Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.
Level 3 - non-randomized controlled study
Prospective non-randomized cohort study with time-varying mediation analysis
PubMed 35912635 · doi:10.1161/ATVBAHA.121.316533
What was done
Researchers evaluated 3,931 community-dwelling US adults aged 65 and older from the Cardiovascular Health Study. Animal-source food (ASF) intakes and plasma trimethylamine N-oxide (TMAO)-related metabolites (including L-carnitine-derived γ-butyrobetaine and crotonobetaine) were measured serially over time. Incident atherosclerotic cardiovascular disease (ASCVD: myocardial infarction, fatal coronary heart disease, stroke, atherosclerotic death) was adjudicated over a median 12.5-year follow-up. Multivariable Cox proportional hazards models with time-varying exposures evaluated associations, and additive hazard models estimated mediation proportions by microbial and traditional risk pathways.
What was found
Higher intake was significantly associated with incident ASCVD per interquintile range: unprocessed red meat (HR 1.15, 95% CI 1.01–1.30), total meat (HR 1.22, 95% CI 1.07–1.39), and total ASF (HR 1.18, 95% CI 1.03–1.34). TMAO-related metabolites statistically mediated these associations: 10.6% (95% CI 1.0–114.5) for unprocessed red meat, 7.8% (95% CI 1.0–32.7) for total meat, and 9.2% (95% CI 2.2–44.5) for total ASF. Processed meat had a non-significant association (HR 1.11, 95% CI 0.98–1.25), and fish, poultry, and egg intakes showed no significant link. Blood glucose, insulin, and C-reactive protein also significantly mediated the total meat association, whereas blood pressure and cholesterol did not.
Why it matters
This study provides prospective human evidence that the cardiovascular risk associated with meat consumption in older adults is partially mediated by gut microbiota-derived metabolites of L-carnitine, alongside glycemic and inflammatory markers, rather than conventional lipid pathways.
Limits
The observational design cannot establish causality or exclude residual confounding. The study population was restricted to US adults aged 65+, limiting generalizability to younger or more diverse populations. Confidence intervals for mediation proportions were very wide, reflecting substantial statistical uncertainty in the precise contribution of the TMAO pathway.
Cited by
- supports Carnitine from meat is converted by gut bacteria into TMAO, an inflammatory molecule mechanistically linked to atherosclerosis and elevated blood pressure.