From Fecal Microbial Potential to Circulating Trimethylamine N-oxide and Cardiovascular Events: A Narrative Review

Trimethylamine N-oxide (TMAO) is frequently presented as a gut microbiota-derived cardiovascular biomarker, but this label compresses several biologically distinct transitions into a single causal narrative. Microbial gene carriage does not establish active trimethylamine (TMA) flux; a fecal TMA or TMAO signal does not quantify the absorbed dose; circulating TMAO integrates microbial and dietary input with intestinal absorption, hepatic flavin-containing monooxygenase 3 (FMO3) activity, tissue distribution, sampling time, and renal clearance; and a prognostic association does not by itself demonstrate causal cardiovascular mediation. This critical narrative review examines the limits of inference across these levels. Meta-analyses of prospective cohorts have generally reported modest associations between higher circulating TMAO and adverse cardiovascular outcomes, while recent community cohorts provide additional positive evidence. Nevertheless, effect sizes and interpretation vary across populations, and null or context-dependent findings remain important. The closest prior compartment-focused systematic review evaluated the effect of red meat on circulating, urinary, and fecal TMAO in randomized trials. The present review addresses a different and broader question: when is it valid to move from stool-based microbial or metabolite measurements to systemic exposure and cardiovascular claims? We organize the evidence as a series of gates linking microbial capacity, realized luminal metabolism, absorption, FMO3-dependent oxidation, circulating concentration, and clinical outcome. The fecal TMAO literature remains sparse, and stool microbial profiles have not reliably predicted diet-induced systemic TMAO responses. Mendelian randomization and kidney-function studies further challenge a simple unidirectional causal interpretation. We propose a matrix-specific conceptual framework for reporting and study design. At present, fecal TMAO is best interpreted as an exploratory intestinal measurement, not as a surrogate for circulating TMAO or an independently validated cardiovascular risk marker. Future studies should pair biological matrices, quantify TMA and TMAO, standardize diet and timing, characterize renal and FMO3-relevant host factors, and test mediation rather than association alone.