Background <p>Despite antiretroviral therapy (ART), people with HIV (PWH) face immunological ageing and accelerated comorbidities including coronary artery disease (CAD). Gut mucosal damage, chronic inflammation, and Tryptophan (Trp) catabolism into Kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO), are associated with HIV disease progression and atherosclerosis. Thus, we comprehensively assessed the interplay between these perturbations in PWH with subclinical CAD under ART.</p> Methods <p>Plasma levels of inflammatory mediators, Trp metabolites, and immune cell subset phenotyping were assessed on blood specimens from PWH and HIV seronegative participants with or without CAD diagnosed by cardiac computed tomography angiography from the Canadian HIV Aging Cohort Study.</p> Results <p>Levels of gut damage markers regenerating islet-derived protein 3 alpha (REG3α), intestinal fatty-acid binding protein (I-FABP) and soluble CD14 (sCD14) were increased in PWH, but only I-FABP was associated with CAD. Among inflammatory soluble markers, soluble receptor type II for the tumor necrosis factor (sTNFRII) was elevated in PWH, while increased interferon-gamma (IFN-γ) and interleukin (IL)-17A levels were associated with CAD. Regardless of CAD, PWH were characterized by upregulated IDO/Kyn pathway and increased Trp metabolites Kyn, 3-hydroxykynurenine (3-H-Kyn), anthranilic acid, along with decreased xanthurenic acid (Xan acid). Accordingly, HIV+CAD+ participants exhibited highest Kyn/Trp and 3-H-Kyn/Xan acid ratios. CAD+ participants had increased classical CD14⁺ and decreased non-classical CD16⁺ monocyte frequencies, regardless of HIV status. HIV status was associated with increased frequencies of Ki67⁺ proliferating, CD28⁻CD57⁺ senescent and CCR4⁺CXCR3⁺ CD4 and CD8 T-cells, while T-cell and regulatory T-cells (Treg) atheroprotective CD73-expressing subsets were decreased in PWH.</p> Conclusions <p>In PWH, subclinical CAD is associated with a distinctive gut-heart immuno-metabolic feature and inflammaging characterized by elevated plasma markers of gut mucosal damage, increased IFN-γ levels and IDO pathway activity, and altered monocyte and T-cell subsets.</p> Graphical Abstract <p>Gut–Heart immuno-metabolic disruption and subclinical Coronary Artery Disease (CAD) in chronic HIV infection. Image was made in part using Servier Medical Art (<a href="https://smart.servier.com/">https://smart.servier.com/</a>).</p> <p></p>