Gut Microbiota and Atherosclerosis in ESRD

描述（由申请人提供）：在维持性血液透析（MHD）患者中，持续性炎症是动脉粥样硬化加速和蛋白质能量浪费增加的基础。然而，MHD患者的非诱发性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。富含低聚果糖的益生元菊粉（p-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）在组织水平上阻止内毒素血症反应中细胞因子的产生，因此补充了对菊粉的作用。在一项二乘二因子临床试验中，我们将随机分配120名MHD患者，每天接受-菊粉/PTX/安慰剂治疗12个月。首先，我们将证明招募随机化的可行性，并保留研究参与者，以记录至少90%参与者的终点。其次，我们将确定对菊粉和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）光谱技术确定动脉粥样硬化的进展/消退；(b)肌肉量和内脏脂肪量的变化将通过大腿和腹部的磁共振成像检查；(c)将根据国际肾脏营养和代谢学会的标准确定蛋白质能量浪费的存在和严重程度的变化。这项试点研究将证明这一概念，确定可行性，并产生初步数据，以证明开展全面临床试验的合理性。

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.