title: Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation.
abstract: OBJECTIVE
  Trimethylamine-N-oxide (TMAO) is produced in host liver from trimethylamine (TMA). TMAO and TMA share common dietary quaternary amine precursors, carnitine and choline, which are metabolized by the intestinal microbiota. TMAO recently has been linked to the pathogenesis of atherosclerosis and severity of cardiovascular diseases. We examined the effects of anti-atherosclerotic compound meldonium, an aza-analogue of carnitine bioprecursor gamma-butyrobetaine (GBB), on the availability of TMA and TMAO.
  
  
  METHODS
  Wistar rats received L-carnitine, GBB or choline alone or in combination with meldonium. Plasma, urine and rat small intestine perfusate samples were assayed for L-carnitine, GBB, choline and TMAO using UPLC-MS/MS. Meldonium effects on TMA production by intestinal bacteria from L-carnitine and choline were tested.
  
  
  RESULTS
  Treatment with meldonium significantly decreased intestinal microbiota-dependent production of TMA/TMAO from L-carnitine, but not from choline. 24hours after the administration of meldonium, the urinary excretion of TMAO was 3.6 times lower in the combination group than in the L-carnitine-alone group. In addition, the administration of meldonium together with L-carnitine significantly increased GBB concentration in blood plasma and in isolated rat small intestine perfusate. Meldonium did not influence bacterial growth and bacterial uptake of L-carnitine, but TMA production by the intestinal microbiota bacteria K. pneumoniae was significantly decreased.
  
  
  CONCLUSIONS
  We have shown for the first time that TMA/TMAO production from quaternary amines could be decreased by targeting bacterial TMA-production. In addition, the production of pro-atherogenic TMAO can be suppressed by shifting the microbial degradation pattern of supplemental/dietary quaternary amines.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia. Electronic address: janis_kuka@biomed.lu.lv.
authors.forename: Janis
authors.initials: J
authors.lastname: Kuka
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Rigas Stradins University, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Marina
authors.initials: M
authors.lastname: Makrecka-Kuka
authors.affiliation: University of Latvia, Institute of Microbiology and Biotechnology, Kronvalda Blvd. 4, Riga LV-1586, Latvia.
authors.forename: Janis
authors.initials: J
authors.lastname: Liepins
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Helena
authors.initials: H
authors.lastname: Cirule
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Daina
authors.initials: D
authors.lastname: Gustina
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Einars
authors.initials: E
authors.lastname: Loza
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Olga
authors.initials: O
authors.lastname: Zharkova-Malkova
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Osvalds
authors.initials: O
authors.lastname: Pugovics
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Rigas Stradins University, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000818:Animals; D001622:Betaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D053898:Biosynthetic Pathways / Q000187:drug effects* / Q000502:physiology; D002247:Carbon Isotopes / Q000378:metabolism; D002331:Carnitine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002794:Choline / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D041981:Gastrointestinal Tract / Q000382:microbiology*; D008744:Methylamines / Q000378:metabolism* / Q000652:urine; D008763:Methylhydrazines / Q000494:pharmacology*; D064307:Microbiota / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D053719:Tandem Mass Spectrometry
chemical_list: D002247:Carbon Isotopes; D008744:Methylamines; D008763:Methylhydrazines; D001622:Betaine; C002889:gamma-butyrobetaine; C050147:3-(2,2,2-trimethylhydrazine)propionate; C005855:trimethyloxamine; D002794:Choline; D002331:Carnitine
keywords: Gamma-butyrobetaine; Intestinal bacteria; L-carnitine; Meldonium; Trimethylamine; Trimethylamine N-oxide