Trimethylamine N-oxide and related metabolites may regulate DNA methylation and trigger cardiovascular disease

Authors: MA, JIANTAO - Tufts University; Lai, Chao Qiang; WANG, MENG - Tufts University; YAO, JIE - University Of California (UCLA); GUO, XIUQING - University Of California (UCLA); TAYLOR, KENT - University Of California (UCLA); ROTTER, JEROME - University Of California (UCLA); BUDOFF, MATHEW - University Of California (UCLA); TANG, WILSON - Case Western Reserve University (CWRU); DIDONATO, JOSEPH - Case Western Reserve University (CWRU); LI, XINMIN - Case Western Reserve University (CWRU); WANG, ZENENG - Case Western Reserve University (CWRU); BRODY, JENNIFER - University Of Washington; LEMAITRE, ROZENN - University Of Washington; FRETTS, AMANDA - University Of Washington; SOTOODEHNIA, NONA - University Of Washington; PSATY, BRUCE - University Of Washington; ORDOVAS, JOSE - Tufts University; SISCOVICK, DAVID - New York Academy Of Medicine; HAZEN, STANLEY - Case Western Reserve University (CWRU); MOZAFFARIAN, DARIUSH - Tufts University

Submitted to: Clinical Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/13/2026
Publication Date: 2/9/2026
Citation: Ma, J., Lai, C., Wang, M., Yao, J., Guo, X., Taylor, K., Rotter, J.I., Budoff, M., Tang, W.W., Didonato, J.A., Li, X.S., Wang, Z., Brody, J.A., Lemaitre, R.N., Fretts, A., Sotoodehnia, N., Psaty, B.M., Ordovas, J.M., Siscovick, D.S., Hazen, S.L., Mozaffarian, D. 2026. Trimethylamine N-oxide and related metabolites may regulate DNA methylation and trigger cardiovascular disease. Clinical Epigenetics. 18. Article 45. https://doi.org/10.1186/s13148-026-02060-w.
DOI: https://doi.org/10.1186/s13148-026-02060-w

Interpretive Summary: Scientists from the Agricultural Research Service (ARS) and their collaborators investigated how chemicals produced by gut bacteria influence our DNA and overall health. These chemicals are generated when we consume red meat and can impact a process called DNA methylation, which regulates gene activity. The study analyzed blood samples from over 1,300 older adults to identify links between these gut-derived chemicals and specific DNA modifications. Researchers discovered 143 connections between these chemicals and DNA sites associated with immune function and heart health. One key finding was that a specific DNA modification linked to lower levels of a chemical called betaine appeared to reduce the risk of heart disease. This suggests that gut bacteria and diet may play a significant role in cardiovascular health. These insights deepen our understanding of how the food we eat influences our genes and disease risk. While more research is needed, this study moves us closer to developing dietary strategies for maintaining heart health by targeting gut microbiota.

Technical Abstract: Background: Trimethylamine N-oxide (TMAO) and its related metabolites have been linked to cardiovascular disease (CVD), but their impact on DNA methylation remains unclear. Investigating these associations may help clarify the role of epigenetic mechanisms in disease risk. Methods: This study analyzed data from 1,356 adults over the age of 45 from the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Using liquid chromatography-mass spectrometry (LC-MS) with stable-isotope dilution, we quantified TMAO and five related metabolites. DNA methylation levels were measured using Illumina BeadChip arrays. Epigenome-wide association analyses and meta-analyses were conducted across approximately 430,000 CpG sites. To explore the functional significance of the identified CpGs, we performed gene set enrichment analysis and Mendelian randomization (MR) analyses. Results: We identified 143 significant metabolite-CpG associations (FDR < 0.05), including four CpGs for TMAO (P = 4.03e-7), 12 for betaine (P = 1.19e-6), 53 for gamma-butyrobetaine (P = 6.11e-6), five for carnitine (P = 5.42e-7), six for choline (P = 2.81e-7), and 63 for crotonobetaine (P = 7.25e-6). CpGs associated with gamma-butyrobetaine showed moderate correlation with crotonobetaine-associated CpGs. In total, these metabolite-linked CpGs were mapped to 108 genes. Gene set enrichment analysis revealed 145 significantly enriched gene sets, including nine highly relevant to CVD risk. Furthermore, CpGs were enriched in 80 immunologic signature gene sets (FDR < 0.05). MR analysis identified three CpGs associated with coronary artery disease (CAD), including hypermethylation at cg18705301 (NDUFAF1), which was inversely associated with betaine levels and linked to a lower risk of CAD (P = 1.8e-5). Conclusion: This study identified specific DNA methylation sites associated with TMAO-related metabolites in older adults. These epigenetic changes may contribute to cardiovascular disease risk through multiple pathways. Future research should validate these findings and explore their potential clinical implications.