PDF(Pubmed)
Abstract：
Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.
摘要：
新的证据表明，肠道菌群的改变在慢性肾脏疾病（CKD）相关的血管钙化（VC）中起着重要作用。我们旨在研究CKD-VC的特定肠道菌群和潜在机制。我们确定了一个增加丰度的Prevotellacocri(P.copri）在CKD大鼠的粪便中（通过使用5/6肾切除术，然后进行高钙和磷酸盐饮食诱导），通过16SrRNA基因的扩增子测序进行主动脉钙化。在CKD患者中，我们进一步证实了P.copri的丰度与主动脉钙化评分之间的正相关。此外，口服活菌可加重CKD相关VC和体内血管平滑肌细胞成骨分化，伴随着肠道的破坏，Toll样受体4（TLR4）的表达增强，和升高的脂多糖（LPS）水平。体外和离体实验一致证明，P.copri衍生的LPS（Pc-LPS）加速了高磷酸盐诱导的VC和VSMC成骨分化。机械上,Pc-LPS与TLR4结合，然后激活核因子κB（NF-κB）和核苷酸结合域，富含亮氨酸的家族，含pyrin结构域-3（NLRP3）炎症小体信号在VC期间。抑制NF-κB可减少NLRP3炎性体并减轻Pc-LPS诱导的VSMC钙化。我们的研究阐明了P.copri在CKD相关VC中的新作用，通过包括Pc-LPS在内的炎症调节代谢物增加的机制，和NF-κB/NLRP3信号通路的激活。这些发现强调了P.copri及其衍生的LPS作为CKD中VC的潜在治疗靶标。
