Trimethylamine-N-oxide (TMAO) predicts fatal outcomes in community-acquired pneumonia patients without evident coronary artery disease

Abstract Introduction The pro-atherosclerotic metabolite trimethylamine-N-oxide (TMAO) is a risk factor for incident cardiovascular events and a potentially modifiable mediator of chronic inflammation through broad-spectrum antibiotic treatment by changing the microbiome. Whether TMAO is associated with adverse clinical outcomes in acute inflammatory community-acquired pneumonia (CAP) patients is unknown. Methods A total of 317 CAP patients from a previous Swiss multicenter trial were prospectively followed for a median of 6.1 years. TMAO plasma levels were measured by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). We used Cox regression models to investigate associations between baseline TMAO levels and all-cause mortality. Results Six-year mortality was 45.1%, and 18.9% of the patients had coronary artery disease (CAD). Median admission TMAO (μmol L − 1 ) levels were significantly higher in non-survivors compared to survivors (4.1 [interquartile range (IQR), 2.2–7.2] vs. 2.5 [IQR, 1.5–4.1]; p < 0.001). A strong association between TMAO and 6-year all-cause mortality was found for patients without CAD (adjusted hazard ratio (HR) 1.9 ([95% CI 1.2–3.1]; p < 0.05). In patients with known CAD, no such association was found (adjusted HR 0.6 (0.2–1.6); p = 0.309, interaction p = 0.009). In patients without antibiotic pretreatment receiving antibiotic treatment, TMAO significantly decreased from admission to day seven (median, 3.9 [IQR, 2.1–7.5] vs. 3.1 [IQR, 1.4–6.6]; p < 0.01). Conclusions TMAO is associated with long-term fatal outcomes in CAP patients without evident CAD and modifiable through antibiotic treatment. Whether chronic modulation of TMAO by targeting the microbiome reduces mortality risk needs to be evaluated in future interventional trials.