Trimethylamine N-Oxide response to a mixed macronutrient tolerance test in a cohort of United States adults

Authors: JAMES, KRISTEN - University Of California, Davis; Gertz, Erik; Kirschke, Catherine; ALLAYEE, H - University Of Southern California; Huang, Liping; Kable, Mary; Newman, John; Stephensen, Charles; Bennett, Brian

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/18/2023
Publication Date: 1/20/2023
Citation: James, K.L., Gertz, E.R., Kirschke-Schneide, C.P., Allayee, H., Huang, L., Kable, M.E., Newman, J.W., Stephensen, C.B., Bennett, B.J. 2023. Trimethylamine N-Oxide response to a mixed macronutrient tolerance test in a cohort of United States adults. International Journal of Molecular Sciences. 24(3). Article 2074. https://doi.org/10.3390/ijms24032074.
DOI: https://doi.org/10.3390/ijms24032074

Interpretive Summary: The circulating metabolome consists of metabolites that are absorbed directly from the diet, produced by human metabolism, and/or that are derived from the metabolism of the gut microbiome. Studies of the plasma metabolome have played tremendous roles in identifying key microbiome-derived metabolites like trimethylamine n-oxide (TMAO), short-chain fatty acids, tryptophan metabolites and bile acids, that are associated with several diseases. How TMAO concentrations change in response to a high-fat meal challenge is unknown. We hypothesized that the MMTT would result in postprandial changes in TMAO concentration due to the release of phosphatidylcholines and bile acids during digestion. We assessed whether there were individualized response types (i.e. non-responder, fast-responder, or slow-responder) and whether the responses were related to the composition of the gut microbiome or the FMO3 genotype. Further, we relate response types to cardiometabolic biomarkers asking whether fasted or total exposure to TMAO over the 6-hour postprandial period was better at predicting metabolic dysregulation. Our results have important implications for precision nutrition, eating behavior, and for broadening our understanding of food sources considered TMAO precursors.

Technical Abstract: Plasma trimethylamine n-oxide (TMAO) concentration increases in responses to feeding TMAO, choline, phosphatidylcholine, L-carnitine, and betaine but it is unknown whether concentrations change following a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO precursors. In this proof-of-concept study, we provided female and male adults (n=97) ranging in age (18-65 years) and BMI (18-44 kg/m2) and who were unmedicated for cardiometabolic disease a MMTT (60% fat, 25% sugar, 42% of a standard 2,000 kilo calorie diet) containing limited TMAO precursors. We recorded their metabolic response at fasting and at 30 min, 3 hours, and 6 hours postprandially and observed varying TMAO responses (timing and magnitude). We quantified total exposure to TMAO (AUC-TMAO) as well as classified individuals by the blood draw they experienced their maximal TMAO concentration (TMAO-response groups). To interrogate postprandial TMAO changes, we related AUC-TMAO to the 16S fecal microbiome, to two SNPs in the exons of the FMO3 gene (rs2266782, G>A, p.Glu158Lys; and rs2266780, A>G, p.Glu308Gly), and to 104 plasma metabolites including phosphatidylcholines, lysophosphatidylcholines, bile acids, and uremic toxins. Finally, we asked whether AUC-TMAO or TMAO-response type was associated with cardiovascular disease biomarkers and observed a strong correlation between TMAO and TNF-a that depended on TMAO response group. Overall, these findings promote precision nutrition and have important ramifications for the eating behavior of adults who could benefit from reducing TMAO exposure, and for understanding factors that generate plasma TMAO.