Cardiovascular complications are the major cause of the marked morbidity and mortality associated with chronic kidney disease (CKD). The classical cardiovascular risk factors such as diabetes and hypertension undoubtedly play a role in the development of cardiovascular disease (CVD) in adult CKD patients; however, CVD is just as prominent in children with CKD who do not have these risk factors. Hence, the CKD-specific pathophysiology of CVD remains incompletely understood. In light of this, studying children with CKD presents a unique opportunity to analyze CKD-associated mechanisms of CVD more specifically and could help to unveil novel therapeutic targets. Here, we comprehensively review the interaction of the human gut microbiome and the microbial metabolism of nutrients with host immunity and cardiovascular end-organ damage. The human gut microbiome is evolutionary conditioned and modified throughout life by endogenous factors as well as environmental factors. Chronic diseases, such as CKD, cause significant disruption to the composition and function of the gut microbiome and lead to disease-associated dysbiosis. This dysbiosis and the accompanying loss of biochemical homeostasis in the epithelial cells of the colon can be the result of poor diet (e.g., low-fiber intake), medications, and underlying disease. As a result of dysbiosis, bacteria promoting proteolytic fermentation increase and those for saccharolytic fermentation decrease and the integrity of the gut barrier is perturbed (leaky gut). These changes disrupt local metabolite homeostasis in the gut and decrease productions of the beneficial short-chain fatty acids (SCFAs). Moreover, the enhanced proteolytic fermentation generates unhealthy levels of microbially derived toxic metabolites, which further accumulate in the systemic circulation as a consequence of impaired kidney function. We describe possible mechanisms involved in the increased systemic inflammation in CKD that is associated with the combined effect of SCFA deficiency and accumulation of uremic toxins. In the future, a more comprehensive and mechanistic understanding of the gut–kidney–heart interaction, mediated largely by immune dysregulation and inflammation, might allow us to target the gut microbiome more specifically in order to attenuate CKD-associated comorbidities.

中文翻译：

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慢性肾脏病儿童的细菌代谢物和心血管风险

心血管并发症是慢性肾脏病 (CKD) 相关的显着发病率和死亡率的主要原因。糖尿病和高血压等经典的心血管危险因素无疑在成年 CKD 患者心血管疾病 (CVD) 的发展中起作用；然而，CVD 在没有这些危险因素的 CKD 儿童中同样突出。因此，CVD 的 CKD 特异性病理生理学仍未完全了解。有鉴于此，研究 CKD 儿童提供了一个独特的机会，可以更具体地分析 CKD 相关的 CVD 机制，并有助于揭示新的治疗靶点。在这里，我们全面回顾了人类肠道微生物组和营养物质的微生物代谢与宿主免疫和心血管终末器官损伤的相互作用。人类肠道微生物组在整个生命过程中受到内源性因素和环境因素的进化调节和修饰。慢性疾病，如 CKD，会严重破坏肠道微生物组的组成和功能，并导致与疾病相关的生态失调。这种生态失调和结肠上皮细胞生化稳态的伴随丧失可能是不良饮食（例如，低纤维摄入量）、药物治疗和潜在疾病的结果。由于生态失调，促进蛋白水解发酵的细菌增加，促进糖酵解发酵的细菌减少，肠道屏障的完整性受到干扰（肠漏）。这些变化破坏了肠道中的局部代谢物稳态并减少了有益的短链脂肪酸 (SCFA) 的产生。而且，增强的蛋白水解发酵会产生不健康水平的微生物来源的有毒代谢物，由于肾功能受损，这些代谢物会进一步积聚在体循环中。我们描述了 CKD 全身炎症增加的可能机制，这与 SCFA 缺乏和尿毒症毒素积累的综合影响有关。未来，对主要由免疫失调和炎症介导的肠道-肾脏-心脏相互作用有更全面和更机械的理解，可能使我们能够更具体地针对肠道微生物组，以减轻 CKD 相关的合并症。我们描述了 CKD 全身炎症增加的可能机制，这与 SCFA 缺乏和尿毒症毒素积累的综合影响有关。未来，对主要由免疫失调和炎症介导的肠道-肾脏-心脏相互作用有更全面和更机械的理解，可能使我们能够更具体地针对肠道微生物组，以减轻 CKD 相关的合并症。我们描述了 CKD 全身炎症增加的可能机制，这与 SCFA 缺乏和尿毒症毒素积累的综合影响有关。未来，对主要由免疫失调和炎症介导的肠道-肾脏-心脏相互作用有更全面和更机械的理解，可能使我们能够更具体地针对肠道微生物组，以减轻 CKD 相关的合并症。