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致病因素。最近，肠道微生物组成的改变(“肠道生物失调”)以及微生物毒素/代谢物向血流的移位与HF的发病机制有关。因此，调节肠道微生物组成以减少全身炎症从而改善心力衰竭进展的概念引起了科学界的广泛兴趣。然而，仍然存在一些挑战，因为到目前为止，由于采用不同方法学进行的典型的小规模单中心研究，与HF相关的核心微生物区系尚未普遍建立。此外，作为结果表型读数的微生物组和代谢组之间的系统相关性在HF中缺失。因此，迫切需要建立更大的患者队列，以建立心力衰竭患者的核心肠道微生物群。THFs可以剖析肠道微生物群与心力衰竭发病机制之间是否存在普遍相关性，从而提出心力衰竭的肠道假说。在拟议的项目中，基于我们自己的初步数据，我们假设肠道微生物组的不适应成分存在，可能对心力衰竭的发病和进展有相关影响。此外，肠道微生物区系及其血液可检测代谢物的特定特征可能是临床上有用的心力衰竭预后和预防的生物标志物。我们认为，需要像这里建议的那样进行全面的机制研究，以确定肠道微生物区系改变对心衰的直接影响，并揭示相关的病理机制。此外，对肠道生物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进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.