Researchers at Yale School of Medicine, University of Pittsburgh Medical Center Montefiore Hospital, Schneider Children's Medical Center of Israel, and the Weizmann Institute of Science, have, for the first time, created a map of the neonatal small intestine, demonstrating at the single-cell level that inflammation is present in all layers – including the epithelial, endothelial, fibroblasts, and immune cells – in babies with necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal complication of prematurity with degree of prematurity being the number one risk factor for NEC. Of severely premature infants, about 10% of them will end up with NEC and a significant proportion of those that survive the disease will have lifelong sequala. Consumption of breast milk has been shown to reduce the risk for NEC, nevertheless infants on exclusive breast milk diets can still develop the disease. However, experts don’t yet know what other significant risk factors may be, lack ways to screen for it, and have limited options for treatment.
The research team was able to develop a single cell atlas of neonatal intestine not affected by NEC, which is important to help them understand how development happens, particularly early in life, and compare it to that affected by NEC. Using these samples, cellular transcriptional signatures and imaging modalities can help determine what drives this type of disease and better understand what future targeted therapies may be.
Liza Konnikova, MD, PhD, assistant professor of pediatrics at Yale, described creating these cellular atlases as, “Something that systems biologists use to identify what cell types are present in a tissue, their phenotypes, and where they’re located. We used single-cell RNA sequencing to define what cells are there and what states they are in, and we coupled this to various imaging techniques to find out where these cells are located and how they communicated with one another.”
A challenge in this type of research is the difficulty in obtaining intestinal tissue samples to study. Adults over 45 are more likely to get colonoscopies and have biopsies performed, so obtaining tissue is easier. Children largely only get colonoscopies if they have or are being screened for a specific disease. Neonates don’t get colonoscopies because they are too small. Non-NEC neonatal intestinal tissue can only be accessed if an infant is undergoing a rare surgery, most commonly performed for an underdeveloped intestine. This is, in part, why research in this area has lagged – not only because of the expertise required for the single-cell analysis, but also because of how long it takes to collect the samples that are to be studied. This study alone took over 6 years to complete.
Looking ahead, the goal is to work toward finding more precise therapies for babies with NEC.
Authors on the article include, Adi Egozi, Oluwabunmi Olaloye, Lael Werner, Tatiana Silva, Blake McCourt, Richard W. Pierce, Xiaojing An, Fujing Wang, Kong Chen, Jordan S. Pober, Dror Shouval, Shalev Itzkovitz, and Liza Konnikova. You can read the full article in PLOS Biology here.