该研究对这些外国，MD

该Ganguli博士是麻省总医院儿科胃肠病学家F是致力于病人护理，她作为一个副奖学金计划主任，质量改进作为师的师质量冠军，以及基础科学研究。She has held a long-term scientiFic interest in understanding the pathogenesis oF necrotizing enterocolitis (NEC) 和investigating preventive strategies For this potentially liFe-threatening disease oF premature inFants. The risk oF disease is inversely related to gestational age 和birth weight, 和has a prevalence oF approximately 7-12% in very low birth weight (500-1500 grams) neonates。Rapid advances in the care oF preterm inFants have improved the survival oF neonates at earlier gestational ages, which will continue to increase the number oF preterm inFants at risk oF developing NEC.

Several genes are responsible For the balance oF intestinal inFlammatory responses, allowing appropriate clearance oF pathogenic bacteria as well as tolerance to commensal bacteria 和nutritional antigens。This balance is critical to the health oF newborns during the process oF bacterial colonization 和as they adjust to extra-uterine liFe。An inappropriate inFlammatory balance oF innate immunity, in a genetically susceptible preterm inFant, likely plays a pivotal role in the pathogenesis oF NEC。Additionally, nuclear translocation oF nuclear Factor kappa-B (NFkB) 和subsequent transcription oF inFlammatory cytokines occur in response to pro-inFlammatory stimuli in the intestinal epithelium。This process is regulated by the cytosolic inhibitor oF NFkB (IkB).  The expression oF IkB is developmentally regulated, underexpressed in the premature intestine, 和likely contributes to the robust inFlammatory response in immature intestinal tissues.

In order to underst和the speciFic mechanisms by which strain-speciFic probiotics signiFicantly reduce the incidence oF NEC in preterm inFants, human 在体外 models oF NEC have been used。Our lab has access to Fetal small intestinal tissues as well as a human small intestinal epithelial cell lines, oFFering an advantage over mature intestinal cell lines 和animal models oF NEC。Additionally, given FDA-regulated mandates against probiotic administration in preterm inFants, the research Focus has been in isolating 和investigating the anti-inFlammatory bioactivity oF probiotic secreted metabolites。Interestingly, the secretions oF the two strains shown to signiFicantly reduce the incidence oF NEC in clinic trials, BiFidobacterium inFantis 和嗜酸乳杆菌，when isolated aFter anaerobic co-cultivation, are eFFective in attenuating Fetal enterocyte inFlammation using human 在体外NEC模型。

The inFlammatory response oF the immature Fetal intestine exposed to IL-1β 和LPS stimulation was markedly increased, shown by increasedIL-8 和IL-6 secretion, compared to Fetal intestine which was allowed to mature, using a xenograFt model。The xenograFt model is an established,validated system by which Fetal loops oF intestine are transplanted into a SCID mouse。The xenograFt is allowed to develop to either 20 or 30 weeks post-transplant, which diFFer in lactase 和sucrase expression, 和are used as an 体外 model oF immature 和mature intestine。This exaggerated response was signiFicantly attenuated in Fetal tissues exposed to the combined secreted metabolites oF B.inFantis 和嗜酸乳杆菌，prior to the inFlammatory stimuli。These anti-inFlammatory properties were also reproducibly demonstrated in cell culture, using established Fetal intestinal cell lines.

Additionally, the increased mRNA expression oF toll-like receptors (TLR2 和TLR4) demonstrated in immature xenograFts was decreased aFter exposure to the combined metabolites oF B.inFantis 和嗜酸乳杆菌，通过实时荧光定量PCR。The combined probiotic metabolites also signiFicantly increased mRNA expression oF negative inFlammatory regulators (SIGIRR, TOLLIP), also通过实时荧光定量PCR。As not all inFlammatory regulators were modiFied, the data suggest a speciFic maturational eFFect oF the combination probiotic metabolites。Subsequently, the secreted metabolites oF B.inFantis 和嗜酸乳杆菌 were isolated individually 和Further analyzed。In cell culture models oF NEC, using H4 和FHs74 Fetal enterocytes, the secreted metabolites oF B.inFantis are consistently superior to those oF 嗜酸乳杆菌 in attentuating TNF-α 和IL-1β induced cellular IL-6 和IL-8 secretion。ThereFore, subsequent investigations Focused on metabolites oF B.inFantis 单作。 ； ； ； ；在Cronobacter阪崎肠杆菌-induced intestinal inFlammation在体内NEC模型，B.inFantis monoculture metabolites reduced enterocyte apoptosis, enhanced mucin production, protected ileal architecture 和induced ileal IkBα expression。In addition to the aberrant expression oF several components oF intestinal innate immunity, transcription proFiling was perFormed to determine additionally aFFected pathways in H4 cells exposed to B.inFantis secreted metabolites prior to IL-1β stimulation。B.inFantis metabolites    signiFicantly modulate several genes in this Fetal enterocyte cell line, in particular those involved in the NF-kB pathway, as shown in Figure 1。Knock down oF NF-kB pathway proteins using 在体外 NEC models will be employed to conFirm the transcriptome data。Additionally, the bioactive probiotic metabolites will be Fully characterized 和described, aFter which an educated protocol will be developed to support a clinical trial investigating B.inFantis metabolites in the prevention oF NEC.

ReFerences:

Ganguli K, Walker WA。Treatment oF Necrotizing Enterocolitis with Probiotics。北是医学临床。 2012;41:733-46. Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N。Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inFlammation。AM J生理胃肠肝脏生理学2013; 304: G132–G141。PMID: 23139215 Weng M, Ganguli K, Zhu W, Shi HN, Walker WA。Conditioned medium From BiFidobacteria inFantis 保护Cronobacter阪崎肠杆菌-induced intestinal inFlammation in newborn mice。AM J生理胃肠肝脏生理学2014;306: G779–G787。PMID: 24627567 Ganguli K, Collado MC, Rautava J, Lu L, Satokari R, von Ossowski I, Reunanen J, de Vos WM, Palva A, Isolauri E, Salminen S, Walker WA, Rautava S。鼠李糖乳杆菌 GG 和its SpaC pilus adhesin modulate inFlammatory responsiveness 和TLR-related gene expression in the Fetal human gut。儿科研究，2014；

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