Role of gut dysbiosis and microbial metabolites in the pathogenesis and progression of heartfailure

心力衰竭（HF）目前被认为是一种多系统疾病，慢性炎症被认为是一个主要的影响因素。肠道微生物组成的改变（“肠道生态失调”）和微生物毒素/代谢物向血流的易位最近与HF发病机制相关。因此，以减少全身炎症从而改善HF进展为目标的调节肠道微生物组成的概念在科学界引起了广泛的兴趣。然而，仍然存在一些挑战，因为与HF相关的核心微生物群尚未普遍建立，这是由于迄今为止使用异质方法进行的典型小型单中心研究。此外，在HF中缺少微生物组和代谢组的系统相关性作为所得表型读数。因此，迫切需要构建更大的患者队列，以在HF患者中建立核心肠道微生物组。THFs将允许剖析肠道微生物组与HF发病机制之间是否存在普遍相关性，提出HF的“肠道假说”。在拟议的项目中，基于我们自己的初步数据，我们假设存在肠道微生物组的适应不良组成，可能对心力衰竭的发病机制和进展产生相关影响。此外，肠道微生物群及其血液可检测代谢物的特定特征可能代表临床上有用的生物标志物，用于心力衰竭的预后和预防。我们认为，需要进行全面的机制研究，如本文提出的研究，以确定改变肠道微生物群对HF的直接影响，并揭示相关的病理机制。此外，对肠道生态失调的实验小鼠模型和患者队列的分析可能使我们能够确定改善治疗和预防的初步方法。

Heart failure (HF) is currently regarded as a multisystem disorder, and chronic inflammation has been hypothesized as a major contributing factor. Alterations in gut microbial composition (“gut dysbiosis”), and translocation of microbial toxins/metabolites to the bloodstream, have recently been associated with HF pathogenesis. Hence, the concept of modulating gut microbial composition with the goal of reducing systemic inflammation thereby ameliorating HF progression has generated broad interest in the scientific community. However, several challenges remain, as the core microbiota linked to HF are not universally established yet due to so far typically small monocentric studies with heterogeneous methodology. Moreover, a systematic correlation of microbiome and metabolome as the resulting phenotypic readout is missing in HF. Thus, there is an urgent need to constitute larger patient cohorts to establish a core gut microbiome in HF patients. THFs would allow to dissect whether there is a universal correlation between gut microbiome and the pathogenesis of HF, putting forward the “gut hypothesis” of HF. In the proposed project, based on our own preliminary data, we hypothesize that a maladaptive composition of the gut microbiome exists that may have a relevant impact on the pathogenesis and progression of heart failure. Moreover, specific features of the gut microbiota and its blood-detectable metabolites could potentially represent clinically useful biomarkers for the prognosis and prevention of heart failure. We believe that comprehensive mechanistic studies such as the one proposed here are needed to identify the direct effects of altered gut microbiota on HF and to unravel the associated pathomechanisms. In addition, analysis of experimental mouse models of gut dysbiosis and patient cohorts may allow us to identify initial approaches to improved therapy and prevention.