<i>Prevotella copri</i> promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway

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 <i>Prevotella copri</i> (<i>P. copri</i>) 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 <i>P. copri</i> and aortic calcification scores. Moreover, oral administration of live <i>P. copri</i> aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells <i>in vivo</i>, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. <i>In vitro</i> and <i>ex vivo</i> experiments consistently demonstrated that <i>P. copri</i>-derived LPS (<i>Pc</i>-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, <i>Pc</i>-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 <i>Pc</i>-LPS-induced VSMC calcification. Our study clarifies a novel role of <i>P. copri</i> in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including <i>Pc</i>-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight <i>P. copri</i> and its-derived LPS as potential therapeutic targets for VC in CKD.