Dr. Cuna Receives NIDDK Grant to Study Inflammatory Bowel Disease in NEC

Alain Cuna, MD, Neonatology, was recently awarded a 5-year, $813,196 K08 Clinical Investigator Career Development grant from the National Institute of Diabetes and Digestive and Kidney Diseases (a part of the National Institutes of Health).

Dr. Cuna’s study “Gene-environment interactions in necrotizing enterocolitis: impact of SIGIRR mutation and gut microbiota on intestinal TLR hyperactivity” aims to gain a deeper understanding of the relationship between genetics and gut microbiome as they connect to the deadly inflammatory bowel disease known as necrotizing enterocolitis (NEC) that is found in some preterm infants. The hope is that these findings will help the study team to better understand the way NEC develops and gain insight that can lead to NEC prevention.

As Dr. Cuna explains, NEC is characterized by excessive activation of the Toll-Like Receptor (TLR) family of innate immune receptors. Previous studies suggest there are two major factors that trigger pathologic TLR activation in the intestines: genetics and gut microbiome. Traditionally, those have been studied separately, but this project will look at both.

“Dr. Venkatesh Sampath, my mentor, identified that genetic mutations in Single-Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) occur at a higher rate in infants who developed NEC compared to non-NEC infants, suggesting that SIGIRR may be a candidate gene for NEC, in addition to the many other candidate genes already identified. To further study this, the lab developed mice that mimic the human mutation found in NEC and, sure enough, the SIGIRR mutated mice show increased TLR4 mediated intestinal inflammation at baseline compared to control mice. The mice represent a unique genetic mouse model of NEC based on a mutation identified in human NEC,” Dr. Cuna said.

The other factor thought to be a big contributor in NEC is the gut microbiome as many studies have shown that infants with NEC have microbial imbalance in the gut before NEC occurs.

“How genetics and the gut microbiome interact with each other to cause NEC remains poorly understood. So, in this study we proposed to use our unique genetic mouse model of NEC (the SIGIRR mutant mice) to study this interaction closely. First, we will compare the gut microbiome of SIGIRR mutant mice with the microbiome of regular mice and see if there are differences in their gut microbiome caused by the genetic mutation itself. Then, by manipulating the gut microbiome (with antibiotics, probiotics, and fecal transplant) we will test if the gut microbiome contributes to the differences in intestinal inflammation we see between SIGIRR mutant mice and normal mice,” said Dr. Cuna.

Dr. Cuna plans to use the knowledge gained from this study to investigate personalized, microbial-based therapies that help maintain gut homeostasis. Such novel, individualized therapies are expected to reduce the incidence of NEC in a safe and effective manner by targeting infants at highest risk of the disease.

Co-investigators on the study include mentor Venkatesh Sampath, MBBS, MD, and collaborator Susana Chavez-Bueno, MD.