Prevotella copri 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 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.

KEYWORDS:

• Vascular calcification
• prevotella copri
• gut microbiota
• chronic kidney disease
• lipopolysaccharides

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

QY Hao performed experiments. J Yan analyzed the data, and wrote the draft. JT Wei performed experiments and analyzed the data. YH Zeng, LY Feng, DD Que, SC Li, JB Guo, Y Fan, YF Ding and XL Zhang performed experiments. PZ Yang conceived and designed the experiments. JW Gao conceived and designed the study and analyzed the data. ZH Li conceived and designed the experiments, analyzed the data, and revised the manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2351532

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (82200442, 82070247, 82370237 and 82000460) and the Guangdong Basic and Applied Basic Research Foundation (2022A1515012263).