Trimethylamine-N-oxideNCT03232099
Red Wine Effects Upon Gut Flora and Plasma Levels of Trimethylamine-N-oxide (TMAO) - WineFlora Study
A study testing Red Wine consumption and Period without alcohol consumption in people with Trimethylamine-N-oxide and Gut Microbiota, run by University of Sao Paulo General Hospital.
Trial summary
Recent evidence indicates that Trimethylamine-N-oxide (TMAO) is a pro-atherosclerotic, phosphatidylcholine-dependent metabolite of diet and intestinal flora. Food substrates derive from carnitine and phosphatidylcholine (lecithin), present mainly in eggs, red meat, liver and pork. Read more about this study
- Who is it for?
- Ages 45 to 70 years, men only
- Conditions the study is for
- Trimethylamine-N-oxide, Gut Microbiota, Effects of Red Wine
- What is being tested?
- Red Wine consumption and Period without alcohol consumption
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- No sites listed yet
- Study dates
- 31 Aug 2016to 15 Apr 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 70 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men, 45-70 years
- Established atherosclerotic diseases defined as:
- Previous history of CAD: angina or acute myocardial infarction (AMI), myocardial revascularization or angioplasty, angiographic evidence of stenosis ≥50% in at least one of the major coronary arteries B. Cerebrovascular disease: transient ischemic stroke or cerebrovascular accident C. Peripheral arterial disease: clinical evidence of extracoronary atherosclerosis
Who cannot join
- Acute events in the last 30 days (AMI, troponin elevation, coronary angioplasty or coronary artery bypass grafting)
- Heart Failure (NYHA functional class ≥ II)
- Renal Failure (clearance creatinine <30 mL / min by the Cockcroft-Gault formula)
- Hepatic Failure
- Gastro-intestinal cancer
- Intestinal inflammatory diseases
Show all 11Show fewer
- Obstructive biliary diseases
- Prior gastrointestinal surgeries: cholecystectomy or colectomy
- Use of antibiotics within the last 2 months or during protocol
- Alcoholism or alcohol intolerance
- Diabetes mellitus or use of antidiabetics drugs
About this study
Official title: Evaluation of Red Wine Effects Upon Gut Flora and Plasma Levels of Trimethylamine-N-oxide (TMAO) in Patients With Established Atherosclerotic Disease
Recent evidence indicates that Trimethylamine-N-oxide (TMAO) is a pro-atherosclerotic, phosphatidylcholine-dependent metabolite of diet and intestinal flora. Food substrates derive from carnitine and phosphatidylcholine (lecithin), present mainly in eggs, red meat, liver and pork. The intestinal flora pattern that favors the formation of TMAO is very similar to that which predisposes to insulin resistance and obesity: a high proportion between phylum Firmicutes over Bacteroidetes. The intestinal microbiota is sensitive and variable; the use of prebiotics and probiotics can change the relationship between Firmicutes/Bacteroidetes phyla. Red wine (RW), for its composition with polyphenols and possible bactericidal role, may play a role in the intestinal flora modification and could promote proliferation of beneficial bacteria. However, the influence of RW on TMAO is not known. This is the hypothesis to be tested in this trial. METHODS: This is a prospective, crossover, randomized, controlled trial with patients from Heart Institute (InCor), FMUSP and volunteers recruited through press releases. We will evaluate 42 patients, all men, with established atherosclerotic disease. Patients will be evaluated in a crossed manner: each subject receives both treatments, intervention and control (in random order), and they will be divided into 2 groups: A and B. In the first intervention stage, after 2 weeks of washout for all patients , group A receives Red Wine (RW) and group B is the control, abstemious. In the 2nd stage of intervention, after 2 weeks of washout for all patients the groups are inverted: group B receives RW; and group A will be abstemious. In the period with wine intervention, patients will receive 250 mL/day of red wine per day, for 5 days of the week, for 3 weeks. Patients will maintain their usual diet without the use of prebiotics or probiotics, or other polyphenolic derivatives. At the beginning and at the end of each stage, patients will be submitted to serum TMAO and intestinal microbiota evaluation. For the intestinal microbiota evaluation, the new generation sequencing will be used in the highly preserved portion of the 16S subunit of the rRNA gene. The determination of TMAO in plasma will be by liquid chromatography coupled to mass spectrometry. Expected results: It is expected to determine if RW acts on the intestinal flora to the point of influencing plasma TMAO concentration.
