Role of gut microbiota in total parenteral nutrition associated injury

肠道微生物群在全肠外营养相关损伤中的作用

• 批准号: 9910396
• 负责人: Ajay K. Jain
• 金额: $ 11.36万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-08 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910396
• 关键词: Adult; Aliquot; Animal Model; Animal Nutrition; Animals; Atrophic; Automobile Driving; Award; Bacteroidetes; Biliary; Bypass; Carbohydrates; Catheters; Childhood; Cholestasis; Complement; Complication; Data; Duodenum; Dyslipidemias; Enteral; Enteral Feeding; Enteral Nutrition; Etiology; Fatty acid glycerol esters; Feces; Fibrosis; Firmicutes; Food; Fruit; Funding; Future; Glucose Intolerance; Grant; Gut Mucosa; Harvest; Hepatic; Hepatobiliary; Histology; Human; Impairment; Individual; Inflammation; Inflammatory; Injury; Intestinal permeability; Intravenous; Knowledge; Lead; Life; Link; Liver; Liver diseases; Mediating; Methods; Micronutrients; Minerals; Modality; Modeling; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Nutrient; Nutrition Therapy; Nutritional; Operative Surgical Procedures; Parenteral Nutrition; Pathway interactions; Patients; Play; Positioning Attribute; Process; Proteins; Publishing; Research; Ribosomes; Role; Savings; Schedule; Secondary to; Serological; Signal Transduction; Signaling Molecule; Study models; Testing; Total Parenteral Nutrition; United States; United States National Institutes of Health; Vitamins; Work; cytokine; deprivation; experimental study; fecal microbiota; fecal transplantation; gut microbiome; gut microbiota; insight; liver injury; microbial; microbiota; novel; novel strategies; novel therapeutic intervention; nutrition; prevent; receptor; response; restoration; serological marker; side effect

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.

项目概要/摘要 全肠外营养（TPN）是绕过肠道进行静脉营养输送的方法 无法接受常规肠内营养（EN）的患者。对于 30,000 多人来说，这是一种至关重要的救生疗法 美国境内永久依赖 TPN 的个人。需要 TPN 治疗的患者数量增加了几倍 持续时间长。不幸的是，这种在世界范围内使用的关键疗法的副作用包括潜在的 可能由多因素病因造成的致命性肝脏和肠道损伤。新兴数据，包括我们 K08 的结果 资金表明，肠道来源的信号因缺乏管腔营养输送而受到破坏， TPN 治疗中发生的情况会导致此类损伤。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动态 TPN 仔猪模型，该模型重现了人类 TPN 输送； 我们在 TPN 上发表了动物肠道微生物群的显着变化。具体来说我们已经展示了 促炎拟杆菌门显着增加，厚壁菌门减少 TPN 动物中的门。我们还注意到关键肝胆受体和 驱动肠道系统信号传导并导致 TPN 相关损伤的转运蛋白。近期数据还 表明继发于微生物变化的炎症细胞因子的改变可能导致这种损伤。 因此，我们认为 TPN 期间肠道微生物群的改变可能在 TPN 中发挥重要作用 相关伤害。因此，我们假设 TPN 动物中改变的肠道微生物群的恢复是通过 从对照 EN 动物转移粪便微生物群将减轻 TPN 相关损伤。 如研究计划中详细说明；在目标 1 中，我们将测试严格监测的粪便的影响 将对照 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 应使用独立于培养物的 16S 核糖体测序客观地识别和量化粪便微生物群 评估血清学肠道损伤标志物、肠道通透性、组织学并进行肠道形态分析。 目标 2 涉及探索粪便移植对肝损伤的影响并严格测试 肠道系统串扰。通过肝胆受体和转运蛋白的改变使这一目标合理化 以及 TPN 治疗引起的微生物变化继发的细胞因子介导的损伤。肝损伤血清学 驱动肠道的标记物、组织学和关键肝胆受体、转运蛋白和信号分子 将评估系统性串扰以获得机制见解。 该提案补充了我们的 K08 工作，可以为肠道的作用提供重要的见解 TPN 相关损伤中的微生物群，并帮助制定减轻这种生活并发症的策略 挽救疗法。