Secretory immunoglobulin A in preterm infants: determination of normal values in breast milk and stool.

BACKGROUND: IgA and its secretory form sIgA impact protection from infection and necrotising enterocolitis but little is known about quantities in preterm mums own milk (MOM) or infant stool, onset of endogenous production in the preterm gut, and what affects these. METHODS: We measured by ELISA in MOM and stool from healthy preterm infants total IgA and sIgA longitudinally and additionally in MOM fresh, refrigerated, frozen, and after traversing feeding systems. RESULTS: In 42 MOM (median gestation 26 weeks), we showed total IgA levels and sIgA were highest in colostrum, fell over 3 weeks, and were not impacted by gestation. Median IgA values matched previous term studies (700 mcg/ml). In MOM recipients stool IgA was detected in the first week, at around 30% of MOM quantities. Formula fed infants did not have detectable stool IgA until the third week. Levels of IgA and sIgA were approximately halved by handling processes. CONCLUSIONS: MOM in the 3 weeks after preterm delivery contains the highest concentrations of IgA and sIgA. Endogenous production after preterm birth occurs from the 3 week meaning preterm infants are dependent on MOM for IgA which should be optimised. Routine NICU practices halve the amount available to the infant. IMPACT: (Secretory) Immunoglobulin A (IgA) is present in colostrum of maternal milk from infants as preterm as 23-24 weeks gestational age, falling over the first 3 weeks to steady levels similar to term. Gestation at birth does not impact (secretory) IgA levels in breast milk. IgA is present in very preterm infant stools from maternal milk fed infants from the first week of life, but not in formula milk fed preterm infants until week three, suggesting endogenous production from this point. Refrigeration, freezing, and feeding via plastic tubing approximately halved the amount of IgA available.

Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotising enterocolitis.

OBJECTIVE: Necrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother's own breast milk (MOM) is protective, possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC. DESIGN: We performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644). RESULTS: Concentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of Bifidobacterium longum and higher relative abundance of Enterobacter cloacae in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by Bifidobacterium spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC. CONCLUSION: These results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.

Use of omic technologies in early life gastrointestinal health and disease: from bench to bedside.

Introduction: At birth, the gastrointestinal (GI) tract is colonized by a complex community of microorganisms, forming the basis of the gut microbiome. The gut microbiome plays a fundamental role in host health, disorders of which can lead to an array of GI diseases, both short and long term. Pediatric GI diseases are responsible for significant morbidity and mortality, but many remain poorly understood. Recent advancements in high-throughput technologies have enabled deeper profiling of GI morbidities. Technologies, such as metagenomics, transcriptomics, proteomics and metabolomics, have already been used to identify associations with specific pathologies, and highlight an exciting area of research. However, since these diseases are often complex and multifactorial by nature, reliance on a single experimental approach may not capture the true biological complexity. Therefore, multi-omics aims to integrate singular omic data to further enhance our understanding of disease.Areas covered: This review will discuss and provide an overview of the main omic technologies that are used to study complex GI pathologies in early life.Expert opinion: Multi-omic technologies can help to unravel the complexities of several diseases during early life, aiding in biomarker discovery and enabling the development of novel therapeutics and augment predictive models.

Maternal breastmilk, infant gut microbiome and the impact on preterm infant health.

AIM: This narrative review summarises the benefits of maternal breastmilk to both the infant and the mother, specifically the benefits that relate to modification of the infant microbiome, and how this might vary in the preterm infant. METHODS: We used PubMed to primarily identify papers, reviews, case series and editorials published in English until May 2020. Based on this, we report on the components of breastmilk, their associated hypothesised benefits and the implications for clinical practice. RESULTS: Breastmilk is recommended as the exclusive diet for newborn infants because it has numerous nutritional and immunological benefits. Additionally, exposure to the maternal breastmilk microbiome may confer a lasting effect on gut health. In the preterm infant, breastmilk is associated with a significant reduction in necrotising enterocolitis, an inflammatory gastrointestinal disease and reduction in other key morbidities, together with improved neurodevelopmental outcomes. CONCLUSION: These impacts have long-term benefits for the child (and the mother) even after weaning. This benefit is likely due, in part, to modification of the infant gut microbiome by breastmilk microbes and bioactive components, and provide potential areas for research and novel therapies in preterm and other high-risk infants.

Human milk microbiota, oligosaccharide profiles, and infant gut microbiome in preterm infants diagnosed with necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a severe intestinal disease of very preterm infants with mother's own milk (MOM) providing protection, but the contribution of the MOM microbiota to NEC risk has not been explored. Here, we analyze MOM of 110 preterm infants (48 NEC, 62 control) in a cross-sectional study. Breast milk contains viable bacteria, but there is no significant difference in MOM microbiota between NEC and controls. Integrative analysis between MOM microbiota, human milk oligosaccharides (HMOs), and the infant gut microbiota shows positive correlations only between Acinetobacter in the infant gut and Acinetobacter and Staphylococcus in MOM. This study suggests that NEC protection from MOM is not modulated through the MOM microbiota. Thus, "'restoring" the MOM microbiota in donor human milk is unlikely to reduce NEC, and emphasis should instead focus on increasing fresh maternal human milk intake and researching different therapies for NEC prevention.

Impact of Transfer for Surgical Management of Preterm Necrotising Enterocolitis or Focal Intestinal Perforation.

OBJECTIVE: To compare outcomes after surgically managed necrotising enterocolitis (NEC) and focal intestinal perforation (FIP) in infants <32 weeks requiring transfer to or presenting in a single surgical centre. DESIGN: Retrospective review of transferred and inborn NEC or FIP, from January 2013 to December 2020. PATIENTS: 107 transfers with possible NEC or FIP contributed 92 cases (final diagnoses NEC (75) and FIP (17)); 113 inborn cases: NEC (84) and FIP (29). RESULTS: In infants with a final diagnosis of NEC, medical management after transfer was as common as when inborn (41% TC vs 54% p = 0.12). Unadjusted all-cause mortality was lower in inborn NEC (19% vs 27%) and FIP (10% vs 29%). In infants undergoing surgery unadjusted mortality attributable to NEC or FIP was lower if inborn (21% vs 41% NEC, 7% vs 24% FIP). In regression analysis of surgically treated infants, being transferred was associated with increased all-cause mortality (OR 2.55 (1.03-6.79)) and mortality attributable to NEC or FIP (OR 4.89 (1.80-14.97)). CONCLUSIONS: These data require replication, but if confirmed, suggest that focusing care for infants at highest risk of developing NEC or FIP in a NICU with on-site surgical expertise may improve outcomes.