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Updated: Aug 4, 2025
Author Spotlight: Development and Characterization of a Mouse Model for Abdominal Aortic Aneurysm
Published on: August 2, 2024
Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and
Tyler W Benson1,2, Kelsey A Conrad1,2,3, Xinmin S Li4,5
1Department of Internal Medicine (T.W.B., K.A.C., T.M.C., C.W.-L., S.F., H.M.R., M. Brooks, M.T., A.P.O.), University of Cincinnati College of Medicine, OH.
Background:
Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.
Methods:
TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr-/-) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3-/-). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.
Results:
Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3-/- mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.
Conclusions:
These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.
Insights
Trimethylamine N-oxide (TMAO), a metabolite from gut microbes, is linked to abdominal aortic aneurysm (AAA) development. Inhibiting TMAO production offers a potential new therapy for AAA.
Area of Science:
- Cardiovascular Science
- Microbiome Research
- Metabolomics
Background:
- Trimethylamine N-oxide (TMAO) is a microbiome-dependent metabolite linked to cardiometabolic diseases.
- The role of TMAO in abdominal aortic aneurysm (AAA) pathogenesis is not well understood.
- Targeting TMAO-producing microbes presents a potential therapeutic strategy for AAA.
Purpose of the Study:
- To investigate the association between TMAO and AAA incidence and progression.
- To explore the mechanistic role of TMAO in AAA development.
- To evaluate the therapeutic potential of targeting TMAO production in AAA.
Main Methods:
- Analyzed TMAO and choline metabolites in plasma from 2129 patients across two cohorts.
- Utilized murine AAA models (angiotensin II infusion and elastase) with dietary choline supplementation.
- Investigated TMAO inhibition via antibiotics, fluoromethylcholine (CutC/D inhibitor), and FMO3-deficient mice.
- Performed RNA sequencing on human vascular smooth muscle cells and mouse aortas to assess TMAO's effects.
Main Results:
- Elevated TMAO levels correlated with increased AAA incidence and growth in patients.
- Dietary choline increased TMAO and aortic diameter in mouse AAA models, effects suppressed by antibiotics.
- Fluoromethylcholine treatment reduced TMAO, attenuated AAA initiation, and halted progression.
- FMO3-deficient mice showed reduced TMAO, smaller aortic diameters, and protection from rupture.
- TMAO upregulated endoplasmic reticulum stress pathways (PERK) in vascular cells and aortas.
Conclusions:
- Gut microbiota-derived TMAO plays a role in AAA pathogenesis by inducing endoplasmic reticulum stress in the aortic wall.
- Inhibiting microbiome-derived TMAO is a promising novel therapeutic strategy for AAA.
- This study establishes a mechanistic link between microbial metabolites and a major vascular disease.
