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 2-catenin degradation and NF-kB 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.

Public Health Relevance

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 #
1R01HD059122-01
Application #
7530812
Study Section
Special Emphasis Panel (ZHD1-DSR-A (18))
Program Officer
Grave, Gilman D
Project Start
2009-01-05
Project End
2013-11-30
Budget Start
2009-01-05
Budget End
2009-11-30
Support Year
1
Fiscal Year
2009
Total Cost
$348,750
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Kane, Andrea F; Bhatia, Anisha D; Denning, Patricia W et al. (2018) Routine Supplementation of Lactobacillus rhamnosus GG and Risk of Necrotizing Enterocolitis in Very Low Birth Weight Infants. J Pediatr 195:73-79.e2
Reid, Graham K; Berardinelli, Andrew J; Ray, Laurie et al. (2017) Timing of developmental reduction in epithelial glutathione redox potential is associated with increased epithelial proliferation in the immature murine intestine. Pediatr Res 82:362-369
Denning, Timothy L; Bhatia, Amina M; Kane, Andrea F et al. (2017) Pathogenesis of NEC: Role of the innate and adaptive immune response. Semin Perinatol 41:15-28
Halpern, Melissa D; Denning, Patricia W (2015) The role of intestinal epithelial barrier function in the development of NEC. Tissue Barriers 3:e1000707
Patel, Ravi Mangal; Denning, Patricia W (2015) Intestinal microbiota and its relationship with necrotizing enterocolitis. Pediatr Res 78:232-8
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
Jakaitis, Brett M; Denning, Patricia W (2014) Human breast milk and the gastrointestinal innate immune system. Clin Perinatol 41:423-35
Weitkamp, Jörn-Hendrik; Rosen, Michael J; Zhao, Zhiguo et al. (2014) Small intestinal intraepithelial TCR??+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis. PLoS One 9:e99042
Jakaitis, Brett M; Denning, Patricia W (2014) Commensal and probiotic bacteria may prevent NEC by maturing intestinal host defenses. Pathophysiology 21:47-54
Denning, Patricia Wei; Maheshwari, Akhil (2013) Necrotizing enterocolitis: hope on the horizon. Clin Perinatol 40:xvii-xix

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