The gut microbiome and vascular disease - A systematic review of mechanistic insights and implications for vascular surgery.

Objective: Observational studies repeatedly linked gut microbial features and metabolites to vascular disease, but it is unclear which associations are reproducible, which remain significant after confounder adjustment, and how they relate to experimental evidence. This review aims to determine which taxa and metabolites are consistently associated across independent human studies; whether the population, phenotype, method, and sample type explain divergent findings; and where the human data converge with, diverge from, or remain untested with the animal and interventional literature. Methods: PubMed/MEDLINE, Embase, Web of Science, and Cochrane Library were searched for human studies of the gut microbiome composition or gut-derived metabolites reporting atherosclerotic, aneurysmal, peripheral arterial, calcific, or arterial stiffness outcomes from database inception to December 31, 2025. Study screening and duplicate article extraction were conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines. The study design was classified explicitly, the covariates in each primary analysis were extracted, and the risk of bias was assessed using the Newcastle-Ottawa Scale or the Joanna Briggs Institute checklist. The findings were then compared with the animal and human interventional literature identified through targeted searching. Results: All the 29 included reports were observational (19 cross-sectional, 3 case-control, and 7 cohort) studies, and none was interventional. The reproducible findings were the enrichment of Proteobacteria-affiliated genera (5 reports) and of oral-origin organisms (3 reports), and the depletion of butyrate producers in carotid disease. The carnitine pathway intermediates gamma-butyrobetaine and trimethyllysine were independently associated with cardiovascular death and major adverse limb events (hazard ratio, 1.93; 95% confidence interval, 1.35-2.76) in two independent cohorts. Trimethylamine N-oxide (TMAO) was outcome-specific; TMAO levels were associated with 5-year mortality in peripheral arterial disease (adjusted hazard ratio, 2.06; 95% confidence interval, 1.36-3.11) and with ankle-brachial-index-defined disease in diabetes (odds ratio, 1.051), but TMAO levels were lower in large-artery stroke than in controls and were unrelated to carotid or limb outcomes once renal function was modelled. In addition, 16 of 29 reports fitted a multivariable model, and only three included renal function; the compositional findings were almost exclusively unadjusted. The risk of bias was good in 11 reports, moderate in 16, and low in 2. Animal models causally implicate TMAO in atherogenesis and aneurysm formation and show butyrate and Conclusions: A small number of gut microbial signals are reproducible, but most have not been adjusted for potential confounders, particularly renal function, which may partly explain the observed associations. The carnitine pathway metabolites with the strongest prognostic signal in surgical populations have never been tested in an animal vascular model. Microbiome profiling has no current role in vascular surgical practice.