Free Choline, but Not Phosphatidylcholine, Elevates Circulating Trimethylamine-N-oxide and This Response Is Modified by the Gut Microbiota Composition in Healthy Men

Abstract

Objectives Trimethylamine-N-oxide (TMAO), a choline-derived gut microbiota-dependent metabolite, is a newly recognized risk marker for cardiovascular disease. However, the contributions of different forms of choline and gut microbiota composition on TMAO production are largely unknown. The objectives of this study were to: 1) compare acute TMAO response to meals containing free choline (choline bitartrate) versus fat-soluble choline (phosphatidylcholine) and 2) to determine the effects of gut microbiota composition on TMAO response. Methods In a controlled, double-blinded, cross-over study, healthy men (n = 37) were provided meals containing (i) 600 mg choline as choline bitartrate (free choline); (ii) 600 mg choline as phosphatidylcholine; or (iii) no choline control in a random order. Blood and urine samples were collected at baseline and throughout the 6-h study period; a one-time stool sample was collected at baseline. Results Compared to no choline and phosphatidylcholine, free choline yielded 295% higher plasma TMAO (P = 0.002) and 250% higher urinary TMAO (P = 0.01), with no difference in TMAO response between phosphatidylcholine and no choline. High-TMAO producers (those with ≥40% increase in urinary TMAO response to free choline) had significantly different beta-diversity measures (unweighted UniFrac; PERMANOVA P = 0.01) compared to low-TMAO producers (those with <40% increase in TMAO response) but showed no difference in alpha-diversity. Analysis of Composition of Microbiomes (ANCOM) revealed that high-TMAO producers had more abundant lineages of Clostridium from Ruminococcaceae and Lachnospiraceae (in phylum Firmicutes) compared to low-TMAO producers (P < 0.05 with the strength of the ANCOM test W = 11 and W = 8, respectively). Conclusions Given that the majority of choline in food is in the form of phosphatidylcholine, the absence of TMAO elevation with phosphatidylcholine counters arguments that dietary choline should be avoided for TMAO-producing characteristics. Further, development of individualized dietary recommendations based on the gut microbiota composition may be a more appropriate strategy to reduce risk of cardiovascular disease. Funding Sources This research was supported by the Utah Agricultural Experiment Station Seed Grants Program.

Differential metabolism of choline supplements in adult volunteers

“…Apparently, the formation of TMA and TMAO depends on individual microbiota, but may be influenced by many factors, like occult inflammation or intestinal transit time. Whereas PC is degraded by colonic microbes, and choline and lyso-PC formed, it is not known whether patients with pancreatic insufficiency and, therefore, fecal choline losses, automatically have increased TMAO levels and whether the supplementation of such patients with PC rather than choline chloride or bitartrate will prevent TMAO formation [ 3 , 34 , 35 ]. It must also be discussed whether egg-PC should be used for supplementation in infants.…”

Maternal nutrients and effects of gestational COVID-19 infection on fetal brain development

“…Higher choline-containing diets >486 mg/day were not associated with increased risk of cardiovascular disease in 14,430 middle aged men and women in the 14-year Atherosclerosis Risk in Communities study [70]. Phosphatidylcholine supplements containing 600 mg choline in 37 healthy men did not increase plasma or urinary TMAO, whereas choline bitartrate containing 600 mg raised plasma TMAO 3-fold [67]. A pharmaceutical company is developing an inhibitor of bacterial production of trimethylamine and commissioned a systematic review of effects of choline and choline and phosphatidylcholine supplements in fetal development [71,72].…”

Die Bedeutung von Cholin für die Entwicklung von Säuglingen und Kindern

“…Sie enthalten meist unphysiologische Cholinsalze, die – auch ohne Fehlbesiedlung des Dünndarms – zu erhöhter bakterieller Bildung von Trimethylamin führen, gefolgt von dessen Oxidation zu Trimethylaminoxid (TMAO) in der Leber. TMAO-Bildung findet bei physiologischen Cholinkomponenten von Lebensmitteln weniger oder gar nicht statt 8 9 .…”