title: Blood Trimethylamine-N-Oxide Originates from Microbiota Mediated Breakdown of Phosphatidylcholine and Absorption from Small Intestine.
abstract: Elevated serum trimethylamine-N-oxide (TMAO) was previously reported to be associated with an elevated risk for cardiovascular events. TMAO originates from the microbiota-dependent breakdown of food-derived phosphatidylcholine (PC) to trimethylamine (TMA), which is oxidized by hepatic flavin-containing monooxygenases to TMAO. Our aim was to investigate the predominant site of absorption of the bacterial PC-breakdown product TMA. A healthy human proband was exposed to 6.9 g native phosphatidylcholine, either without concomitant treatment or during application with the topical antibiotic rifaximin, or exposed only to 6.9 g of a delayed-release PC formulation. Plasma and urine concentrations of TMA and TMAO were determined by electrospray ionization tandem mass spectrometry (plasma) and gas chromatography-mass spectrometry (urine). Native PC administration without concomitant treatment resulted in peak plasma TMAO levels of 43 ± 8 μM at 12 h post-ingestion, which was reduced by concomitant rifaximin treatment to 22 ± 8 μM (p < 0.05). TMAO levels observed after delayed-release PC administration were 20 ± 3 μM (p < 0.001). Accordingly, the peak urinary concentration at 24 h post-exposure dropped from 252 ± 33 to 185 ± 31 mmol/mmol creatinine after rifaximin treatment. In contrast, delayed-release PC resulted in even more suppressed urinary TMAO levels after the initial 12-h observation period (143 ± 18 mmol/mmol creatinine) and thereafter remained within the control range (24 h: 97 ± 9 mmol/mmol creatinine, p < 0.001 24 h vs. 12 h), indicating a lack of substrate absorption in distal intestine and large bowel. Our results showed that the microbiota in the small intestine generated the PC breakdown product TMA. The resulting TMAO, as a cardiovascular risk factor, was suppressed by topical-acting antibiotics or when PC was presented in an intestinally delayed release preparation.
authors.affiliation: Department of Gastroenterology, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.affiliation: Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Kathrin V
authors.initials: KV
authors.lastname: Schmidt
authors.affiliation: Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Schuhmann
authors.affiliation: Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Kratzer
authors.affiliation: Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Sven F
authors.initials: SF
authors.lastname: Garbade
authors.affiliation: Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Langhans
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
authors.affiliation: Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood* / Q000473:pathology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D008744:Methylamines / Q000097:blood* / Q000652:urine; D064307:Microbiota / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010087:Oxides / Q000378:metabolism; D010713:Phosphatidylcholines / Q000008:administration & dosage; D012294:Rifamycins / Q000008:administration & dosage; D000078262:Rifaximin; D012307:Risk Factors; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D008744:Methylamines; D010087:Oxides; D010713:Phosphatidylcholines; D012294:Rifamycins; D006899:Mixed Function Oxygenases; C005855:trimethyloxamine; D000078262:Rifaximin; C023336:trimethylamine