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Human Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we use a systems biology framework that integrates glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we construct models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. Our model aggregation approach recovers 2 of 2 previously known gene-enzyme relations and 2 of 3 empirically confirmed gene-enzyme relations. The top genes we propose for the remaining 5 linkage reactions are consistent with previously published literature. These results provide the molecular basis of HMO biosynthesis necessary to guide progress in HMO research and application with the goal of understanding and improving infant health and development. Human milk oligosaccharides are fundamental to infant health. Here the authors deploy a multi-omics systems biology approach to elucidate their biosynthetic network, including the associated enzymes and likely structures of ambiguous oligosaccharides.

Lactational mastitis is an excellent target to study possible interactions between HMOs, immune factors and milk microbiota due to the infectious and inflammatory nature of this condition. In this work, microbiological, immunological and HMO profiles of milk samples from women with (MW) or without (HW) mastitis were compared. Secretor status in women (based on HMO profile) was not associated to mastitis. DFLNH, LNFP II and LSTb concentrations in milk were higher in samples from HW than from MW among Secretor women. Milk from HW was characterized by a low bacterial load (dominated by Staphylococcus epidermidis and streptococci), high prevalence of IL10 and IL13, and low sialylated HMO concentration. In contrast, high levels of staphylococci, streptococci, IFNγ and IL12 characterized milk from MW. A comparison between subacute (SAM) and acute (AM) mastitis cases revealed differences related to the etiological agent ( S. epidermidis in SAM; Staphylococcus aureus in AM), milk immunological profile (high content of IL10 and IL13 in SAM and IL2 in AM) and milk HMOs profile (high content of 3FL in SAM and of LNT, LNnT, and LSTc in AM). These results suggest that microbiological, immunological and HMOs profiles of milk are related to mammary health of women.

Human milk is a complex and variable ecosystem fundamental to the development of newborns. This study aimed to investigate relationships between human milk oligosaccharides (HMO) and human milk bacterial profiles and infant body composition. Human milk samples (n = 60) were collected at two months postpartum. Infant and maternal body composition was measured with bioimpedance spectroscopy. Human milk bacterial profiles were assessed using full-length 16S rRNA gene sequencing and 19 HMOs were quantitated using high-performance liquid chromatography. Relative abundance of human milk bacterial taxa were significantly associated with concentrations of several fucosylated and sialylated HMOs. Individual human milk bacteria and HMO intakes and concentrations were also significantly associated with infant anthropometry, fat-free mass, and adiposity. Furthermore, when data were stratified based on maternal secretor status, some of these relationships differed significantly among infants born to secretor vs non-secretor mothers. In conclusion, in this pilot study the human milk bacterial profile and HMO intakes and concentrations were significantly associated with infant body composition, with associations modified by secretor status. Future research designed to increase the understanding of the mechanisms by which HMO and human milk bacteria modulate infant body composition should include intakes in addition to concentrations.

Human milk oligosaccharide (HMO) composition varies throughout lactation and can be influenced by maternal characteristics. This study describes HMO variation up to three months postpartum and explores the influences of maternal sociodemographic and anthropometric characteristics in a Brazilian prospective cohort. We followed 101 subjects from 28–35 gestational weeks (baseline) and throughout lactation at 2–8 (visit 1), 28–50 (visit 2) and 88–119 days postpartum (visit 3). Milk samples were collected at visits 1, 2 and 3, and 19 HMOs were quantified usinghigh-performance liquid chromatography with fluorescence detection (HPLC-FL). Friedman post-hoc test, Spearman rank correlation for maternal characteristics and HMOs and non-negative matrix factorization (NMF) were used to define the HMO profile. Most women were secretors (89.1%) and presented high proportion of 2′-fucosyllactose (2′FL) at all three sample times, while lacto-N-tetraose (LNT, 2–8 days) and lacto-N-fucopentaose II (LNFPII, 28–50 and 88–119 days) were the most abundant HMOs in non-secretor women. Over the course of lactation, total HMO weight concentrations (g/L) decreased, but total HMO molar concentrations (mmol/L) increased, highlighting differential changes in HMO composition over time. In addition, maternal pre-pregnancy body mass index (BMI) and parity influence the HMO composition in healthy women in this Brazilian cohort.

