Gut microbiome mediates the protective effects of empagliflozin on experimental abdominal aortic aneurysm formation and progression

Abdominal aortic aneurysm is a life-threatening vascular disease lacking effective pharmacotherapies. This study aimed to investigate the protective effect of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, against angiotensin II (AngII)-induced AAA in ApoE −/− mice and explore the underlying mechanisms. Twelve-week-old male ApoE −/− mice were randomly divided into Control, AngII-induced AAA (AAA group), and empagliflozin-treated (Empa group, 3 mg/kg/day) groups. After 28 days, empagliflozin significantly reduced AAA incidence (26.6% vs. 73.3% in AAA group), decreased maximum abdominal aortic diameter, improved survival rate (86.7% vs. 73.3%, P = 0.0032), and reduced the rate of aortic rupture. At the vascular tissue level, empagliflozin reduced inflammatory cell infiltration, preserved medial elastic fiber integrity, and decreased the AngII-induced upregulation of MMP9 ( P = 0.0188) and MMP2 ( P = 0.0039) in aortic tissues. 16 S rRNA sequencing revealed that empagliflozin reshaped gut microbiota composition, increasing the abundance of Tenericutes at the phylum level and Sutterella , Allobaculum , Colinsella , and Pelomonas at the genus level, while decreasing Methylobacterium . Targeted LC–MS/MS analysis revealed empagliflozin-associated changes in fecal SCFAs and plasma TMAO, accompanied by reduced intestinal permeability and attenuation of aortic TLR4/NF-κB signaling. Moreover, empagliflozin improved intestinal barrier integrity by restoring villus structure, upregulating ZO-1 and Occludin expression (both mRNA and protein levels), and reducing plasma LPS concentration ( P < 0.0001). Gut microbiota depletion with antibiotics completely abolished the protective effects of empagliflozin, whereas fecal microbial transplantation from empagliflozin-treated mice recapitulated the beneficial effects, including reduced AAA incidence, attenuated vascular inflammation, and improved intestinal barrier function. Empagliflozin inhibits AngII-induced AAA formation and progression by regulating the gut microbiota-intestinal barrier axis, providing a novel preventive strategy for AAA.