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)
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Study Section
Special Emphasis Panel (ZHD1-DSR-A (18))
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Grave, Gilman D
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University of Illinois at Chicago
Schools of Medicine
United States
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Namachivayam, Kopperuncholan; MohanKumar, Krishnan; Garg, Lalit et al. (2017) Neonatal mice with necrotizing enterocolitis-like injury develop thrombocytopenia despite increased megakaryopoiesis. Pediatr Res 81:817-824
MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Cheng, Feng et al. (2017) Trinitrobenzene sulfonic acid-induced intestinal injury in neonatal mice activates transcriptional networks similar to those seen in human necrotizing enterocolitis. Pediatr Res 81:99-112
MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Ho, Thao T B et al. (2017) Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis. Semin Perinatol 41:52-60
MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Chapalamadugu, Kalyan C et al. (2016) Smad7 interrupts TGF-? signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis. Pediatr Res 79:951-61
Namachivayam, Kopperuncholan; Coffing, Hayley P; Sankaranarayanan, Nehru Viji et al. (2015) Transforming growth factor-?2 is sequestered in preterm human milk by chondroitin sulfate proteoglycans. Am J Physiol Gastrointest Liver Physiol 309:G171-80
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Ma, Irene T; McConaghy, Suzanne; Namachivayam, Kopperuncholan et al. (2015) VEGF mRNA and protein concentrations in the developing human eye. Pediatr Res 77:500-5
Ho, T T B; Groer, M W; Luciano, A A et al. (2015) Red blood cell transfusions increase fecal calprotectin levels in premature infants. J Perinatol 35:837-41
Maheshwari, Akhil (2015) Immunologic and Hematological Abnormalities in Necrotizing Enterocolitis. Clin Perinatol 42:567-85
Namachivayam, Kopperuncholan; MohanKumar, Krishnan; Arbach, Dima et al. (2015) All-Trans Retinoic Acid Induces TGF-?2 in Intestinal Epithelial Cells via RhoA- and p38? MAPK-Mediated Activation of the Transcription Factor ATF2. PLoS One 10:e0134003

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