- Being tested
- Red Wine consumption, Period without alcohol consumption
- Keywords
- trimethylamine-N-oxide, TMAO, Gut Microbiota, Gut Flora, Atherosclerosis, Wine, Red Wine
- Medical subject headings
- Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Red Wine consumptionDietary supplement
After a two weeks washout period,in the intervening period with red wine, patients will receive 250 mL / day of red wine per Day, 5 days a week, for 3 weeks.
Period without alcohol consumptionOther
Also called Abstain Period
After a two weeks washout period,in the Abstemious period, patients should not consume any kind of alcohol beverages, for 3 weeks
| Study group | Role | What they receive |
|---|---|---|
| Red Wine group (RW) | Experimental | After a two weeks washout period,in the intervening period with red wine, patients will receive 250 mL / day of red wine per Day, 5 days a week, for 3 weeks. Receives: Dietary Supplement: Red Wine consumption |
| Abstemious | Active comparator | After a two weeks washout period,in the Abstemious period, patients should not consume any kind of alcohol beverages, for 3 weeks Receives: Other: Period without alcohol consumption |
What is being measured
The primary outcome is the main question the study is designed to answer.
Gut flora modification assessed by 16S ribosomal rNA gene sequencing and plasma concentration of TMAO changes measured by liquid chromatography coupled to mass spectrometry in 42 patients after ingestion 250 mL of Red Wine 5 days/week, for 3 weeks
Patients will be divided into 2 groups: A and B. In the first intervention stage, after 2 weeks of washout for all patients , group A receives Red Wine (RW) and group B is the control, abstemious. In the 2nd stage of intervention, after 2 weeks of washout for all patients the groups are inverted: group B receives RW; and group A will be abstemious. In the period with wine intervention, patients will receive 250 mL/day of red wine per day, for 5 days of the week, for 3 weeks. Patients will maintain their usual diet without the use of prebiotics or probiotics, or other polyphenolic derivatives. At the beginning and at the end of each stage, patients will be submitted to serum TMAO and intestinal microbiota evaluation. For the intestinal microbiota evaluation, the new generation sequencing will be used in the highly preserved portion of the 16S subunit of the rRNA gene. The determination of TMAO in plasma will be by liquid chromatography coupled to mass spectrometry
Measured: up to 10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2017
- Study start31 Aug 2016
- Primary completion22 Mar 2018
- Study completion15 Apr 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Trimethylamine-N-oxideStudies of the same condition, open and under way.
- More trials run by University of Sao Paulo General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Forty two men with established atherosclerotic disease will be studied:after a 2 week washout period, each subject receives both treatments, intervention and control
- Masking
- None (open label)
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Fundação de Amparo à Pesquisa do Estado de São Paulo, IBRAVIN
- Responsible party
- Sponsor
- Investigators
- Protasio L da Luz, Professor, Study chair, Instituto do Coração - InCor - University of Sao Paulo General HospitalElisa A Haas, MD, Principal investigator, Instituto do Coração - InCor - University of Sao Paulo General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03232099
- Sponsor's protocol ID
- 57379216.0.0000.0068
- Other IDs
- 2015/212606, 2015
- Status last verified
- May 2017
- First submitted
- 20 Jun 2017
- Last updated
- 15 Mar 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.1056/NEJMoa1109400.
PubMed 23614584Zoetendal EG, Collier CT, Koike S, Mackie RI, Gaskins HR. Molecular ecological analysis of the gastrointestinal microbiota: a review. J Nutr. 2004 Feb;134(2):465-72. doi: 10.1093/jn/134.2.465.
PubMed 14747690Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005 Jun 10;308(5728):1635-8. doi: 10.1126/science.1110591. Epub 2005 Apr 14.
PubMed 15831718Andersson AF, Lindberg M, Jakobsson H, Backhed F, Nyren P, Engstrand L. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS One. 2008 Jul 30;3(7):e2836. doi: 10.1371/journal.pone.0002836.
PubMed 18665274Brown JM, Hazen SL. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med. 2015;66:343-59. doi: 10.1146/annurev-med-060513-093205.
