A-001 The Postprandial Levels of the Metabolites in the Metaorganismal Trimethylamine N-Oxide (TMAO) Pathway are Altered in A Diet-, Microbe-, and Sex-Specific Manner

Abstract

Abstract Background Cardiovascular disease (CVD) remains the leading cause of death in developed countries. Elevated levels of the gut-microbe-associated metabolite trimethylamine-N-oxide (TMAO) have been associated with increased risk for CVD mortality in many large independent studies. In fact, large laboratory corporations such as Labcorp and Quest Diagnostic now offer TMAO diagnostic tests for the assessment of CVD risk and as a marker for disease-associated dysbiosis, using samples obtained from fasting patients. Although the strong association between TMAO levels and CVD risk has been established in fasting blood samples, here we are investigating the potential for a single meal to dynamically alter TMAO-related metabolites based on sex, diverse dietary substrates, and microbial influences. Methods 35 healthy participants were randomized to one of four study groups with approximately 8-9 subjects in each arm. Half of the participants were randomly assigned to receive a three-day broad spectrum antibiotic regimen (ciprofloxacin, metronidazole, and vancomycin) while the others received no antibiotics. These two groups were further subdivided into a group consuming a highly processed meal (originating from local fast food restaurants) or alternatively a whole food meal (containing a variety of fruits, vegetables, and healthy fiber). Blood samples were taken at baseline (after an overnight fast), and then postprandially at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after meal ingestion. Targeted plasma metabolites were quantified using a stable isotope dilution, liquid chromatography - tandem mass spectrometry (LC-MS/MS) method Results While plasma TMAO levels between food groups did not change significantly within the total cohort, there were clear individualized responses to either highly processed or whole food meals. Separation based on sex showed that TMAO levels were significantly reduced in females at 6 hours but remained steady in males for both food groups. Particularly, in the processed food group, TMAO levels were significantly lower in females than males at the 6-hour time point. Neither of these observations held true for TMAO precursors choline, carnitine, or betaine. However, plasma levels of a dietary precursor for TMAO, γ-butyrobetaine, showed clear diet-microbe-host interactions. For males in the processed food group, plasma γ-butyrobetaine levels were significantly increased in subjects on broad spectrum antibiotics. Conclusions Our results show the postprandial levels of TMAO, and its nutrient precursors dynamically change in a diet-, microbe-, and sex-dependent manner. These findings provide new insights into the postprandial levels of TMAO-related metabolites and may inform precision nutritional approaches in those who could benefit from TMAO-lowering strategies.