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.
Key Findings
Results
Plasma TMAO levels were significantly elevated in SLE patients compared to healthy controls, with the highest levels observed in hypertensive SLE patients.
Hypertensive and normotensive SLE patients were recruited alongside healthy controls for plasma TMAO quantification and blood pressure assessment.
Plasma TMAO levels were 'significantly elevated in SLE patients, particularly in those with HTN.'
TMAO levels showed a positive correlation with proteinuria in SLE patients.
This finding suggests a link between gut microbiota-derived metabolite production and both cardiovascular and renal manifestations of SLE.
Results
Choline supplementation increased blood pressure in both control and IMQ-treated (SLE) mice.
An SLE murine model was generated through toll-like receptor 7 activation using imiquimod (IMQ).
Mice were fed a choline-enriched diet to elevate TMAO levels.
Choline supplementation increased blood pressure in both control and IMQ-treated groups.
The blood pressure elevation was associated with impaired acetylcholine-mediated vasorelaxation.
A shift toward a contractile aortic phenotype was observed, especially in SLE mice.
Results
Elevated TMAO levels in IMQ-treated mice were associated with decreased expression of renal cortical transporters involved in TMAO excretion.
Renal cortical transporter expression was assessed in the IMQ murine SLE model.
Decreased expression of renal cortical transporters involved in TMAO excretion was identified in IMQ-treated mice.
This impaired renal excretion may contribute to the accumulation of TMAO observed in SLE.
This finding provides a mechanistic explanation for why SLE patients show elevated circulating TMAO levels.
Results
Vascular dysfunction induced by TMAO occurred independently of enhanced immune activation or autoantibody production.
The study specifically examined whether TMAO-associated vascular effects were mediated through immune pathways.
Vascular dysfunction 'occurred independently of enhanced immune activation or autoantibody production.'
This finding distinguishes the TMAO-mediated vascular pathway from classical autoimmune mechanisms in SLE.
The trimethylamine lyase inhibitor dimethyl-butanol (DMB) was used to pharmacologically inhibit TMAO production in mice.
Results
TMAO-induced endothelial dysfunction was mechanistically associated with increased reactive oxygen species generation via NLRP3 inflammasome activation.
The NLRP3 inflammasome was identified as a key mediator of TMAO-induced vascular dysfunction.
Increased reactive oxygen species (ROS) generation was linked to NLRP3 inflammasome activation.
This pathway represents an 'inflammasome-driven proinflammatory' mechanism distinct from autoantibody-mediated pathways.
The mechanism connects gut microbiota-derived metabolites to endothelial dysfunction through innate immune signaling.
Methods
Treatment with the trimethylamine lyase inhibitor dimethyl-butanol (DMB) was used to test the causal role of TMAO in SLE-associated vascular dysfunction.
DMB is a trimethylamine lyase inhibitor that reduces TMAO production by gut bacteria.
Mice were both fed a choline-enriched diet and treated with DMB to pharmacologically manipulate TMAO levels.
This dual intervention design allowed the study to establish a causal link between TMAO and vascular outcomes.
The IMQ murine model was used as the SLE disease model in combination with dietary and pharmacological interventions.
Background
SLE is characterized by elevated cardiovascular mortality largely driven by vascular dysfunction and hypertension, and gut microbiota-derived metabolites modulate these vascular complications through immune regulation.
SLE is described as 'an autoimmune disorder associated with elevated cardiovascular mortality.'
Cardiovascular mortality is 'largely driven by vascular dysfunction and hypertension.'
'Increasing evidence suggests that gut microbiota-derived metabolites modulate vascular complications in SLE through immune regulation.'
TMAO has 'emerged as a key regulator of vascular function' among these metabolites.
What This Means
This research suggests that a gut bacteria-derived chemical called trimethylamine N-oxide (TMAO) plays an important role in the high blood pressure and blood vessel damage seen in people with systemic lupus erythematosus (SLE), an autoimmune disease. The researchers found that SLE patients — especially those with high blood pressure — had significantly higher TMAO levels in their blood compared to healthy people, and that higher TMAO was also linked to more kidney damage (as measured by protein in the urine). In mouse models of SLE, increasing TMAO by feeding the animals a choline-rich diet raised their blood pressure and impaired blood vessel function, while blocking TMAO production prevented these effects.
Importantly, the study found that TMAO causes blood vessel damage through a specific biological pathway involving the NLRP3 inflammasome — a part of the immune system that triggers inflammation — leading to increased oxidative stress in blood vessel cells. This mechanism appeared to operate independently of the autoantibodies (self-attacking immune proteins) that are typically associated with SLE, suggesting TMAO is a distinct contributor to cardiovascular problems in this disease. The researchers also found that SLE mice had reduced kidney transporter activity, which may impair the body's ability to clear TMAO, causing it to accumulate.
This research suggests that the gut microbiome and its metabolites, particularly TMAO, represent a previously underappreciated pathway linking gut health to cardiovascular disease in SLE. Approaches that reduce TMAO production — such as dietary changes or drugs that inhibit the gut bacterial enzymes that make TMAO — could potentially be a new strategy for reducing blood pressure and protecting blood vessels in people with SLE, though further clinical research would be needed to confirm this.
Miñano S, González-Correa C, Moleón J, Jiménez-Moleón I, Sabio J, Martín-Armada M, et al.. (2026). Gut microbiota-derived trimethylamine N-oxide promotes vascular dysfunction and hypertension in systemic lupus erythematosus.. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. https://doi.org/10.1016/j.biopha.2026.119397