Background: Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily
affecting premature infants, with a poorly understood aetiology. Prior studies have
found associations in different cases with an overabundance of particular elements of
the faecal microbiota (in particular Enterobacteriaceae or Clostridium perfringens ),
but there has been no explanation for the different results found in different cohorts.
Immunological studies have indicated that stimulation of the TLR4 receptor is involved
in development of NEC, with TLR4 signalling being antagonised by the activated TLR9
receptor. We speculated that differential stimulation of these two components of the
signalling pathway by different microbiota might explain the dichotomous findings of
microbiota-centered NEC studies. Here we used shotgun metagenomic sequencing
and qPCR to characterise the faecal microbiota community of infants prior to NEC
onset and in a set of matched controls. Bayesian regression was used to segregate
cases from control samples using both microbial and clinical data.
Results: We found that the infants suffering from NEC fell into two groups based on
their microbiota; one with low levels of CpG DNA in bacterial genomes and the other
with high abundances of organisms expressing LPS. The identification of these
characteristic communities was reproduced using an external metagenomic validation
dataset. We propose that these two patterns represent the stimulation of a common
pathway at extremes; the LPS-enriched microbiome suggesting overstimulation of
TLR4, whilst a microbial community with low levels of CpG DNA suggests reduction of
the counterbalance to TLR4 overstimulation.
Conclusions: The identified microbial community patterns support the concept of NEC
resulting from TLR-mediated pathways. Identification of these signals suggests
characteristics of the gastrointestinal microbial community to be avoided to prevent
NEC. Potential pre- or pro-biotic treatments may be designed to optimise TLR
signalling.