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.

项目摘要/摘要 全肠外营养(TPN)是一种经肠道静脉输送营养的方法。 不能接受常规肠内营养(EN)的患者。对于30,000多人来说，这是一种至关重要的救命疗法 美国的个人永久依赖TPN。需要TPN的患者数量增加了几倍 持续时间延长。不幸的是，世界范围内使用的这种关键疗法的副作用可能包括 致命性肝脏和肠道损伤可能是由多因素引起的。新兴数据，包括我们K08的结果 资金表明，由于缺乏腔内营养供应，肠道来源的信号受到干扰， 与TPN疗法一起发生的情况会导致这种伤害。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一种新的非卧床TPN仔猪模型，它概括了人类TPN的传递； 我们已经在TPN上发表了动物肠道微生物区系的重大变化。具体地说，我们已经展示了 致炎类杆菌门的显著增加和细菌的减少 TPN动物中的门。我们还注意到关键的肝胆受体和 驱动肠道系统信号传递并导致TPN相关损伤的转运体。最近的数据还 表明继发于微生物转移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，肠道微生物区系的改变可能在TPN中起着重要作用 相关损伤。因此，我们假设TPN动物肠道微生物区系的恢复通过 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。 正如研究计划中所详述的那样；在目标1中，我们将测试严格监测粪便的影响 将对照EN动物移植到TPN组动物，并评估肠道损伤。作为这一目标的一部分，我们 应使用独立于培养的16S核糖体测序来客观地鉴定和量化粪便微生物区系 评估血清肠道损伤标志物、肠道通透性、组织学并进行肠道形态计量学分析。 目的2探讨粪便移植对肝损伤的影响，并对 直觉--系统性的串音。通过改变肝胆受体和转运体，这一目标变得更加合理。 以及细胞因子介导的继发于TPN治疗的微生物移位的损伤。肝损伤血清学 标志物、组织学和关键的肝胆受体、转运体和信号分子驱动肠道- 将对系统性串扰进行评估，以获得机械性的见解。 这项建议是对我们K08工作的补充，可以为深入了解Gut的作用提供重要的见解 TPN相关损伤中的微生物群和帮助制定策略以减少这一生活的并发症 拯救疗法。