Preterm infants are at a greater risk for the development of asthma and atopic disease, which can lead to lifelong negative health consequences. This may be due, in part, to alterations that occur in the gut microbiome and metabolome during their stay in the Neonatal Intensive Care Unit (NICU). To explore the differential roles of family history (i.e., predisposition due to maternal asthma diagnosis) and hospital-related environmental and clinical factors that alter microbial exposures early in life, we considered a unique cohort of preterm infants born ≤ 34 weeks gestational age from two local level III NICUs, as part of the MAP (Microbiome, Atopic disease, and Prematurity) Study. From MAP participants, we chose a sub-cohort of infants whose mothers had a history of asthma and matched gestational age and sex to infants of mothers without a history of asthma diagnosis (control). We performed a prospective, paired metagenomic and metabolomic analysis of stool and milk feed samples collected at birth, 2 weeks, and 6 weeks postnatal age. Although there were clinical factors associated with shifts in the diversity and composition of stool-associated bacterial communities, maternal asthma diagnosis did not play an observable role in shaping the infant gut microbiome during the study period. There were significant differences, however, in the metabolite profile between the maternal asthma and control groups at 6 weeks postnatal age. The most notable changes occurred in the linoleic acid spectral network, which plays a role in inflammatory and immune pathways, suggesting early metabolomic changes in the gut of preterm infants born to mothers with a history of asthma. Our pilot study suggests that a history of maternal asthma alters a preterm infants’ metabolomic pathways in the gut, as early as the first 6 weeks of life.

Background Synthetic human milk oligosaccharides (HMOs) are used to supplement infant formula despite limited understanding of their impact on the post-weaned developing gut microbiota. Here, we assess the influence of 0.5 g/L 2-fucosyllactose (2’FL) and 4.0 g/L pooled HMOs (pHMOs) on the composition and activity of cultured fecal-derived microbial communities from seven healthy young children. Results Exposure to pHMOs induced significant shifts in both the microbial community composition and metabolic output, including an increased abundance of several genera, notably Bacteroides , and the production of health-associated metabolites. In contrast, 2’FL alone did not lead to substantial changes in the communities. A total of 330 bacterial isolates, spanning 157 species, were cultured from these communities and individually evaluated for their responses to HMOs. Over 100 non- Bifidobacterium species showed enhanced growth upon pHMOs treatment and a high degree of intraspecies variation in HMO metabolism was observed. Conclusion Our study provides valuable insight into the health-enhancing properties of HMOs while highlighting the need for future research into the efficacy of incorporating individual structures into infant formula, particularly when aiming to modulate the gut microbiota. DLoTGpXbSBXfYGWsHwkdt7 Video Abstract

Background/Objectives: Human milk oligosaccharides (HMOs) are bioactive carbohydrates abundant in human milk that shape the infant gut microbiome, yet their influence on the oral microbiome remains poorly understood. This study investigated associations between HMO concentrations and infant HMO intakes and the composition of the oral microbiome in predominantly (n = 2) and exclusively (n = 54) breastfed infants. Methods: We profiled infant oral samples collected at 2 months of age using full-length 16S rRNA gene sequencing, alongside paired milk HMO analyses from 56 mother–infant dyads from the Western Australian BLOSOM cohort. Daily HMO intakes were calculated using 24 h milk intake data. Results: Concentrations of human milk 3FL and LNFPIII were negatively associated with infant oral Shannon diversity (p = 0.027) and richness (p = 0.037), respectively. LNFPII concentration and daily intake were linked to increased abundance of Neisseria subflava (both p = 0.025), while daily intakes of DFLNT and DFLNH were positively associated with Streptococcus parasanguinis (p = 0.028 and p = 0.040). Notably, the associations observed for daily HMO intakes were modest in effect size. Conclusions: These findings demonstrate a statistically significant but biologically limited effect of HMOs on the development of the infant oral microbiome. By clarifying how specific components of human milk shape early microbial development, this work provides mechanistic insights relevant to nutritional and supportive interventions that promote breastfeeding success.

