Trimethylamine-N-oxide Production and Metabolism
Condition: Healthy
Study type: Interventional

Summary: 
      The purpose of this study was to understand the production of trimethylamine-N-oxide (TMAO)
      and its metabolites from dietary precursors found in fish, eggs and beef. In addition, this
      study traced the fate of supplemental TMAO that has been labeled with deuterium to determine
      how TMAO is being used in the body.
    

Detailed description: 
      Trimethylamine-N-oxide (TMAO) is a carbon-containing organic compound formed from dietary
      precursors including TMAO (high in fish), choline (high in eggs) and carnitine (high in
      beef). However, TMAO production is highly variable (Zhang AQ et al., 1999), appears to be
      influenced by genetics (Cashman JR et al., 2001) and gut microbiome (Wang Z et al., 2011;
      Koeth RA et al., 2013), and is linked to heart disease in cardiac patients (Wang Z et al.,
      2011) and colorectal cancer among post-menopausal women (Bae S et al., 2015). At present,
      very little is known about the metabolic fate of TMAO and how it is used within the human
      body (Bain MA et al., 2005). This study sought to (i) quantify the effects of eggs, beef and
      fish on TMAO biomarkers in plasma, muscle, urine and stool; (ii) examine the metabolic fate
      of supplemental TMAO labeled isotopically with deuterium; and (iii) determine whether TMAO
      production is a function of the gut microbiome.

      To accomplish these objectives, a randomized, controlled cross-over study was conducted in
      healthy male participants (n=40). The study incorporated four arms comprised of study meals
      representing animal sources of TMAO (egg, beef and fish) along with a fruit control. The
      study meals were (i) 3 whole hard-boiled eggs; (ii) 6 oz beef (Philly-Gourmet Beef Patties);
      (iii) 6 oz fish (cod fillet); and (iv) 2 single-serve packages of Mott's natural applesauce.
      Each meal was served with one cup of water, administered in a single day and separated by a
      1-week washout period. For the fruit control, 50 mg deuterium-labeled methyl-d9-TMAO
      (d9-TMAO; Cambridge Isotopes) was added to one cup of water for oral consumption to enable
      the tracing of the metabolic fate of TMAO, and to assess its bioavailability and clearance.

      Baseline blood sample was obtained by a phlebotomist using a standard venipuncture procedure,
      and participants collected their baseline urine sample. They also turned in self-collected
      baseline 24 h urine and stool samples. Following the consumption of the study meal, serial
      blood samples were collected at 15, 30 min and 1, 2, 4 and 6 h, while urine samples were
      collected throughout the 6 h study period. At 4.5 h, participants were provided a fixed fruit
      snack (i.e., applesauce) and water. On the day that participants consumed the d9-TMAO tracer,
      participants collected their urine throughout the next 24 h and their stool at the next bowel
      movement. In addition, a subset of this group (n=6) were invited to undergo a muscle biopsy
      procedure 6 h after the fruit + d9-TMAO tracer consumption.
    

Intervention name(s): TMAO dietary precursors; Control (or active comparator)
Intervention type(s): Other; Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Trimethylamine-N-oxide; Biomarkers; Production; Metabolism; Gut microbiome; Healthy