Highlight
- Elevated plasma trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, is independently associated with the presence of abdominal aortic aneurysm (AAA).
- Higher circulating TMAO levels predict fast-growing AAAs (≥4.0 mm/year) and increased likelihood of surgical intervention in large, well-characterized European and US cohorts.
- Incorporating TMAO measurements improves prediction models beyond traditional cardiovascular risk factors, identifying patients who may benefit from closer monitoring or early surgical repair.
- This biomarker-anchored approach offers new avenues for personalized risk stratification and therapeutic targeting in AAA management.
Study Background and Disease Burden
Abdominal aortic aneurysm (AAA) is a critical vascular condition characterized by pathological dilation of the abdominal aorta, which can culminate in rupture, causing life-threatening hemorrhage and high mortality. AAA prevalence increases with age, particularly affecting men and patients with atherosclerotic risk factors such as smoking, hypertension, and dyslipidemia. Current clinical management hinges on periodic aortic imaging surveillance to monitor aneurysm size and growth rate, with surgical intervention recommended when diameter exceeds 5.5 cm or rapid expansion occurs (≥4.0 mm per year). However, prediction of aneurysm progression remains challenging, leading to missed opportunities for timely intervention or excessive monitoring.
Emerging evidence implicates gut microbiota-derived metabolites, particularly trimethylamine N-oxide (TMAO), in cardiovascular pathology including atherosclerosis and thrombosis. Animal studies have further demonstrated that TMAO promotes AAA progression and rupture, and pharmacologic inhibition of TMAO production attenuates aneurysm growth and fatal outcomes. However, the translational relevance of circulating TMAO as a biomarker for AAA risk and progression in humans had remained unclear.
In this context, a reliable blood biomarker reflecting individual risk for incident AAA, accelerated aneurysm expansion, or imminent need for surgical repair would substantially enhance personalized risk stratification and clinical decision-making.
Study Design
This prospective cohort study incorporated two independent clinical populations undergoing serial abdominal aorta imaging surveillance: a European cohort and a United States cohort. Patients were recruited from single-center vascular studies based in Uppsala, Sweden, and Cleveland, Ohio, respectively.
The European cohort included 237 individuals (median age 65 years; predominantly male 89.0%), and the US cohort comprised 658 individuals (median age 63 years; 79.5% male). Participants underwent repeated aortic imaging with long-term follow-up to track aneurysm size and clinical outcomes.
Plasma concentrations of TMAO were quantified using a sensitive and specific method—stable isotope dilution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Clinical endpoints evaluated included the presence of AAA, rapid aneurysm expansion defined as growth ≥4.0 mm per year, and the recommendation for surgical repair based on either rapid growth or aneurysm diameter ≥5.5 cm.
Statistical analyses adjusted for conventional cardiovascular risk factors and renal function to isolate the independent association of TMAO with AAA-related outcomes.
Key Findings
In the European cohort, elevated plasma TMAO levels were significantly associated with the presence of AAA independent of age, sex, smoking status, hypertension, hyperlipidemia, and kidney function. Importantly, higher TMAO predicted a more than twofold increased risk of fast-growing AAA (adjusted odds ratio [aOR] 2.75; 95% confidence interval [CI], 1.20–6.79) and similarly elevated odds for recommendation of surgical intervention (aOR 2.67; 95% CI, 1.24–6.09).
Consistent results were observed in the larger US cohort as well as in the combined analysis of both cohorts:
– Fast-growing AAA: US cohort aOR 2.71 (95% CI, 1.53–4.80); combined cohorts aOR 2.30 (95% CI, 1.47–3.62).
– Recommended surgical intervention: US cohort aOR 2.73 (95% CI, 1.56–4.80); combined cohorts aOR 2.41 (95% CI, 1.55–3.74).
Notably, adding TMAO measurements to predictive models containing traditional cardiovascular risk variables significantly improved risk stratification capabilities for rapid AAA growth and surgical indication. These enhancements suggest TMAO contributes unique biological information beyond established clinical risk factors.
The study did not report significant safety issues related to biomarker measurement.
Expert Commentary
This comprehensive study provides compelling clinical evidence linking circulating TMAO, a metabolite produced by gut microbiota metabolism of dietary nutrients such as choline and carnitine, with the natural history of AAA in humans. The findings corroborate prior animal models where TMAO accelerated aneurysm formation and rupture, and demonstrate translational relevance in diverse patient cohorts.
By independently associating TMAO with both aneurysm presence and rapid expansion, the study highlights a potential pathogenic role for TMAO beyond being merely a marker of cardiovascular risk. The ability of TMAO levels to improve prediction of fast-growing AAAs and the need for surgery underscores its potential utility as a noninvasive biomarker for personalized surveillance strategies.
From a mechanistic perspective, TMAO may promote vascular inflammation, oxidative stress, and matrix degradation, all of which are key in aneurysm pathogenesis and growth. Therapeutic targeting of TMAO-producing microbial pathways could emerge as a novel intervention to slow or prevent AAA progression.
Limitations include the observational nature which cannot prove causation, the predominance of male participants limiting certainty in females, and potential residual confounding. Further studies are warranted to validate these findings across broader populations and to explore targeted therapies.
Conclusion
This prospective cohort investigation identifies elevated plasma TMAO as a significant biomarker associated with increased risk of abdominal aortic aneurysm development, accelerated aneurysm growth, and higher likelihood of requiring surgical intervention. Measurement of circulating TMAO provides incremental prognostic information beyond traditional risk factors and may facilitate more tailored surveillance schedules and timely surgical referral.
The findings support integration of TMAO assessment into clinical practice to enhance AAA risk stratification. Additionally, targeting TMAO metabolic pathways could offer innovative therapeutic approaches to mitigate aneurysm progression and prevent catastrophic rupture. Future clinical trials should evaluate interventions aimed at modulating gut microbiota metabolism to reduce TMAO and AAA-related morbidity and mortality.
References
Cameron SJ, Li XS, Benson TW, Conrad KA, Wang Z, Fleifil S, Maegdefessel L, Mani K, Björck M, Scalise A, Pham M, Shim S, Wanhainen A, Sharew B, Tian MY, Wu Y, Lusis AJ, Lyden SP, Tang WHW, Owens AP 3rd, Hazen SL. Circulating Trimethylamine N-Oxide and Growth Rate of Abdominal Aortic Aneurysms and Surgical Risk. JAMA Cardiol. 2025 Aug 20:e252698. doi: 10.1001/jamacardio.2025.2698. Epub ahead of print. PMID: 40833686; PMCID: PMC12368795.
Additional literature:
Tang WHW, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–1584.
Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63.
These foundational studies support the emerging role of gut microbial metabolites in cardiovascular diseases including AAA.
