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.
- molecular biology
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Twitter @ACMasi10, @DrChrisLamb, @clairelgranger, @CJStewart7
Contributors NDE, JEB and CJS conceived and designed the study. ACM, CAL, GY, CLG, JEB and CJS collected the samples and overseen the logistics. JN and LB performed the HMO profiling. KLH and JFP performed the bioinformatics on fastq files. ACM, DPS and CJS performed the analysis. NDE, JEB and CJS supervised the study. ACM, NDE, CAL, JEB and CJS cowrote the manuscript and all authors approved the final submission.
Funding This work was supported by the MRC Discovery Medicine North Doctoral Training Partnership (to AM and CS), the Newcastle University academic career track scheme (to CS) and Astarte Medical for funding stool sample retrieval and shipment for metagenomic sequencing (to CS). The funders played no part in the study design, analysis, interpretation or reporting.
Competing interests CS declares performing consultancy for Astarte Medical and honoraria from Danone Early Life Nutrition. NDE declares research funding from Prolacta Biosciences US and Danone Early Life Nutrition, and received lecture honoraria from Baxter and Nestle Nutrition Institute, but has no share options or other conflicts. LB is UC San Diego Chair of Collaborative Human Milk Research, endowed by the Family Larsson-Rosenquist Foundation and serves on the foundation’s scientific advisory board. LB is coinventor on patent applications regarding human milk oligosaccharides in prevention of necrotising enterocolitis and other inflammatory disorders. The other authors declare that they have no competing interests.
Patient consent for publication Not required.
Ethics approval Ethics approval was obtained from the County Durham and Tees Valley Research Ethics Committee (REC10/H0908/39) and the parents gave informed consent for stool and data collection.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. All sequencing data generated and analysed in this study have been deposited in the European Nucleotide Archive under study accession number PRJEB39610. The metagenomic data are publically available and can be accessed online (https://www.ebi.ac.uk/ena/browser/view/PRJEB39610). HMO data are avilable upon request.
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