The Gut–Vascular Axis as a Therapeutic Hub: Rationale and Evidence for Combined Gut-Directed and Endothelium-Directed Interventions

Background: The gut–vascular axis linking gut microbiota, intestinal barrier, and vascular endothelium is a key pathophysiological interface in chronic metabolic diseases. Dysbiosis and “leaky gut” enable bacterial products and gut-derived metabolites to enter the circulation, driving systemic inflammation and endothelial dysfunction. Single-target interventions show limited efficacy; combined gut-directed and endothelium-directed strategies remain underexplored. Methods: PubMed was searched from database inception to 31 August 2026 using a predefined search strategy combining terms for the gut–vascular axis, intestinal barrier, microbiota/metabolites, endothelial dysfunction, and combined interventions. Preclinical and clinical studies evaluating gut barrier integrity, microbiota modulation, or endothelial protection, alone or in combination, were included. No formal risk-of-bias scoring was performed; study design, sample size, endpoint type, follow-up, and limitations were appraised. Results: (1) The axis comprises three core components: gut barrier, endothelium, and microbial metabolites. (2) Pathological activation involves leaky-gut-driven endotoxemia, dysbiosis-induced metabolic inflammation, and immune crosstalk sustaining vascular inflammation. (3) Animal models demonstrate that combined interventions can reduce atherosclerotic plaque, improve endothelium-dependent relaxation, and lower systemic inflammation to a greater extent than some monotherapies; however, most studies have not directly compared combination therapy with both corresponding monotherapies or performed formal interaction testing, so true synergy remains unproven. (4) Limited clinical studies in metabolic syndrome and heart failure suggest improvements in surrogate endpoints, but large-scale randomised trials with hard cardiovascular endpoints are lacking. Conclusions: The gut–vascular axis is a promising therapeutic framework for cardiometabolic diseases, with a strong biological rationale. Combined gut- and endothelium-directed interventions offer a rational multi-target approach, but direct evidence that they provide superior clinical outcomes remains limited. Future research must prioritise hard-endpoint trials, standardised interventions and endpoints, long-term safety, reproducibility, multi-omics-based patient stratification, and next-generation microbiome therapies.