Circulating microbiome and premature mortality in hemodialysis patients

终末期肾病（ESRD）是一种特征为不成比例的高风险过早死亡的疾病。 心血管（CV）发病率和死亡率，部分原因是低度慢性炎症。努力减少 ESRD中炎症负荷在很大程度上是不成功的。微生物转移到血液中， 在ESRD中通过不同途径发生，包括受污染的透析液、透析导管和受损的肠道 粘膜，并且可以是慢性炎症的潜在原因。虽然细菌内毒素已被广泛 研究了血液中可识别的微生物成分，微生物DNA测序的最新进展 已经允许鉴定体循环中高度多样的微生物群落（a.k.a. 循环微生物组），即使在没有明显感染的情况下。此外，无论是定量还是定性 循环微生物组的变化已被证明与慢性炎症相关的疾病有关。 炎症，如CV疾病，可能通过其免疫刺激性、致动脉粥样硬化性和心脏毒性 特性.这些结果表明，循环微生物组可能导致慢性阻塞性肺病的高发病率。 炎症和ESRD过早死亡。然而，迄今为止还没有任何工作描述了 循环微生物组及其与ESRD临床结局的纵向关系。核心假设 这一建议的一个重要方面是，包括细菌、古细菌和真菌在内的微生物长期存在于 ESRD患者的体循环，并导致慢性炎症的过度风险， 过早死亡本项目的目的是描述ESRD中循环微生物组的特征， 调查它与过早死亡的关系。长期目标是阐明生物学 循环微生物组与ESRD过早死亡之间关系的潜在机制。到 为了验证我们的假设，我们建议对从全国范围内前瞻性纵向收集的血液样本进行分析， 978名流行血液透析（HD）患者的队列，具有以下特定目的：1）确定水平， 通过应用宏基因组测序分析循环微生物组的组成和时间变化 2）检查循环微生物组与全因和CV死亡率的相关性，以及 确定炎症是否作为这种关联的介导者;以及3）识别与炎症相关的临床因素。 与HD患者中死亡相关的循环微生物组， 创新的数据驱动技术，以发现潜在的可修改的风险因素。我们建议的调查结果 这项研究将加深我们对血液透析患者循环微生物组特征和作用的理解 并为未来开发新的诊断和预后生物标志物以及靶向驱动的 降低ESRD死亡率过度风险的治疗策略。

End stage renal disease (ESRD) is a condition characterized by a disproportionately high risk of premature cardiovascular (CV) morbidity and mortality, due in part to low-grade chronic inflammation. Efforts to reduce the inflammatory load in ESRD have been largely unsuccessful. Microbial translocation into the bloodstream can occur via different routes in ESRD, including contaminated dialysate, dialysis catheter, and impaired intestinal mucosa, and can be a potential cause of chronic inflammation. While bacterial endotoxins have been extensively studied among microbial components identifiable in the blood, recent advances in microbial DNA sequencing have allowed the identification of highly diverse microbial communities in the systemic circulation (a.k.a. circulating microbiome), even in the absence of overt infection. In addition, both quantitative and qualitative changes in circulating microbiome have been shown to be associated with conditions linked to chronic inflammation, such as CV disease, potentially through their immunostimulatory, atherogenic, and cardiotoxic properties. These results suggest that the circulating microbiome may contribute to the high rates of chronic inflammation and premature mortality in ESRD. Nevertheless, no work to date has described the nature of the circulating microbiome and its longitudinal relationships with clinical outcomes in ESRD. The central hypothesis of this proposal is that microorganisms including bacteria, archaea and fungi are chronically present in the systemic circulation of patients with ESRD and contribute to the excess risk of chronic inflammation and premature mortality. The objective of this project is to characterize the circulating microbiome in ESRD and to investigate its associations with premature mortality. The long-term goal is to elucidate the biological mechanisms underlying the relationships between circulating microbiome and premature mortality in ESRD. To test our hypothesis, we propose to analyze longitudinally collected blood samples from a nationwide prospective cohort of 978 prevalent hemodialysis (HD) patients, with the following specific aims: 1) Determine the levels, composition, and temporal changes of the circulating microbiome by applying metagenomic sequencing techniques; 2) Examine the association of circulating microbiome with all-cause and CV mortality, and also determine if inflammation acts as a mediator of this association; and 3) Identify clinical factors that are associated with mortality-related circulating microbiome in HD patients by utilizing both traditional regression analyses and innovative data-driven techniques to discover potentially modifiable risk factors. The findings of our proposed study will enhance our understanding of the characteristics and roles of circulating microbiome in HD patients and pave the way for the future development of novel diagnostic and prognostic biomarkers and target-driven therapeutic strategies to reduce excess risk of mortality in ESRD.