The Gut Microbiota–Metabolite–Vascular Wall Axis in Abdominal Aortic Aneurysm: Mechanisms, Biomarkers, and Translational Opportunities

Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disorder associated with substantial rupture-related mortality and persistent lack of effective pharmacological therapy. Traditionally regarded as a localized structural disease, AAA is now recognized as a systemic inflammatory and remodeling disorder. Key processes include inflammation, oxidative stress, endothelial dysfunction, vascular smooth muscle cell apoptosis and switching, extracellular matrix degradation, and thrombo-inflammatory remodeling. The gut microbiota–metabolite–vascular wall axis has emerged as a candidate upstream regulator of these processes. In this review, this axis refers to the biological continuum through which intestinal microbial dysbiosis and microbial or host–microbial metabolites influence immune activation, endothelial injury, thrombosis, and matrix remodeling in aneurysmal wall. This review synthesizes advances in understanding gut microbiota dysbiosis and microbiota-derived metabolites in AAA, with emphasis on mechanistic, translational, and clinically relevant developments. Current evidence suggests that gut microbial imbalance may promote aneurysm progression through immune and inflammatory pathways. One important mechanism is enhanced neutrophil extracellular trap formation. Among microbial mediators, trimethylamine N-oxide has become the most intensively studied candidate, with growing evidence linking elevated circulating levels to AAA occurrence, growth rate, and progression-related events, alongside experimental data supporting inflammatory and apoptotic mechanisms. In contrast, short-chain fatty acids may exert protective immunometabolic and barrier-supportive effects, whereas lipopolysaccharide may function as a key inflammatory amplifier linking intestinal barrier dysfunction to vascular injury. Insights from related disorders, including atherosclerosis, hypertension, metabolic syndrome, and inflammatory bowel disease, further strengthen the biological plausibility of microbiota-mediated aneurysmal remodeling. Despite this progress, major challenges remain, including taxonomic inconsistency, cohort heterogeneity, analytical standardization, and unresolved causality. Future studies should prioritize function-oriented microbiome analysis, integrated multi-omics, imaging-linked phenotyping, and mechanism-based intervention trials. Collectively, emerging evidence supports a conceptual shift in which AAA is viewed within a broader microbiome–metabolite–immune–matrix framework, opening new possibilities for biomarker development and non-surgical disease modification.