Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with elevated cardiovascular mortality, largely driven by vascular dysfunction and hypertension (HTN). Increasing evidence suggests that gut microbiota-derived metabolites modulate vascular complications in SLE through immune regulation. Among these metabolites, trimethylamine N-oxide (TMAO) has emerged as a key regulator of vascular function. This study investigates the specific contribution of TMAO to SLE-associated HTN. Methods: Hypertensive and normotensive SLE patients, together with healthy controls, were recruited for plasma TMAO quantification and blood pressure assessment. Additionally, an SLE murine model was generated through toll-like receptor 7 activation using imiquimod (IMQ). Mice were fed a choline-enriched diet and treated with the trimethylamine lyase inhibitor dimethyl-butanol. Plasma TMAO levels were significantly elevated in SLE patients, particularly in those with HTN, and showed a positive correlation with proteinuria. In mice, choline supplementation increased blood pressure in both control and IMQ-treated groups. This effect was associated with impaired acetylcholine-mediated vasorelaxation and a shift toward a contractile aortic phenotype, especially in SLE mice. Elevated TMAO levels in IMQ-treated mice were associated with decreased expression of renal cortical transporters involved in TMAO excretion. Notably, vascular dysfunction occurred independently of enhanced immune activation or autoantibody production. Mechanistically, TMAO-induced endothelial dysfunction was associated with increased reactive oxygen species generation via NLRP3 inflammasome activation. TMAO contributes to blood pressure elevation in SLE through endothelial dysfunction mediated by inflammasome-driven proinflammatory pathways and increased vascular contractile phenotype, largely independent of autoantibody-mediated mechanisms. • Elevated plasma TMAO levels are associated with hypertension and renal damage in SLE patients. • TMAO may raise blood pressure and cause endothelial dysfunction, partly independent of autoimmune activation. • TMAO promotes a shift toward a contractile vascular phenotype, particularly in SLE conditions. • Vascular effects of TMAO are mediated by NLRP3 inflammasome activation and increased oxidative stress. • Modulating TMAO levels (via choline or TMA lyase inhibition) highlights its role in SLE-related vascular dysfunction.
Miñano et al. (Sun,) studied this question.