Necrotizing enterocolitis (NEC) is a life-threatening inflammatory bowel disorder of unknown cause that affects approximately 10% of premature infants born <1500gm. Prematurity is the greatest risk factor rather than any particular insult, suggesting that intestinal immaturity is a fundamental issue. However, the exact aspects of immaturity contributing to NEC are poorly understood. I have found that a key point of developmental difference between immature and mature intestinal epithelial cells (IEC) is regulation of nuclear factor kappaB. In response to RFA-HD-07-08 """"""""New Approaches for the prevention and treatment of necrotizing enterocolitis,"""""""" I propose to test the hypothesis that an intrinsic immaturity of intestinal epithelial cell NF-kB regulation leads to an exaggerated inflammatory response predisposing the preterm infant to NEC. Furthermore I hypothesize that soluble factors secreted by probiotic bacteria can modulate NF-kB regulation and preserve intestinal barrier function, thus decreasing inflammation and protecting against NEC. Preliminary data for this proposal demonstrate that compared to mature IEC, immature IEC have differences in regulation of both inhibitory kappaB alpha and A20 - key NF-kB down-regulatory proteins. Furthermore, our preliminary data demonstrate that secreted products from probiotic bacteria can decrease NF-kB activity and protect against NEC in an animal model. Probiotics are bacteria which have beneficial health effects beyond their inherent nutritive value. Recent clinical trials suggest that probiotics may confer some protection against NEC. This proposal is designed to 1. Assess possible mechanisms behind deficient down-regulation of NF-kB signaling via IkBa and A20 in immature IEC. 2. Determine the ability of secreted bacterial products from the probiotic organisms Lactobacillus plantarum, Lactobacillus acidophilus, and Bifidobacterium infantis to protect against necrotizing enterocolitis in an animal model without the introduction of live organisms. The experimental design uses two models of immature IEC - IEC isolated from pre-weaned mice and the human fetal small intestinal cell line H4. Both conventional and germ-free mice will be used. To model disease, the well established Caplan rat model of NEC will be used. This proposal will yield important information regarding aspects of intestinal immaturity which contribute to NEC and which are relevant to understanding the effect of any proposed treatment. Furthermore understanding the potential role of microbe free probiotic conditioned media may allow a means to administer the beneficial effects of probiotics without the risk of live organisms, thus providing a novel approach to treating or preventing NEC in at risk infants.
Necrotizing Enterocolitis is a poorly understood, life threatening inflammatory bowel disease of premature infants. Although 20-30% of patients die and survivors are at risk for significant intestinal and neurodevelopmental consequences, there is no known specific treatment. This proposal will investigate what aspects of intestinal immaturity contribute to this disease and determine if factors secreted by certain beneficial or probiotic bacteria can influence these aspects, thus decreasing the susceptibility of vulnerable infants to necrotizing enterocolitis.
|Cortese, Rene; Lu, Lei; Yu, Yueyue et al. (2016) Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 11:205-15|
|Mustafi, Devkumar; Shiou, Sheng-Ru; Fan, Xiaobing et al. (2014) MRI of neonatal necrotizing enterocolitis in a rodent model. NMR Biomed 27:272-9|
|Claud, Erika C; McDonald, Julie A K; He, Shu-Mei et al. (2014) Differential expression of 26S proteasome subunits and functional activity during neonatal development. Biomolecules 4:812-26|
|Yu, Yueyue; Shiou, Sheng-Ru; Guo, Yuee et al. (2013) Erythropoietin protects epithelial cells from excessive autophagy and apoptosis in experimental neonatal necrotizing enterocolitis. PLoS One 8:e69620|
|Shiou, Sheng-Ru; Yu, Yueyue; Guo, Yuee et al. (2013) Synergistic protection of combined probiotic conditioned media against neonatal necrotizing enterocolitis-like intestinal injury. PLoS One 8:e65108|
|Musch, Mark W; Wang, Yunwei; Claud, Erika C et al. (2013) Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig Dis Sci 58:668-77|
|Shiou, Sheng-Ru; Yu, Yueyue; Guo, Yuee et al. (2013) Oral administration of transforming growth factor-?1 (TGF-?1) protects the immature gut from injury via Smad protein-dependent suppression of epithelial nuclear factor ?B (NF-?B) signaling and proinflammatory cytokine production. J Biol Chem 288:34757-66|
|Shiou, Sheng-Ru; Yu, Yueyue; Chen, Sangzi et al. (2011) Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis. J Biol Chem 286:12123-32|
|Claud, Erika C (2011) Probiotics and neonatal necrotizing enterocolitis. Anaerobe 17:180-5|
|Liedel, Jennifer L; Guo, Yuee; Yu, Yueyue et al. (2011) Mother's milk-induced Hsp70 expression preserves intestinal epithelial barrier function in an immature rat pup model. Pediatr Res 69:395-400|
Showing the most recent 10 out of 13 publications