Singapore's pioneering researchers from A*STAR's Institute for Human Development and Potential, Duke-NUS Medical School, and collaborators have unveiled critical insights into how human milk oligosaccharides shape early infant health. The latest analysis from the GUSTO cohort study highlights the pivotal role of maternal factors in determining these vital milk components, offering new pathways to enhance neonatal outcomes in multi-ethnic populations.

Human milk oligosaccharides, often abbreviated as HMOs, represent the third most abundant solid component in breast milk after lactose and lipids. These complex, indigestible carbohydrates serve as prebiotics, selectively nourishing beneficial gut bacteria in infants while acting as decoys against pathogens. By fostering a healthy microbiome, HMOs support immune maturation, reduce infection risks, and promote cognitive and physical development during the crucial first months of life.

Unpacking the GUSTO Cohort: A Singapore Success Story

The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study stands as one of Asia's largest prospective mother-offspring cohorts, launched in 2009. Involving over 1,200 families from Chinese, Malay, and Indian backgrounds, it tracks prenatal, birth, and childhood factors influencing long-term health. Key partners include A*STAR's research arms like the former Genome Institute of Singapore (GIS), now integrated into broader genomics efforts, Duke-NUS Medical School, National University Hospital, and KK Women's and Children's Hospital.

This multi-disciplinary effort has produced hundreds of publications, from genomics to nutrition. The recent HMO investigation builds on GUSTO's milk banking and biobanking infrastructure, analyzing 408 samples from 248 mothers at 3 weeks and 3 months postpartum. Such depth allows unprecedented views into dynamic milk composition tailored to Singapore's diverse demographics.

Decoding HMO Diversity: Secretor Status Takes Center Stage

Central to the findings is the secretor status, governed by the FUT2 gene. About 70% of GUSTO mothers were secretors, characterized by elevated levels of 2'-fucosyllactose (2'-FL)—the most abundant HMO in secretors at 16% of total at 3 weeks, dropping to 10.4% by 3 months. Non-secretors showed negligible 2'-FL (0.3% and 0.2%) but higher 3-fucosyllactose (3-FL), reaching 42.9% by 3 months.

This genetic dichotomy, confirmed with 97% accuracy via the FUT2 SNP rs1047781, profoundly shapes milk's prebiotic profile. Secretor milk promotes Bifidobacterium species growth, crucial for gut barrier integrity. In Singapore's context, where Bifidobacterium infantis prevalence is low among Asian infants per related GUSTO analyses, these profiles may influence allergy and infection susceptibilities.

Maternal Influences: From BMI to Delivery Mode

Beyond genetics, maternal factors modulate HMO levels. Parity emerged as significant: multiparous mothers exhibited distinct profiles, possibly from accumulated physiological adaptations. Pre-pregnancy body mass index (BMI) and gestational weight gain correlated with sialylated HMOs like 3'-sialyllactose (3'-SL), vital for brain development.

Preterm delivery stood out, with preterm mothers showing 1.23 standard deviations higher 3'-SL at 3 weeks—a potential compensatory mechanism for immature infant guts. Mode of delivery and breastfeeding exclusivity also played roles, underscoring how obstetric history tailors milk to neonatal needs.

Photo by Danist Soh on Unsplash

• Parity: Higher-order births linked to altered fucosylated HMOs.
• BMI/Gestational Gain: Positive associations with sialylated species.
• Preterm Status: Elevated 3'-SL for neuroprotection.
• Ethnicity: Remarkably uniform across Chinese (73.8%), Malay (14.5%), and Indian (11.7%) groups.

Ethnic Harmony in HMO Profiles: A Singaporean Strength

Unlike Western cohorts with stark ethnic variances, GUSTO mothers showed comparable HMO concentrations across groups. Total HMO levels averaged similar, with secretor proportions consistent. This uniformity suggests shared Asian evolutionary adaptations, where lower 2'-FL (vs. Caucasians) and higher 3-FL may optimize local pathogen resistance.

For Singapore's melting pot, this implies universally beneficial breastfeeding, but tailored interventions for non-secretors or preterm infants could amplify benefits. The full GUSTO HMO study details these profiles, urging region-specific infant formula designs.

Tracking Changes: From Colostrum to Mature Milk

Longitudinally, HMO concentrations shifted predictably: fucosylated HMOs declined, sialylated stabilized. From 3 weeks to 3 months, 71 matched pairs revealed consistent trajectories across secretors/non-secretors, reflecting mammary gland maturation.

These dynamics align infant nutrition with evolving gut needs, from pathogen blockade to microbiota establishment.

Translating to Infant Health: Gut, Immunity, and Beyond

HMOs' prebiotic magic fosters Bifidobacterium dominance, curbing pathogens like E. coli. GUSTO extensions link secretor milk to lower respiratory infections and better microbiota maturity. In Singapore, where allergies rise, non-secretor milk's higher 3-FL may offer alternative protections.

Preterm boosts in 3'-SL support sialic acid for ganglioside synthesis, aiding neurodevelopment. Amid formula HMO supplementation, GUSTO data guides precise mimicking for vulnerable infants. Explore the GUSTO platform for ongoing infant health insights.

Singapore's Research Ecosystem: A*STAR GIS and Duke-NUS Lead

A*STAR's GIS legacy in genomics underpins GUSTO's genetic analyses, now amplified by IHDP. Duke-NUS clinicians like Prof. Fabian Yap integrate bedside data, bridging lab to clinic. This synergy exemplifies Singapore's biomedical hub status, with implications for national breastfeeding policies.

Photo by TSquared Lab on Unsplash

Challenges and Future Horizons

While promising, gaps persist: long-term infant outcomes tied to specific HMOs need tracking. Diet's role remains underexplored; trials modulating maternal intake could personalize milk. As climate and diets evolve, GUSTO Phase 2 scales to 100,000 genomes, promising HMO-infant health breakthroughs.

For parents, evidence bolsters exclusive breastfeeding; for researchers, it calls multi-ethnic HMO atlases. Singapore positions as HMO innovation leader, eyeing fortified formulas and therapeutics.