Gut Microbiota and Atherosclerosis in ESRD

ESRD 中的肠道微生物群和动脉粥样硬化

基本信息

批准号：
8586103
负责人：
Dominic S Raj
金额：
$ 38.5万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586103
关键词：
Abdomen Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Atrophic Attenuated Bacteria Body Composition Cardiac Cardiovascular Diseases Caring Chronic Kidney Failure Clinical Clinical Trials Colon Complement Data Dietary Fiber Dietary Practices Disease End stage renal failure Endotoxemia Endotoxins Equilibrium Etiology Fatty acid glycerol esters Food Generations Growth Healthcare Heart Diseases Hemodialysis Human Imaging Techniques Inflammation Inflammatory Inflammatory Response Insulin Resistance Intake International Intervention Studies Intestines Inulin Kidney Knowledge Link Lipids Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maintenance Metabolic Metabolism Muscle Muscle Proteins Nutritional Obesity Outcome Study Participant Patients Pentoxifylline Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phosphodiesterase Inhibitors Pilot Projects Placebos Plasma Prevalence Proteins Randomized Recovery Recruitment Activity Reporting Research Design Research Personnel Resources Risk Risk Factors Safety Severities Skeletal Muscle Societies Source Symbiosis Techniques Thigh structure Time Tissues Toxin Visceral atherogenesis catalyst cytokine follow-up gut microbiota improved inflammatory marker microbial mortality muscle form novel nutrition prebiotics public health relevance response restoration treatment effect wasting

项目摘要

DESCRIPTION (provided by applicant): Persistent inflammation underpins the accelerated atherosclerosis and increased prevalence of protein-energy wasting in maintenance hemodialysis (MHD) patients. However, the etiology of unprovoked inflammation in MHD patients remains unresolved. The human gut harbors 1014 bacteria, and gut microbial imbalance has been linked to inflammation, insulin resistance and atheroscleroisis. Prebiotic oligofructose enriched inulin (p-inulin) has been shown to restore gut microbial balance, thereby reducing endotoxin generation and inflammation. Pentoxifylline (PTX) blocks cytokine generation in response to endotoxemia at the tissue level, and hence complements the actions of p-inulin. In a two-by-two factorial clinical trial, we will randomize 120 MHD patients to receiv p-inulin/PTX/placebo daily for 12 months. First, we will demonstrate the feasibility of recruitment randomization, and retention of study participants in order to record endpoints in at least 90% of participants. Secondly, we will establish the safety and efficacy of p-inulin and PTX in reducing systemic inflammation. Finally, we propose to evaluate the effect of study intervention on selected exploratory clinical end-points: (a) Progression/regression of atherosclerosis will be determined using phase-sensitive dual inversion recovery magnetic resonance (MR) spectroscopy technique; (b) Alterations in muscle mass and visceral fat mass will be examined by MR imaging of thigh and abdomen; and (c) Changes in presence and severity of protein-energy wasting will be determined according to the International Society of Renal Nutrition and Metabolism criteria. This pilot study will prove the concept, establish feasibility and generate preliminary data to justify the launching of a full-clinical trial.

描述（由申请人提供）：持续性炎症是维持性血液透析（MHD）患者动脉粥样硬化加速和蛋白质能量浪费患病率增加的基础。然而，MHD 患者无端炎症的病因仍未解决。人类肠道内有 1014 种细菌，肠道微生物失衡与炎症、胰岛素抵抗和动脉粥样硬化有关。富含益生元低聚果糖的菊粉（β-菊粉）已被证明可以恢复肠道微生物平衡，从而减少内毒素的产生和炎症。己酮可可碱 (PTX) 可在组织水平上阻断内毒素血症引起的细胞因子生成，从而补充 p-菊粉的作用。在一项 2×2 析因临床试验中，我们将随机 120 名 MHD 患者每天接受 p-菊糖/PTX/安慰剂治疗，持续 12 个月。首先，我们将证明招募随机化和保留研究参与者的可行性，以便记录至少 90% 的参与者的终点。其次，我们将确定 p-菊粉和 PTX 在减少全身炎症方面的安全性和有效性。最后，我们建议评估研究干预对选定的探索性临床终点的影响：（a）将使用相敏双反转恢复磁共振（MR）波谱技术确定动脉粥样硬化的进展/消退； (b) 通过大腿和腹部的磁共振成像检查肌肉量和内脏脂肪量的变化； (c) 蛋白质-能量浪费的存在及其严重程度的变化将根据国际肾脏营养和代谢学会的标准来确定。该试点研究将证明这一概念，建立可行性并生成初步数据，以证明启动全临床试验的合理性。