Gut Microbiota and Atherosclerosis in ESRD

描述(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消耗增加的基础。然而，MHD患者无缘性炎症的病因仍未解决。人类肠道中含有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。益生素低聚果糖强化菊粉(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)在组织水平阻断细胞因子的产生，从而补充p-菊糖的作用。在一项二乘二析因临床试验中，我们将随机选择120名MHD患者，在12个月内每天服用p-菊粉/PTX/安慰剂。首先，我们将论证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在减轻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)动脉粥样硬化的进展/消退将使用相敏的双反转恢复磁共振(MR)波谱技术来确定；(B)肌肉质量和内脏脂肪质量的变化将通过大腿和腹部的MR成像来检查；以及(C)蛋白质能量消耗的存在和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。这项先导性研究将证明这一概念，确定可行性，并产生初步数据，以证明启动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.