1, 3/4-fucosylated OS, respectively.

Non-genetic factors such as gestational age (GA) at delivery, stage of lactation, gender of baby, seasons of lactation, sociodemographic and environmental factors have been reported to play a role in the composition and concentration of HMOs.

New discoveries

In this study, 20 healthy lactating mothers of term and preterm infants were recruited at the Neonatology Department of the Dana-Dwek Children’s Hospital of the Tel Aviv Medical Center between August 2020 and August 2021.

The collected demographic and clinical data included maternal age, BMI, diet and habits, mode of delivery, parity, infant gestational age, gender, birth weight, and admission to NICU. A total of 53 human milk samples were collected and seasons of BM sampling were recorded. 

The resulting data showed that 55% of the sample were secretors. These numbers are lower than those reported for Brazil (81.2%)​, Bangladesh (66%)​, Germany (85.3%)​, and other European countries (77%)​.

The team state: "These specific inherent genetic population variations may likely reflect natural evolution selection driving reduced α1–2-fucosylated HMOs, which may ultimately influence the infant’s disease risk or maturation. Additionally, sociodemographic factors may contribute to the human milk HMO secretor composition."

They also found that during summer, BM samples had significantly lower concentrations of LNT, LNFP II, and LNFP III compared to the other seasons. 

A significant variation in HMO levels was also found in association with with infants’ sex. They found that 2′-FL and LNFP I concentrations, FUT2-dependent HMs, were significantly higher in the milk of mothers to boys. This finding is supported by the results of Zimmermann and Curtis​, who reviewed 44 studies investigating 3105 breast milk samples from 2655 women.

The team hypothesise the significantly high concentration of 3-FL that was found in non-secretor mothers of boys can be explained by a possible compensation for the lack of 2′-FL in non-secretors that they also discovered.

They also found significantly higher concentrations of 3′-SL and DSLNT in the breast milk of mothers to girls. This trend was significant for secretors 3′-SL and for non-secretors DSLNT, which can also be explained by possible compensation between these two phenotypes.

The authors note that a limitation of the study is that participants were recruited in a single tertiary centre with a rather homogenous socioeconomic background from central Israel. 

Source: Nutrients (registering DOI)

"Human Milk Oligosaccharide Profile across Lactation Stages in Israeli Women—A Prospective Observational Study"

Authors: Asher. A .T., et al

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