Role of gut microbiota in total parenteral nutrition associated injury

项目概要/摘要 全肠外营养（TPN）是一种绕过肠道的静脉营养输送方法， 不能接受常规肠内营养（EN）的患者。这是一种重要的拯救生命的疗法， 在美国永久依赖TPN的个人。需要TPN的患者数量是其他患者的数倍， 持续时间延长。不幸的是，这种在世界范围内使用的关键疗法的副作用可能包括： 可能是多因素病因导致的致命性肝和肠损伤。新兴数据，包括K 08的结果 资金表明，响应于管腔营养输送的缺乏的肠源性信号的中断， 因为TPN治疗会导致这种损伤。我们的实验室一直在研究这种信号的作用。 使用我们实验室开发的新型非卧床TPN仔猪模型，该模型重现了人类TPN输送; 我们已经发表了TPN对动物肠道微生物群的显著改变。具体来说，我们已经表明， 促炎拟杆菌门显著增加，厚壁菌门减少 TPN动物中的门。我们还注意到关键肝胆受体的显著变化， 这些转运蛋白驱动肠道-全身信号传导并导致TPN相关损伤。最近的数据也 表明继发于微生物变化的炎性细胞因子的改变可导致这种损伤。 因此，我们认为，在TPN过程中，肠道菌群的改变可能在TPN中起着重要作用。 相关伤害。因此，我们假设通过以下方法恢复TPN动物中改变的肠道微生物群： 来自对照EN动物的粪便微生物群的转移将减轻TPN相关的损伤。 如研究计划所述，目标1将测试严格监测粪便的影响。 从对照EN动物移植到TPN动物并评估肠道损伤。作为这一目标的一部分，我们 应使用不依赖培养的16 S核糖体测序客观地识别和量化粪便微生物群 并评估血清学肠道损伤标志物、肠道通透性、组织学和进行肠道形态测定分析。 目的2涉及探索粪便移植对肝损伤的影响， 肠道系统串扰这一目的是合理的改变肝胆受体和转运 以及TPN治疗中继发于微生物变化的细胞因子介导的损伤。肝损伤血清学 标志物、组织学和关键肝胆受体、转运蛋白和驱动肠道的信号分子- 系统串扰将被评估以获得机械的见解。 该提案补充了我们的K 08工作，并可以为肠道的作用提供重要的见解。 微生物群在TPN相关损伤中的作用，并帮助制定减轻这种生活并发症的策略 拯救治疗

PROJECT SUMMARY / ABSTRACT Total Parenteral nutrition (TPN) is the method of intravenous nutrition delivery bypassing the gut in patients unable to receive regular enteral nutrition (EN). It is a crucial lifesaving therapy for over 30,000 individuals in the US permanently dependent on TPN. Several fold higher number of patients require TPN for a prolonged duration. Unfortunately, side effects of this critical therapy used world-wide include potentially fatal liver and gut injury from a likely multifactorial etiology. Emerging data, including results from our K08 funding suggests that a disruption of gut-derived signals in response to a lack of luminal nutrient delivery, as occurring with TPN therapy drives such injury. Our lab has been investigating the role of such signaling. Using a novel ambulatory TPN piglet model, developed at our lab which recapitulates human TPN delivery; we have published significant alterations in the gut microbiota of animals on TPN. Specifically we have shown a significant increase in the pro-inflammatory Bacteroidetes phylum and a decrease in the Firmicutes phylum in TPN animals. We have also noted significant alterations in key hepatobiliary receptors and transporters that drive gut-systemic signaling and contribute to TPN associated injury. Recent data also suggests that alteration in inflammatory cytokines secondary to microbial shifts can lead to such injury. Therefore we believe that the altered gut microbiota, during TPN, may have a prominent role in TPN associated injury. We thus hypothesize that a restoration of the altered gut microbiota in TPN animals by a transfer of fecal microbiota from control EN animals will mitigate TPN-associated injury. As detailed in the research plan; with Aim 1 we will test the impact of rigorously monitored fecal transplantation from control EN animals to those on TPN and evaluate gut injury. As part of this aim, we shall objectively identify and quantify stool microbiota using culture independent 16S ribosomal sequencing and assess serological gut injury markers, gut permeability, histology and perform gut morphometric analysis. Aim 2 relates to exploring the impact of fecal transplantation on hepatic injury and critically testing the gut-systemic cross talk. This aim is rationalized by an alteration of hepatobiliary receptors and transporters as well as cytokine mediated injury secondary to microbial shifts with TPN therapy. Liver injury serological markers, histology and key hepatobiliary receptors, transporters and signaling molecules driving the gut- systemic cross talk will be assessed to gain mechanistic insights. This proposal complements our K08 work and could provide important insights into the role of gut microbiota in TPN associated injury and help develop strategies to mitigate complication of this life saving therapy.