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Trial record 4 of 4 for:    21475195 [PUBMED-IDS]

Trimethylamine-N-oxide Production and Metabolism

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ClinicalTrials.gov Identifier: NCT02558673
Recruitment Status : Completed
First Posted : September 24, 2015
Last Update Posted : November 2, 2016
Sponsor:
Collaborators:
American Egg Board
National Cattlemen's Beef Association
Information provided by (Responsible Party):
Cornell University

Brief 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.

Condition or disease Intervention/treatment Phase
Healthy Other: TMAO dietary precursors Other: Control (or active comparator) Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Impact of Diet and Gut Microbiota on Trimethylamine-N-oxide Production and Fate in Humans
Study Start Date : May 2014
Actual Primary Completion Date : July 2014
Actual Study Completion Date : July 2016

Arm Intervention/treatment
Experimental: Egg
Study meals were administered in commonly consumed serving sizes (3 hard-boiled eggs) and provided comparable amounts of TMAO dietary precursors. Each meal was served with one cup of water, administered in a single day and separated by a 1-week washout period.
Other: TMAO dietary precursors
Experimental: Beef
Study meals were administered in commonly consumed serving sizes (6 oz beef [Philly-Gourmet Beef Patties]) and provided comparable amounts of TMAO dietary precursors. Each meal was served with one cup of water, administered in a single day and separated by a 1-week washout period.
Other: TMAO dietary precursors
Experimental: Fish
Study meals were administered in commonly consumed serving sizes (6 oz fish [cod fillet]) and provided comparable amounts of TMAO dietary precursors. Each meal was served with one cup of water, administered in a single day and separated by a 1-week washout period.
Other: TMAO dietary precursors
Active Comparator: Fruit
Study meals were administered in commonly consumed serving sizes (2 single-serve packages of Mott's natural applesauce) and provided comparable amounts of control (or active comparator). 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.
Other: Control (or active comparator)



Primary Outcome Measures :
  1. TMAO biomarkers [ Time Frame: Assess change from baseline; randomized, controlled, cross-over design with 4 study sessions with 1-week wash-out between visits. Participants were followed for 6 h (egg, beef and fish), and for 6-24 h (fruit + d9-TMAO) ]
  2. Gut microbiome profile [ Time Frame: Baseline ]

Secondary Outcome Measures :
  1. Flavin monooxygenase 3 (FMO3) 472 G>A [ Time Frame: Baseline ]
  2. One-carbon related biomarkers and carnitine [ Time Frame: Assess change from baseline; randomized, controlled, cross-over design with 4 study sessions with 1-week wash-out between visits. Participants were followed for 6 h (egg, beef and fish), and for 6-24 h (fruit + d9-TMAO) ]


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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria (main study):

  • Healthy men of age 21-50 y
  • BMI of 20-29.9 kg/m2 who are willing to comply with the study protocol (consumption of study meals and sample collections)

Inclusion Criteria (sub-study involving muscle biopsy):

  • Healthy participants who are able to undergo or watch medical procedures

Exclusion Criteria (main study):

  • Men over 50 y of age
  • BMI ≥ 30 kg/m2
  • Women, vegetarians, smokers, individuals with gastrointestinal diseases or complaints, chronic illnesses or other metabolic diseases (including trimethylaminuria), abnormal laboratory values, and those taking nutritional supplements, antibiotics or probiotics within 2 months of recruitment.

Exclusion Criteria (sub-study involving muscle biopsy):

  • Men with history of a negative or allergic reaction to local anesthetics
  • Tendency toward easy bleeding or bruising, on medications that may increase the chance of bleeding or bruising (e.g., Aspirin, Coumadin, Anti-inflammatories, Plavix)
  • Currently on any immunosuppressive medications (e.g., glucocorticoid steroids, chemotherapy), with disease pathologies that would impair the healing process (e.g., diabetes, cancer, keloids, hereditary healing disorders, jaundice, alcoholism, HIV/AIDS)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02558673


Locations
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United States, New York
Gannett Health Services, Cornell University
Ithaca, New York, United States, 14853
Human Metabolic Research Unit, Cornell University
Ithaca, New York, United States, 14853
Sponsors and Collaborators
Cornell University
American Egg Board
National Cattlemen's Beef Association
Investigators
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Principal Investigator: Marie A. Caudill, PhD Cornell University

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Cornell University
ClinicalTrials.gov Identifier: NCT02558673     History of Changes
Other Study ID Numbers: OSP 72118
First Posted: September 24, 2015    Key Record Dates
Last Update Posted: November 2, 2016
Last Verified: November 2016

Keywords provided by Cornell University:
Trimethylamine-N-oxide
Biomarkers
Production
Metabolism
Gut microbiome
Healthy