Septicaemia and meningitis in premature neonates: defining the role of the developing intestinal microbiota.
The risk of meningitis is highest in the first year of life, but newborns – especially premature newborns – are particularly susceptible and have higher mortality and morbidity (ill health) than older babies.
Meningitis and septicaemia follow the spread of bacteria through the bloodstream, the microbes originally invading from the skin or from membranes lining the gut. It has been proposed that surveillance of the gut bacterial population may allow detection of changes, which, if nipped in the bud, may prevent the development of meningitis and septicaemia.
What the research team did
This exciting and innovative project has now concluded and we are pleased to share some of Professor Kroll’s findings.
Professor Kroll and his team recruited 369 babies under 32 weeks gestational age to be involved with the study. Sadly, but as expected, about one in ten of these very premature babies developed blood stream infections such as meningitis and septicaemia.
The team collected daily faecal samples and clinical data from each infant – a total of nearly 11,000 samples and 1,000,000 data entries in total. These samples and data entries covered the period from at least two weeks before, to nearly two weeks after the day the baby first fell ill, and were compared with samples from healthy babies (controls).
New molecular detection techniques allowed surveillance of the gut bacterial population to be carried out at a level of detail previously impossible. Using the latest gene technology, and analysing the very large datasets obtained using advanced computational biology tools available at Imperial College, the team compared the complex populations of bacteria found in the faeces of babies who develop meningitis and septicaemia to those from healthy babies.
Summary and impact of results
After two years of research, the team have made a number of observations that can help identify premature infants that are at high risk of developing infection and may also help us to understand the differences in development that lead to these infants being particularly vulnerable.
They have demonstrated that mechanically-aided ventilation and the presence of the invasive lines (such as catheters) provide a useful indicator of when an infant is at particularly high risk of developing infection. High proportions of a particular bacterial family, Staphylococcus, within the community of bacteria that inhabit the baby’s gut increases this risk further still.
Whilst many premature babies have high proportions of Staphylococci in their gut bacterial community shortly after birth, Staphylococci are particularly dominant in infants that later go on to develop septicaemia.
The gut bacterial community of healthy infants also gradually starts to change after birth. As the oxygen levels of the gut reduce, bacteria that find oxygen to be toxic begin to flourish and later dominate the community. In infants most likely to develop septicaemia, we see that this development occurs more slowly, most likely due to oxygen levels remaining unusually high in the gut.
The team are interested in a possible relationship between the greater use of mechanically-aided ventilation and the possible over saturation of oxygen in babies who develop septicaemia.
They also identified factors that can help determine which groups of bacteria are most likely to be in the blood of a baby with septicaemia. Infants that are comparatively mature (compared to other premature infants) are most likely to be at risk of Staphyococcal infections.
Babies who require many invasive lines during their hospital admission, and who have a gut bacterial community that isn’t very diverse and features high proportions of Enterobacteriaceae, are also particularly at risk of Enterobacteriaceae infections.
By identifying these risk factors, Professor Kroll and his team have provided the medical community with more ways to monitor premature babies at increased risk of infection.
With further research, it may be possible to adjust either the oxygen levels in the gut of babies at risk of septicaemia, or attempt to steer the development of the gut bacterial community through treatment with bacteria that are part of the normal, healthy gut community.
Publications and posters
Sim, K, Powell E, Shaw AG, McClure Z, Bangham M, Kroll JS. The neonatal gastrointestinal microbiota: the foundation of future health? Arch Dis Child Fetal Neonatal Ed. 2013; 98: F362-4
"Missing bifidobacteria: systematic undercounting in neonatal gastrointestinal microbiota resolved with novel, universal, barcoded 454 primers".
Sim K, Shaw A, Cox MJ, Wopereis H, Martin R, Knol J, Li MS, Cookson WOCM, Moffatt MF, Kroll JS
- International Human Microbiome Conference, March 2012, Paris
- Exploring Human Host-Microbiome Interactions in Health and Disease, May 2012, Cambridge
- 7th Yakult International Symposium, April 2013, London.
"Dysbiosis anticipating necrotizing enterocolitis in very premature infants".
Sim, K, Shaw AG, Randell R, Cox M, McClure ZE, Li MS, Haddad M, Langford PR, Cookson WOCM, Moffatt MF, Kroll JS.
- 2nd International Necrotizing Enterocolitis Conference, September 2014, London.