Harnessing the microbiome to prevent necrotizing enterocolitis in premature infants

Premature babies face a host of respiratory, neurological and digestive problems because their organs didn't have enough time to develop inside the womb. One of the most dangerous conditions is necrotizing enterocolitis (NEC), a life-threatening inflammatory bowel disorder that develops in about 10 percent of preterm infants. NEC has a mortality rate between 30 and 50 percent, and babies who do survive can suffer from long-term problems with nutrition, growth and neurodevelopmental disorders, including a higher risk for cerebral palsy.

The specific cause of NEC is unknown, but scientists do know that bacteria living in the intestine play an important role. A healthy gut contains a mix of microbes that aid in digestion and help the immune system. In a full-term baby, the first bacterial colonies are provided by the mother, but in premature infants the intestine-and its microbial community-hasn't had a chance to fully develop. It isn't prepared to digest formula or breast milk and the bacteria that come with it.

Erika Claud, a neonatologist at the University of Chicago Medicine Comer Children's Hospital, studies NEC, specifically what it is about the immature intestine and its microbiome that predisposes premature infants to the disease. She and her colleagues hope that by understanding the differences between babies who develop NEC and those who don't, their work can lead to an effective way to prevent this devastating condition from developing in the first place.

In 2009, Claud and her colleagues published a study in which they analyzed the DNA of intestinal bacteria from preterm infants with and without NEC. They saw an overall decrease in diversity of bacterial species-an indicator of poor health-in the babies with NEC. The patients were tested near the onset of the disease, so the question at the time was what could be causing this change in diversity.

"We know that it's a completely normal thing for bacteria to encounter the intestine, and that bacteria in and of itself actually has a role in the maturing of the intestine," Claud said. "So the question became, is it really something bad at the time of disease that's making these kids sick? Or is it perhaps something early on, where something beneficial is present in some patients so that they're protected later on?"

In other words timing matters, in both the development of the babies' digestive tract and the onset of disease. In a study published last summer, Claud and her colleagues analyzed weekly fecal samples from five babies who developed NEC and five who did not-including a set of twins, one healthy and one sick-to track how the microbial patterns differed. They found that the bacterial community in babies who later developed NEC began to diverge from the healthy ones three weeks prior to diagnosis, and the majority of the differences were related to how the bacteria help metabolize carbohydrates. These findings suggest a marked difference between babies who get sick and those who don't, but what is causing those changes? And what, if anything, can be done to prevent them?

Antibiotics could be one factor. Premature babies tend to get antibiotics to fight infections early and often, which can drastically alter and damage the bacterial communities in their bodies. Diet could also play a role. Premature babies who receive formula instead of breastfeeding have a higher risk of developing NEC, and miss out on the beneficial hormones and antibodies passed on from their mothers that help shape a healthy bacterial community. Claud said that the key to developing an effective way to prevent NEC is to understand both what a healthy and unhealthy system looks like. Then, doctors could recognize when a child begins to diverge from that healthy path early enough to intervene.

"If we were able to identify a harmful community enough that we could develop a biomarker, we could be testing these babies periodically," she said. "If one of them starts skewing in a particular direction we could introduce an intervention at that time."

She and her colleagues are now working with animal models to further study what goes on with bacteria at the intestinal level. They're looking at what byproducts and chemicals bacteria produce as they interact with each other and the body, and how they shape overall health. This will in turn create a bigger picture that could help all premature infants as they struggle to overcome their early start.

"If we could get a better idea of what a mature intestine looks like, or what health looks like, then that would be beneficial to all babies, whether or not they go on to develop disease," she said. "At some level no preterm infant is completely normal, and there could be something we could do for all these babies to optimize their outcomes."

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Wang Y., Hoenig J.D., Malin K.J., Qamar S., Petrof E.O., Sun J., Antonopoulos D.A., Chang E.B. & Claud E.C. (2009). 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis, The ISME Journal, 3 (8) 944-954. DOI: 10.1038/ismej.2009.37Claud E.C., Keegan K.P., Brulc J.M., Lu L., Bartels D., Glass E., Chang E.B., Meyer F. & Antonopoulos D.A. (2013). Bacterial community structure and functional contributions to emergence of health or necrotizing enterocolitis in preterm infants, Microbiome, 1 (1) 20. DOI: 10.1186/2049-2618-1-20