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Gut microbiota dysbiosis promotes aortic aneurysm and dissection through FPR1-driven vascular inflammation

ABSTRACT: Aortic aneurysm and dissection (AAD) are life-threatening cardiovascular disorders for which effective preventive strategies remain limited. Although the gut microbiota is recognized as a critical modulator of multiple cardiovascular diseases, its role in AAD remains unclear. Using microbiome sequencing, we identified gut microbiota dysbiosis in AAD patients, characterized by the expansion of Escherichia coli (E. coli). Further evidence indicates that E. coli is a key AAD-promoting strain, exacerbating aortic inflammation. Moreover, through transcriptomic profiling and high-performance liquid chromatography-mass spectrometry analyses, E. coli-derived fMLF was identified as a microbial metabolite that promotes AAD progression via formyl peptide receptor 1 (FPR1). Mechanistically, FPR1 is activated by fMLF in macrophages, enhancing macrophage chemotaxis and the proinflammatory responses through the p38/ERK MAPK signaling pathways. These findings confirm the crucial role of the gut microbiota and its metabolites in the pathogenesis of AAD, and provide insights for developing effective preventive and therapeutic strategies for AAD.

ORGANISM(S): Mus Musculus

SUBMITTER: Tingtao Chen

PROVIDER: PXD075915 | iProX | Fri Mar 20 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Endometritis, a prevalent reproductive system disease with high incidence, leads to reproductive dysfunction and potential miscarriage in both humans and animals, impacting human health and the dairy industry, resulting in significant economic loss. Gut microbiota plays an important role in the pathogenesis of endometritis. However, the specific microbial and metabolic mediators participating in the pathogenesis remain to be identified. In this study, we found that the concentration of itaconate in the feces of mice increased after endometritis induced by Escherichia coli (E. coli) infection, suggesting a potential association between itaconate and inflammatory processes. Here, we investigated the specific role of dimethyl itaconate (DI), a derivative of itaconate with potent anti-inflammatory and immunomodulatory properties on endometritis. Oral administration of DI ameliorated the symptoms of E. coli-induced endometritis in mice. The protective effect was abolished by antibiotic-induced depletion of the gut microbiota, and fecal microbiota transplantation (FMT) from DI-treated mice to recipient mice ameliorated E. coli-induced endometritis. Integrative multiomics revealed that the addition of DI led to an enrichment of Muribaculaceae and the microbial purine metabolite guanosine in the feces. Muribaculum intestinale (DSM 28989), a bacterium of Muribaculaceae or guanosine supplementation alleviated E. coli-induced endometritis in mice. Mechanistically, DI promoted the multiplication of Muribaculaceae, and supplementation of M. intestinale upregulated the level of guanosine in the uterus. Transcriptome data and antibody-neutralizing experiment demonstrated the protective effect of guanosine in E. coli-induced endometritis was mediated by activating the expression of CXCL14 in uterine epithelial cells. In conclusion, our study elucidates the significant role of the gut microbiota and its metabolites in safeguarding the uterus against pathogen infections, providing substantiation for the regulation of distal organ by the gut microbiota, and establishing a basis for preventive measures against related diseases through the gut-X axis.

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Gut microbiota dysbiosis promotes aortic aneurysm and dissection through FPR1-driven vascular inflammation

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