Targeting the Gut Vascular Axis in Atherosclerosis: Probiotic and Phytoantioxidant Crosstalk as a Hypothesis-Generating Framework for Residual Cardiovascular Risk

Despite decades of effective statin therapy, a clinically important proportion of patients with atherosclerosis continue to experience ischemic events, even when low-density-lipoprotein cholesterol (LDL-C) is at guideline-recommended levels. This shortfall is increasingly attributed to residual inflammatory, oxidative, and gut microbial pathways that lipid lowering therapy was never designed to address. This review establishes the mechanistic rationale for combining two emerging dietary intervention classes, probiotics and phytoantioxidants, as adjuncts acting on the gut vascular axis. We systematically trace the evidence for each class. For probiotics, we elucidate the restoration of gut-barrier integrity, short-chain fatty acid (SCFA) signaling, bile acid metabolism, and suppression of the trimethylamine to trimethylamine-N-oxide (TMA-TMAO) axis, including strain-specific efficacy and sex-based disparities in microbial composition. For phytoantioxidants, we detail the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), suppression of mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling, and sirtuin 1 (SIRT1)-dependent endothelial protection. We critically appraise the biological plausibility of their combined administration while explicitly defining where this rationale remains a testable hypothesis rather than an established strategy. To date, only one small randomized trial has evaluated a combined probiotic and phytoantioxidant formulation against an atherosclerosis relevant biomarker, and it lacked single-agent comparator arms necessary to attribute benefit to synergy rather than individual components. Furthermore, evidence for each class alone remains constrained by small sample sizes and heterogeneous dosing. Finally, we propose a novel, sex-stratified, strain-specified combination trial framework designed to rigorously evaluate this dual-target approach. This synthesis is intended to generate testable hypotheses for future research rather than to establish an evidence base for current adjunctive clinical use.