Computational Network Analysis Evidence for a Novel Atherosclerosis- Ace2- Dysbiosis Triad: A System-Level Approach to Understand Pathological Flow and Drug Repurposing

Objective: Introduction: Chronic inflammation is the central driver of atherosclerosis, with gut dysbiosis and angiotensin-converting enzyme 2 (ACE2) acting as key modulators. Although individual links between these components have been reported, a unified mechanistic framework connecting them remains unexplored. Aims & objectives: Test the hypothesis that the Gut Dysbiosis-Atherosclerosis-Reduced ACE2 Axis forms a novel, self-perpetuating triad driving atherosclerosis by network analysis & identifying key molecular interactions that drives the triad and proposing novel triad based therapeutics Design and method: We constructed a multi-omics interaction network using literature curation and the OmicsNet platform, integrating proteins, metabolites, and dysbiotic microbes. Guilt by Association (GBA) analysis was used to identify influential nodes. The network was then segmented using topological clustering, followed by pathway enrichment analysis and drug target mapping to identify repurposable drug candidates Results: Network analysis validated the mechanistic links within the atherosclerosis-reduced ACE2-dysbiosis triad, identifying key molecular connectors such as IL-6, TNF-alpha, NLRP3, SLC6A19, FMO3, and TLR4. GBA analysis strongly implicated gut dysbiosis as the initiating trigger, with microbial nitrogen and carbohydrate metabolism enzymes acting as primary hubs. These microbial factors appear to generate metabolites like tryptophan and arginine, which activate host inflammatory hubs (e.g., TLR2, TLR5), promoting vascular damage and barrier dysfunction, ultimately leading to ACE2 downregulation. From 39 topological modules, 12 were significant (P < 0.05), revealing 9 enriched molecular pathways central to the triad. Drug target mapping on these pathways identified 53 potential drugs, including 21 promising repurposing candidates such as minocycline, doxycycline, anakinra, and canakinumab, which target critical inflammatory and metabolic signaling pathways (e.g., PI3K-Akt, NOD-like receptor, TNF signaling) Conclusions: This study establishes a novel, systems-level framework that unifies atherosclerosis, reduced ACE2, and gut dysbiosis into a single pathological triad. We identified key molecular connectors and pinpointed microbial dysbiosis as the upstream driver of chronic inflammation in this cascade. The identification of 21 repurposable drugs provides a data-driven foundation for developing targeted therapeutic strategies that modulate ACE2 and gut microbiota interactions to combat atherosclerosis.