Temporal development of maternal and infant microbiomes during early life impacts short- and long-term infant health. This study aimed to characterize bacterial dynamics within maternal faecal, human milk (HM), infant oral, and infant faecal samples during the exclusive breastfeeding period and to document associations between human milk oligosaccharide (HMO) intakes and infant oral and faecal bacterial profiles. Maternal and infant samples (n = 10) were collected at 2–5, 30, 60, 90 and 120 days postpartum and the full-length 16S ribosomal RNA (rRNA) gene was sequenced. Nineteen HMOs were quantitated using high-performance liquid chromatography. Bacterial profiles were unique to each sample type and changed significantly over time, with a large degree of intra- and inter-individual variation in all sample types. Beta diversity was stable over time within infant faecal, maternal faecal and HM samples, however, the infant oral microbiota at day 2–5 significantly differed from all other time points (all p < 0.02). HMO concentrations and intakes significantly differed over time, and HMO intakes showed differential associations with taxa observed in infant oral and faecal samples. The direct clinical relevance of this, however, is unknown. Regardless, future studies should account for intakes of HMOs when modelling the impact of HM on infant growth, as it may have implications for infant microbiota development.

Background One potential mechanism for protection from SARS-CoV-2 in children is through passive immunity via breast milk from a mother infected with the novel coronavirus. The primary objectives of this study were to establish the presence of SARS-CoV-2-specific IgA and IgG and to characterize the antigenic regions of SARS-CoV-2 proteins that were reactive with antibodies in breast milk. Methods Between March 2020 and September 2020, 21 women with confirmed SARS-CoV-2 infection were enrolled in Mommy’s Milk. Participants donated serial breast milk samples around their time of illness. Breast milk samples were used to probe a multi-coronavirus protein microarray containing full-length and variable-length overlapping fragments of SARS-CoV-2 proteins. Samples were also tested against S and N proteins by electrochemiluminescence assay. Results The breast milk samples contained IgA reactive with a variety of SARS-CoV-2 antigens. The most IgA-reactive SARS-CoV-2 proteins were N (42.9% of women responded to ≥1 N fragment) and S proteins (23.9% responded to ≥1 fragment of S1 or S2). IgG responses were similar. A striking observation was the dissimilarity between mothers in antibody recognition, giving distinct antibody reactivity and kinetic profiles. Conclusions Individual COVID-19 cases had diverse and unique milk IgA profiles following the onset of symptoms. Impact In this observational longitudinal case series of 21 women with confirmed SARS-CoV-2 infection, IgA binding to SARS-CoV-2 proteins detected by orthologous proteome microarray and electrochemiluminescence assays was observed in >75% of women, but there was heterogeneity in which antigens and how many were reactive between women. Immunological profiles of protein regions recognized by each woman were distinct. Diverse repertoires of mucosal breast milk antibody to SARS-CoV-2 reflect heterogeneous passive transfer of maternal antibody to exposed breastfeeding infants.

Human milk oligosaccharides (HMOs) are bioactive factors that benefit neonatal health, but little is known about effects on growth in very preterm infants (<32 weeks’ gestation). We aimed to quantify HMO concentrations in human milk fed to very preterm infants during the neonatal hospitalization and investigate associations of HMOs with infant size and body composition at term-equivalent age. In 82 human-milk-fed very preterm infants, we measured HMO concentrations at two time points. We measured anthropometrics and body composition with air displacement plethysmography at term-equivalent age. We calculated means of individual and total HMOs, constructed tertiles of mean HMO concentrations, and assessed differences in outcomes comparing infants in the highest and intermediate tertiles with the lowest tertile using linear mixed effects models, adjusted for potential confounders. The mean (SD) infant gestational age was 28.2 (2.2) weeks, and birthweight was 1063 (386) grams. Exposure to the highest (vs. lowest) tertile of HMO concentrations was not associated with anthropometric or body composition z-scores at term-corrected age. Exposure to the intermediate (vs. lowest) tertile of 3FL was associated with a greater head circumference z-score (0.61, 95% CI 0.15, 1.07). Overall, the results do not support that higher HMO intakes influence growth outcomes in this very preterm cohort.