Gut microbiota-derived trimethylamine N-oxide promotes vascular dysfunction and hypertension in systemic lupus erythematosus.

BACKGROUND

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.

PURPOSE: 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.

RESULTS

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.

CONCLUSION

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.