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Necrotising enterocolitis is a devastating gastrointestinal disease, most commonly affecting extremely preterm infants within the first four weeks of life. Mother's own milk (MOM) is protective against necrotising enterocolitis (NEC) in preterm infants but some infants who only ever receive MOM still develop NEC. In a UK based population, more than half the infants who developed NEC had only ever received maternal breast milk. MOM microbiome does not correlate with NEC development, but the bioactive immunomodulatory factors of MOM are potential mechanisms through which breast milk receipt may modulate NEC risk. Variation in human milk oligosaccharides (HMOs) with lower DSLNT is seen in breast milk received by infants developing NEC compared to controls but otherwise exploration of MOM variation and potential impact on NEC is limited. Milk constituents including HMOs and Immunoglobulin A (IgA) in its secretory form (sIgA) have previously been linked to NEC development, and we have shown variation in total and secretory IgA levels in preterm milk influenced by gestation and storage factors.
sIgA is in both breast milk and mucosal secretions and is critical in exclusion of pathogens and education of the immune system and constitutes dimeric or polymeric IgA. Its role within the gut is delicately balanced between pro-inflammatory and anti-inflammatory responses and is influential in the education of the intestinal microbiota, promoting antigen transfer to dendritic cells bound by a "J" chain, complexed to secretory component (SC). The SC binds to dimeric IgA within the intestinal epithelium during membrane transcytosis utilising a glycoprotein, polymeric Ig receptor and is potentially crucial in delaying proteolysis and digestion in the gut lumen. This is particularly critical in early life, prior to production of endogenous sIgA (Demers Mathieu 2019). The authors demonstrated that IgA in 20 preterm infants with a mean gestational age (GA) of 30 weeks, only 1% of stool IgA is secretory, hypothesising that the secretory component is cleaved from the complex whilst in the intestinal lumen. The secretory form of IgA (sIgA) binds bacteria in the gut thus prevents invasion of mucosal surfaces, as well as enhancing uptake of commensal bacteria by Peyer's patches. Through this mechanism, sIgA is hypothesised to regulate the constituents of the microbiome by promoting obligate anaerobes and limiting facultative anaerobes that may increase the pro-inflammatory response. Previous work has shown changes in patterns of IgA bound and unbound bacteria within health and disease, in mice or adult humans. Kubinak et al. compared IgA bound and unbound bacterial populations in the stool of mice who were bred as germ free, then mono-colonised with B. fragilis-OVA, showing that IgA bound bacteria more closely resembled the host mucosal microbiota than faecal communities. They also found that IgA preferentially bound bacteria that are more prone to cause disease, such as Enterobacteriaceae. More recently in preterm neonates, Gopalakrishna et al. showed a reduction in the relative fraction of IgA bound bacteria, with a higher proportion of Enterobacteriaecae, before NEC onset compared to controls.
We aimed to explore the relationship between IgA and sIgA concentration in MOM and infant stool and the development of NEC. We hypothesised that higher (s)IgA concentration in milk would result in higher availability of (s)IgA in the gastrointestinal tract, available to bind to potentially pathogenic bacteria, reducing the capacity of unbound bacteria to contribute to mechanisms involved in NEC development and cause disease.