1. Prevotella copri promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway.
- Author
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Hao QY, Yan J, Wei JT, Zeng YH, Feng LY, Que DD, Li SC, Guo JB, Fan Y, Ding YF, Zhang XL, Yang PZ, Gao JW, and Li ZH
- Subjects
- Animals, Humans, Male, Rats, Feces microbiology, Inflammasomes metabolism, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Osteogenesis drug effects, Rats, Sprague-Dawley, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic microbiology, Renal Insufficiency, Chronic pathology, Toll-Like Receptor 4 metabolism, Toll-Like Receptor 4 genetics, Gastrointestinal Microbiome, Lipopolysaccharides metabolism, NF-kappa B metabolism, Prevotella metabolism, Signal Transduction, Vascular Calcification metabolism, Vascular Calcification microbiology, Vascular Calcification pathology
- 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.
- Published
- 2024
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