Mechanisms of L. reuteri in regulating intestinal inflammation

NIH NCCAM RFA-AT-11-001 L.机制罗伊氏调节肠道炎症 PI：Marc Rhoads，MD和Yuying Liu，PhD 摘要 罗伊氏乳杆菌（LR）在几种人类疾病中具有有益效果。坏死性 小肠结肠炎（NEC）是最常见的严重胃肠道疾病， 早产儿我们的初步研究表明，在新生小鼠与实验 NEC认为，LR喂养降低了死亡率和肠道炎症，同时增加了肠道 粘膜调节性T细胞（TCRs），具有抗炎特性的细胞。 具体目标： 1.为了确定LR是否通过以下途径促进致耐受性树突状细胞（DC）的产生： DC上的细菌识别受体（“哨兵细胞”）称为Toll样受体（TLR）。肠道 炎症被认为是通过DC与粘膜辅助性T细胞（Th 1）的相互作用而持续的 和Th 17），并被TdR减少。我们将测量NEC的严重程度，对LR的反应， TLR遗传缺陷小鼠中Tcl 3、Th 1和Th 17效应子的百分比。 2.为了阐明LR条件化的THBE是否会更有效地抑制Th 1/Th 17效应子， 发炎的肠道，我们将从LR喂养的小鼠中过继转移携带同源标记的TlR 小鼠至经历NEC的新生小鼠，以确定外源性THBE是否保护。 3.确定LR是否能够在肠粘膜中诱导THP（iTHP） 当天然T细胞（nTreg）耗尽时，我们将通过抗CD 25抗体耗尽nTreg， 确定LR是否增强iTreg发育并保持能够减少肠道免疫反应。 炎症 这些目的将为罗伊氏乳杆菌调节细胞凋亡的机制提供新的见解。 新生儿肠道炎症结果将有助于选择生物标志物，以遵循 NEC的演变，并比较不同益生菌在人类婴儿中的效力。

NIH NCCAM RFA-AT-11-001 Mechanisms of L. reuteri in regulating intestinal inflammation PI: Marc Rhoads, MD and Yuying Liu, PhD Abstract Lactobacillus reuteri (LR) has beneficial effects in several human diseases. Necrotizing enterocolitis (NEC) is the most common severe gastrointestinal condition affecting 7% of premature infants. Our preliminary studies demonstrated in neonatal mice with experimental NEC that LR feeding reduces mortality and intestinal inflammation, while increasing intestinal mucosal regulatory T cells (Tregs), cells with anti-inflammatory properties. Specific Aims: 1. To determine whether LR facilitates the generation of tolerogenic dendritic cells (DCs) via bacterial recognition receptors on DC ("sentinel cells") called Toll like receptors (TLRs). Gut inflammation is believed to be sustained by DC interaction with mucosal helper T cells (Th1 and Th17) and reduced by Tregs. We will measure NEC severity, response to LR, percentage of Tregs, Th1, and Th17 effectors in mice genetically deficient in TLRs. 2. To elucidate if LR-conditioned Tregs will be more efficient to suppress Th1/Th17 effectors in the inflamed gut, we will adoptively transfer Tregs bearing congenic markers from LR-fed mice to newborn mice undergoing NEC to determine if exogenous Tregs protect. 3. To determine whether LR is capable of inducing Tregs (iTregs) in the intestinal mucosa when natural Tregs (nTreg) are depleted, we will deplete nTregs by anti-CD25 antibody and determine if LR enhances iTreg development and remains capable of reducing intestinal inflammation. These Aims will provide novel insights into mechanisms of Lactobacillus reuteri regulation of neonatal intestinal inflammation. Results will facilitate the selection of biomarkers to follow the evolution of NEC and to compare the potency of different probiotics in the human infant.