Diet–Microbiota–Metabolome Interactions: The Role of Trimethylamine-N-Oxide (TMAO) as a Nutritional Metabolomics Biomarker in Humans

Introduction:
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite increasingly studied as a biomarker linking diet, host metabolism, and cardiometabolic health. It is produced from dietary precursors such as choline, betaine, and L-carnitine, making it a key component of the diet–microbiota–metabolome axis.

Methods:
A literature review was conducted to assess how dietary patterns influence circulating and urinary TMAO levels in humans. Studies were retrieved from PubMed, Scopus, and Cochrane databases up to July 2026. Eligible studies were original human research examining TMAO in relation to diet interventions or patterns. Out of 447 records, 31 studies met the inclusion criteria and were analyzed qualitatively, considering study quality and methodological limitations.

Results:
Dietary patterns strongly influence TMAO concentrations, supporting its role as a metabolomic marker of diet-related metabolic responses. Plant-based diets (Mediterranean, vegetarian, vegan, DASH) are generally linked to lower TMAO levels, while diets rich in red meat and animal products tend to increase them. Weight loss and caloric restriction are also associated with reduced TMAO. Intervention studies show that TMAO levels can change rapidly with dietary modifications. However, the relationship is complex: increases in TMAO have been observed after consuming foods considered cardioprotective, such as fish and whole grains. This suggests that elevated TMAO is not always indicative of unhealthy diets. Inter-individual variability, influenced by host and microbial factors, further complicates interpretation, and gut microbiota composition alone does not fully predict TMAO production.

Conclusions:
TMAO is a promising biomarker in nutritional metabolomics for studying interactions between diet, gut microbiota, and metabolism. While responsive to dietary changes, its interpretation in cardiometabolic risk requires caution, as its role depends on dietary context, host characteristics, and microbial activity. More longitudinal and controlled studies integrating metabolomic, microbiome, and clinical data are needed to clarify its biological significance and potential in precision nutrition.