Circulating microbiome and premature mortality in hemodialysis patients

终末期肾病(ESRD)是一种以早产风险不成比例地高为特征的疾病。 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的炎性负荷在很大程度上并不成功。微生物移位到血液中可以 ESRD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，并可能是慢性炎症的潜在原因。虽然细菌内毒素已经被广泛地 研究血液中可识别的微生物成分，微生物DNA测序的最新进展 使得能够识别体循环中高度多样化的微生物群落(又名。 循环微生物群)，即使在没有明显感染的情况下。此外，无论是数量上还是质量上 循环微生物群的变化已被证明与慢性疾病有关 炎症，如心血管疾病，可能通过其免疫刺激、致动脉粥样硬化和心脏毒性 属性。这些结果表明，循环中的微生物群可能与慢性病的高发病率有关。 终末期肾病的炎症和过早死亡。然而，到目前为止，还没有任何作品描述了 终末期肾病患者循环微生物群及其与临床结局的纵向关系。中心假说 包括细菌、古生菌和真菌在内的微生物长期存在于 终末期肾病患者的体循环，并导致慢性炎症和 过早死亡。本项目的目标是描述ESRD中循环微生物群的特征，并 调查其与过早死亡的关系。长期的目标是阐明生物学上的 ESRD患者循环微生物群与过早死亡之间关系的机制。至 为了验证我们的假设，我们建议对全国范围内纵向采集的血液样本进行分析 对978例普遍存在的血液透析(HD)患者进行队列调查，其具体目的如下：1)测定血药浓度， 应用元基因组测序技术研究循环微生物组的组成和时间变化 技术；2)检查循环微生物群与全原因和心血管疾病死亡率的关系，以及 确定炎症是否作为这种关联的中介；以及3)确定与此关联的临床因素 应用传统回归分析与血液透析患者死亡相关循环微生物群 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 研究将加深我们对血液透析患者循环微生物群特征和作用的了解 为新的诊断和预后生物标志物和靶向驱动的未来发展铺平了道路 降低终末期肾病患者过度死亡风险的治疗策略。

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.