PFOS aggravates atherosclerosis via Bacteroides caecimuris expansion-driven bile acid remodeling and subsequent intestinal FXR-TLR3 signaling cascade

Jiang, L.; Huang, S.; Xu, Z.; Guo, R.; Zhu, J.; Liang, H.; Yuan, C.; Zhao, Z.; Lv, F.; Ai, Y.; Xu, K.; Wu, Y.; Li, X.; Qin, G.; Li, C.; Hu, S.; Liu, T.; Zhang, M.; Zhou, Z.; Li, Y.; Liu, B.; Wu, Q.; Chen, K.; Fang, Z.

doi:10.64898/2026.07.01.735947

bioRxiv · 10.64898/2026.07.01.735947

PFOS aggravates atherosclerosis via Bacteroides caecimuris expansion-driven bile acid remodeling and subsequent intestinal FXR-TLR3 signaling cascade

Jiang, L.·Huang, S.·Xu, Z.·Guo, R.·Zhu, J.·Liang, H.·Yuan, C.·Zhao, Z.·Lv, F.·Ai, Y.·Xu, K.·Wu, Y.·Li, X.·Qin, G.·Li, C.·Hu, S.·Liu, T.·Zhang, M.·Zhou, Z.·Li, Y.·Liu, B.·Wu, Q.·Chen, K.·Fang, Z.

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Abstract

BACKGROUNDPerfluorooctane sulfonate (PFOS) is a widely distributed persistent organic pollutant in the environment and has been associated with an increased risk of atherosclerosis. However, the underlying pathogenic mechanisms remain largely unclear. This study aimed to investigate the effects of PFOS on atherosclerosis and its associated gut-vascular axis. METHODSPseudo-germ-free mouse models and fecal microbiota transplantation (FMT) were used to determine the role of the gut microbiota in PFOS-induced atherosclerosis. Metagenomic sequencing was performed to characterize alterations in gut microbial composition following PFOS exposure, and targeted metabolomics was used to assess bile acid profiles in the ileum and plasma. Transcriptomic analysis of Bacteroides caecimuris (B.caecimuris) was conducted to explore the reasons for the increased abundance of B.caecimuris after PFOS exposure. In addition, intestinal transcriptomics and ChIP-qPCR were performed to validate transcriptional regulation within the FXR-TLR3 signaling axis. RESULTSAmong 127 participants with paired serum and fecal samples, including 82 patients undergoing coronary angiography with Gensini scores (GS score), fecal PFOS levels were significantly associated with lipid profiles and GS score, whereas serum PFOS showed no such association.Mechanistically, PFOS exposure promotes intestinal enrichment of B.caecimuris by upregulating its tolC gene, thereby enhancing efflux capacity.This microbial shift was accompanied by reduced levels of tauro-ursodeoxycholic acid (TUDCA) and aberrant activation of intestinal FXR signaling.Further analyses demonstrated that FXR activation upregulated TLR3 expression and promoted inflammatory responses and atherosclerosis progression via the TLR3-NF-{kappa}B signaling axis. Both intestinal epithelial-specific FXR deficiency (Fxr{Delta}IE) and TUDCA supplementation significantly suppressed pathway activation and alleviated disease phenotypes.Functional experiments identified TLR3 as a key downstream effector of FXR. Overexpression of TLR3 abolished the protective effects observed in Fxr{Delta}IE mice. Moreover, pharmacological inhibition of TLR3 using CU CPT-4a significantly improved established atherosclerotic lesions in vivo. CONCLUSIONSThis study identifies a gut microbiota-driven FXR-TLR3 signaling axis that mediates PFOS-induced atherosclerosis. These findings provide new mechanistic insights into environmentally induced cardiovascular disease and suggest potential targets for risk assessment and therapeutic intervention.

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Jiang, L., Huang, S., Xu, Z., Guo, R., Zhu, J., Liang, H., Yuan, C., Zhao, Z., Lv, F., Ai, Y., Xu, K., Wu, Y., Li, X., Qin, G., Li, C., Hu, S., Liu, T., Zhang, M., Zhou, Z., Li, Y., Liu, B., Wu, Q., Chen, K., Fang, Z.. 2026-07-08. PFOS aggravates atherosclerosis via Bacteroides caecimuris expansion-driven bile acid remodeling and subsequent intestinal FXR-TLR3 signaling cascade. https://doi.org/10.64898/2026.07.01.735947

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