25 January 2019
NEC and the chaotic gut microbiome
Dr Christopher Stewart
Institute of Cellular Medicine
I recently had the pleasure of attending my first Special Interest Group in Necrotizing Enterocolitis (SIGNEC) meeting, where I presented my talk entitled “Infant microbiome in health and disease: current understanding and future direction”. In this blog post I discuss some of my thoughts on microorganisms, human evolution, and preterm infant health and disease.
I am an academic researcher and Research Fellow at Newcastle University in England. I am in the early stages of setting up my own research group, with a focus on preterm infants. For the past 10 years, I have worked closely with passionate clinicians from the UK and across the pond. We share the same common goal: to better understand necrotizing enterocolitis so that biomarkers and therapeutics can be developed.
NEC is a devastating bowel condition that almost exclusively affects preterm infants. The risk for developing disease is inversely correlated with the gestational age of the baby; meaning the more preterm a baby is delivered, the greater risk of disease. Clinically, NEC is challenging to detect and diagnose. Rapid progression of disease and the inherent risk of performing surgery on such vulnerable babies represent further challenges, underscoring the need for diagnostic biomarkers and therapies that may prevent disease progression in the first instance.
Humans have co-evolved with our microbial counterparts living upon and within us. Indeed, most recent estimates show that the number of bacterial cells in the human body outnumber our own human cells. While bacteria are generally thought of with negative connotations, entry of bacteria into the human body at birth is normal and necessary for health. Once in the gut, bacteria contribute to a range of important functions including digestion of dietary components, protection from injury, and training of the immune system. Put simply, without bacteria colonising the human gut, termed the ‘gut microbiome’, we would be less healthy. Because evolution over hundreds of thousands of years has shaped what is normal, or expected, we consider full term, vaginally delivered, breastfed infants to represent the gold standard of health. This is supported by a range of epidemiological studies showing birth by caesarean section and/or no breastmilk in early life can increase the risk of later life diseases, including allergy, obesity, and immune deficiencies. Of course, procedures such as preterm delivery or caesarean section are usually medically indicated as necessary for the survival of mother and/or infant. But these procedures, while undoubtedly a credit to modern day medicine, result in alterations to the microbiome that we are only beginning to understand.
Recent work from our group, and others, have demonstrated that changes in bacteria that colonise preterm infants may play a role in the onset or prevention of NEC. It is important to highlight that this evidence is association based, meaning we cannot be certain of cause or effect. In other words, changes in the bacteria may be the result of underlying disease processes and therefore are not causing the onset of NEC per se. While it is now widely recognised that no single bacterium predisposes an infant to NEC, recent work from our group has shown that babies who go on to develop NEC show more chaotic development in the microbiome, compared to controls. See the video below:
Conversely, recent work from our group has also shown that babies with high levels of Bifidobacterium (a species of bacteria) early in life do not go on to develop NEC. Interestingly, we know that breastmilk contains special sugars that are specifically produced by the mother, not to feed her offspring, but to feed her offspring’s microbiome. More specifically, these sugars (called human milk oligosaccharides) promote the growth of Bifidobacterium. Thus, it is striking that evolution has designed us in such a way to want Bifidobacterium to colonise the gut in early life.
So, why don’t we just put Bifidobacterium (i.e. a probiotic) or human milk oligosaccharides (i.e. prebiotics) into preterm babies to protect them from NEC? The short answer is we are trying but, like everything in biology, it is never straightforward. For example, a recent probiotic vs. placebo trial 1 of 1,315 preterm infants found that giving babies a specific Bifidobacterium had no influence on NEC. Other work using different Bifidobacterium, as well as other beneficial bacteria, is currently ongoing. Prebiotics, including supplement milk sugars or human milk fortifier, are also being rigorously tested currently and we will know so much more about this in the coming years.
We mustn’t lose sight that these are also relatively recent discoveries and translating findings from the lab into changes in clinical practice will take time – and money. While the research funding for NEC does not attract the same support as other diseases, there is a worldwide team of really fantastic researchers and clinicians working hard every day to understand more about this devastating disease. In the North of England we are lucky enough to have access to a large biorepository of samples from nearly 1000 infants born at <32 weeks gestation, containing stool, urine, blood, secretions and breast milk at the Great North Neonatal Biobank. This allows us (and others) to potentially move this work forward faster and we welcome collaborations.
Events like SIGNEC that bring parents, clinicians, surgeons, researchers, funders, and charities all under one roof help enormously in pushing the dialogue and driving discoveries. Our knowledge and understanding of NEC is increasing all the time and, as we put all the pieces of the jigsaw together, there is real promise ahead for both biomarkers and therapeutics.
The button below will bring up my presentation to the sixth SIGNEC meeting. Clicking on the photograph beneath it will take you to news coverage of our NEC research and where parents also speak of their experiences. For more information on the Newcastle Neonatal Research Team, please come and visit our website.
Infant microbiome in health and disease: current understanding and future direction
1. Costeloe KL, Bowler U, Brocklehurst P, Hardy P, Heal P, Juszczak E, et al. A randomised controlled trial of the probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial. Health Technol Assess 2016;20(66)
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