Necrotizing enterocolitis (NEC) is an acquired, life-threatening gastrointestinal disease affecting 5-15% of neonates born weighing less than 1500 g and is a leading cause of death in these patients. The disease is characterized by an intense inflammatory response, ischemic changes, and necrosis. Although the etiopathogenesis of NEC is not well understood, the disease is believed to occur when mucosal injury or altered permeability allows bacterial translocation into the lamina propria, causing leukocyte recruitment and tissue destruction. This model of unrestricted acute inflammation due to bacteria/bacterial products is inconsistent with recent observations that in the adult, intestinal cells such as macrophages are profoundly `anergic'to bacterial products due to the effect of stromal cell-derived factors such as transforming growth factor (TGF)-2. The investigators present preliminary data and propose a novel hypothesis that NEC is seen almost exclusively in the premature infant because mucosal tolerance to bacterial products, which is due to the effects of TGF-2, is developmentally regulated and therefore deficient in the preterm intestine, and that augmentation of TGF-2 expression or bioactivity can prevent/ameliorate NEC-like intestinal injury. This application is designed to investigate strategies to augment TGF-2 activity in the developing intestine in order to enhance mucosal tolerance to bacterial products. There are three specific aims: 1) to determine whether specific patterns of bacterial colonization of the neonatal intestinal mucosa affect the normal developmental downregulation of inflammatory pathways in the intestinal mucosa or influence susceptibility to NEC-like intestinal injury;2) to determine the role of milk-borne TGF-22 in protection against NEC-like intestinal injury, and whether enteral supplementation of TGF-22 in the neonate can provide additional protection against NEC-like intestinal injury;and 3) to determine whether pharmacological upregulation of TGF-22 expression or activation in the developing intestine can protect against NEC-like intestinal injury. The long-term goals of this project are to identify newer preventive/therapeutic strategies against NEC that can be tested in future clinical studies.

Public Health Relevance

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely premature infants. In this application, the investigators present a novel hypothesis that NEC occurs almost exclusively in premature infants because normal tolerance to gut bacteria is not yet established in these infants and propose three different strategies to correct this deficiency, which can, in turn, help prevent or treat NEC.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-A (18))
Program Officer
Grave, Gilman D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
Jain, Sunil K; Baggerman, Eric W; Mohankumar, Krishnan et al. (2014) Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 306:G361-9
Remon, J; Kampanatkosol, R; Kaul, R R et al. (2014) Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance. J Perinatol 34:549-54
Kampanatkosol, Richard; Thomson, Tricia; Habeeb, Omar et al. (2014) The relationship between reticulated platelets, intestinal alkaline phosphatase, and necrotizing enterocolitis. J Pediatr Surg 49:273-6
Maheshwari, Akhil (2014) Neutropenia in the newborn. Curr Opin Hematol 21:43-9
Frost, Brandy L; Jilling, Tamas; Lapin, Brittany et al. (2014) Maternal breast milk transforming growth factor-beta and feeding intolerance in preterm infants. Pediatr Res 76:386-93
MohanKumar, Krishnan; Killingsworth, Cheryl R; McIlwain, R Britt et al. (2014) Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet. Lab Invest 94:150-60
Maheshwari, Akhil; Schelonka, Robert L; Dimmitt, Reed A et al. (2014) Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants. Pediatr Res 76:100-8
Namachivayam, Kopperuncholan; Blanco, Cynthia L; MohanKumar, Krishnan et al. (2013) Smad7 inhibits autocrine expression of TGF-*2 in intestinal epithelial cells in baboon necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 304:G167-80
Namachivayam, Kopperuncholan; Blanco, Cynthia L; Frost, Brandy L et al. (2013) Preterm human milk contains a large pool of latent TGF-*, which can be activated by exogenous neuraminidase. Am J Physiol Gastrointest Liver Physiol 304:G1055-65
Amin, Sachin C; Pappas, Cleo; Iyengar, Hari et al. (2013) Short bowel syndrome in the NICU. Clin Perinatol 40:53-68

Showing the most recent 10 out of 23 publications