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

Abstract

ObjectiveNecrotising 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.DesignWe 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).ResultsConcentration 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.ConclusionThese 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.

Human Milk Oligosaccharides (HMOs) and Infant Microbiota: A Scoping Review

“…The studies included in the present review were conducted in Brazil [ 15 ], United States [ 28 , 29 , 30 ], United Kingdom [ 16 ], Netherlands [ 17 , 20 ], Italy [ 18 , 31 ], Belgium [ 18 ], Canada [ 19 ], Kenya [ 21 ], China [ 22 ], Finland [ 23 ], Gambia [ 24 ], Australia [ 25 , 27 ], and Japan [ 26 ].…”

“…Most of the studies were prospective observational cohort studies [ 16 , 17 , 19 , 20 , 22 , 23 , 25 , 27 , 28 , 31 ], and another was a proof-of-concept study [ 29 ]. We have also included one classified as a quasi-experimental cohort study [ 30 ].…”

“…In the De Leoz (2015) study [ 29 ], the HMOs analysis was carried out on fecal samples. MSeS was determined by the presence/absence of different fucosylated HMO [ 15 , 16 , 22 ], by determination of relative HMOs abundance [ 19 , 25 , 28 ], or by HMO quantification [ 23 ]. A hemagglutination inhibition technique was used in one work [ 27 ], and genotyping was used in the Lewis study [ 24 ].…”

“…HMO analysis was performed by capillary electrophoresis with laser-induced fluorescence (CE-LIF) in only one study [ 19 ]. In the rest of the works, the analysis of the profile of HMOs was carried out with various chromatographic and detection techniques: high performance (HP) anion exchange chromatography–pulsed amperometry detection (HPAEC-PAD) [ 21 , 23 , 31 ], porous graphitized carbon-ultra HPLC-mass spectrometry (PGC-UPLC-MS) [ 17 ], UPLC [ 20 ], HPLC-MS [ 15 , 16 , 19 ], matrix-assisted laser desorption/ionization–time of fight-mass spectrometry (MALDI-TOF-MS) [ 23 ], LC-QTOF-MS [ 22 , 24 ], or Nano-HPLC-chip/TOF-MS [ 25 , 28 , 29 , 30 ]. Detailed analysis of oligosaccharides remains very challenging due to the variety of hydrophilicity and ionization properties of the different structures [ 29 ].…”

“…Research papers that investigated associations between maternal status (Se+ or Se-) and infant microbiome were the majority [ 15 , 16 , 19 , 21 , 22 , 23 , 24 , 25 , 27 , 28 ]. One of them examines the intestinal flora at two years of age [ 27 ].…”