Gut-immune-PVAT axis is involved in ethanol-induced abdominal aortic dysfunction via IL-17RA, TLR4, and FPR1 signaling.

Alcohol consumption and gut dysbiosis are risk factors for cardiovascular diseases (CVD), yet their mechanistic interplay remains unclear. We investigated whether gut microbiota-associated signaling modulates ethanol-induced abdominal aorta and perivascular adipose tissue (PVAT) dysfunction. Male C57BL/6J mice subjected to a chronic plus binge ethanol protocol exhibited leaky gut, systemic inflammation, and vascular dysfunction, along with greater systemic exposure to microbiota-derived products (fMLP and LPS) and immune response activation, including M1 macrophage polarization and Th17 expansion. Ethanol-induced vascular hyporesponsiveness was linked to FPR1 upregulation, while smooth muscle FPR1 conditional deletion prevented this effect. PVAT-intact aorta from ethanol-treated mice exhibited increased contractile responses compared with PVAT-devoid vessels, indicating PVAT dysfunction. This phenotype was attenuated by pharmacological inhibition or genetic deletion of FPR1. Notably, these PVAT-dependent alterations were absent in germ-free, Rag1-/-, IL-17RA-/-, or TLR4-/- mice, supporting a role for gut microbiota-driven immune response signaling. Redox imbalance also contributed to vascular and PVAT dysfunction. Our findings demonstrate that ethanol exposure triggers a gut-redox cascade which elicits the Th17/TLR4 axis and targets the PVAT to drive vascular injury. In conclusion, positioning PVAT as a central integrator of gut microbiota-derived signals identifies the gut-vascular interface as a promising therapeutic target for alcohol-related CVD.