Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). Because current therapies remain unsatisfying and often unsuccessful, research on the development of preventive strategies is now a stated priority. The pathogenesis of NEC is poorly understood. A leading hypothesis in the field is that an injury sustained during the neonatal period elicits an exaggerated inflammatory response by the "immature" intestinal epithelial cells of the premature infant. Furthermore, recently, aberrant or excessive apoptosis of the gut epithelia has been recognized as either an initiating or necessary step in the pathogenesis of NEC, and abnormal bacterial colonization of the premature infant intestine may exacerbate the pathological process. Recent laboratory and clinical studies suggest that NEC may be prevented by probiotics, which may normalize bacterial populations within the gut of premature infants and also promote cytoprotective intestinal responses. Probiotic commensal bacteria can affect intestinal epithelial responses through TLR signaling, which can regulate intestinal epithelial host defenses by improving cell survival and by mitigating inflammatory responses to injury. Furthermore, commensal bacteria can also generate low levels of reactive oxygen species (ROS), which activate proliferative signaling and prevent inflammatory signaling in the intestinal epithelial cell by inactivating the specific ubiquitin ligase complex responsible for ?-catenin degradation and NF-?B activation respectively. We hypothesize that probiotics may help in the prevention of NEC not only by normalizing gut flora but also by directly improving host defense through improved cell survival and reduced proinflammatory mediators, via TLR and ROS signal transduction. Our long term goal is to explain how the probiotic commensal bacterium Lactobacillus rhamnosus (LGG) might act to prevent NEC in newborn humans. In this proposal, we aim to explain how the probiotic commensal, LGG reduces apoptosis, promotes proliferation, and inhibits excessive inflammation in the developing intestine of the premature infant using a murine model of immature intestines. Future studies with genetically altered mice will elucidate the importance of TLR and ROS signaling in mediating these protective effects. Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in the neonatal intensive care unit. Recent laboratory and clinical studies suggest that NEC may be prevented by probiotics, which may normalize bacterial populations within the gut of premature infants and also promote cytoprotective intestinal responses. In this proposal, we plan to investigate how the probiotic commensal Lactobacillus rhamnosus reduces apoptosis, promotes proliferation, and inhibits excessive inflammation in the developing intestine of the premature infant utilizing a murine model of immature intestines.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD059122-05
Application #
8392296
Study Section
Special Emphasis Panel (ZHD1-DSR-A (18))
Program Officer
Grave, Gilman D
Project Start
2009-01-05
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$396,921
Indirect Cost
$140,843
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Neumann, Philipp-Alexander; Koch, Stefan; Hilgarth, Roland S et al. (2014) Gut commensal bacteria and regional Wnt gene expression in the proximal versus distal colon. Am J Pathol 184:592-9
Patel, Ravi Mangal; Denning, Patricia Wei (2013) Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence? Clin Perinatol 40:11-25
Patel, Ravi M; Myers, Loren S; Kurundkar, Ashish R et al. (2012) Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am J Pathol 180:626-35
Mirpuri, Julie; Brazil, Jennifer C; Berardinelli, Andrew J et al. (2010) Commensal Escherichia coli reduces epithelial apoptosis through IFN-alphaA-mediated induction of guanylate binding protein-1 in human and murine models of developing intestine. J Immunol 184:7186-95
Lin, Patricia W; Myers, Loren E S; Ray, Laurie et al. (2009) Lactobacillus rhamnosus blocks inflammatory signaling in vivo via reactive oxygen species generation. Free Radic Biol Med 47:1205-11