PubMed 25587655Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013 Sep 6;341(6150):1241214. doi: 10.1126/science.1241214.
PubMed 24009397Caricilli AM, Saad MJ. The role of gut microbiota on insulin resistance. Nutrients. 2013 Mar 12;5(3):829-51. doi: 10.3390/nu5030829.
PubMed 23482058Haas EA, Saad MJA, Santos A, Vitulo N, Lemos WJF, Martins AMA, Picossi CRC, Favarato D, Gaspar RS, Magro DO, Libby P, Laurindo FRM, Da Luz PL; WineFlora Study. A red wine intervention does not modify plasma trimethylamine N-oxide but is associated with broad shifts in the plasma metabolome and gut microbiota composition. Am J Clin Nutr. 2022 Dec 19;116(6):1515-1529. doi: 10.1093/ajcn/nqac286.
PubMed 36205549
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of Red Wine Effects Upon Gut Flora and Plasma Levels of Trimethylamine-N-oxide (TMAO) in Patients With Established Atherosclerotic Disease
- ClinicalTrials.gov ID
- NCT03232099
- Acronym / sponsor ID
- 57379216.0.0000.0068
- Keywords
- trimethylamine-N-oxide, TMAO, Gut Microbiota, Gut Flora, Atherosclerosis, Wine, Red Wine
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- University of Sao Paulo General HospitalUniversity, hospital or other
- Collaborators
- Fundação de Amparo à Pesquisa do Estado de São Paulo, IBRAVIN
- Study start
- 31 Aug 2016 (actual)
- Primary completion
- 22 Mar 2018 (actual)
- Study completion
- 15 Apr 2018 (actual)
- First posted
- 27 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Recent evidence indicates that Trimethylamine-N-oxide (TMAO) is a pro-atherosclerotic, phosphatidylcholine-dependent metabolite of diet and intestinal flora. Food substrates derive from carnitine and phosphatidylcholine (lecithin), present mainly in eggs, red meat, liver and pork. The intestinal flora pattern that favors the formation of TMAO is very similar to that which predisposes to insulin resistance and obesity: a high proportion between phylum Firmicutes over Bacteroidetes. The intestinal microbiota is sensitive and variable; the use of prebiotics and probiotics can change the relationship between Firmicutes/Bacteroidetes phyla. Red wine (RW), for its composition with polyphenols and possible bactericidal role, may play a role in the intestinal flora modification and could promote proliferation of beneficial bacteria. However, the influence of RW on TMAO is not known. This is the hypothesis to be tested in this trial. METHODS: This is a prospective, crossover, randomized, controlled trial with patients from Heart Institute (InCor), FMUSP and volunteers recruited through press releases. We will evaluate 42 patients, all men, with established atherosclerotic disease. Patients will be evaluated in a crossed manner: each subject receives both treatments, intervention and control (in random order), and they will be divided into 2 groups: A and B. In the first intervention stage, after 2 weeks of washout for all patients , group A receives Red Wine (RW) and group B is the control, abstemious. In the 2nd stage of intervention, after 2 weeks of washout for all patients the groups are inverted: group B receives RW; and group A will be abstemious. In the period with wine intervention, patients will receive 250 mL/day of red wine per day, for 5 days of the week, for 3 weeks. Patients will maintain their usual diet without the use of prebiotics or probiotics, or other polyphenolic derivatives. At the beginning and at the end of each stage, patients will be submitted to serum TMAO and intestinal microbiota evaluation. For the intestinal microbiota evaluation, the new generation sequencing will be used in the highly preserved portion of the 16S subunit of the rRNA gene. The determination of TMAO in plasma will be by liquid chromatography coupled to mass spectrometry. Expected results: It is expected to determine if RW acts on the intestinal flora to the point of influencing plasma TMAO concentration.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Forty two men with established atherosclerotic disease will be studied:after a 2 week washout period, each subject receives both treatments, intervention and control
| Arm | Type | Receives |
|---|---|---|
| Red Wine group (RW) | Experimental | Dietary Supplement: Red Wine consumptionAfter a two weeks washout period,in the intervening period with red wine, patients will receive 250 mL / day of red wine per Day, 5 days a week, for 3 weeks. |
| Abstemious | Active comparator | Other: Period without alcohol consumptionAfter a two weeks washout period,in the Abstemious period, patients should not consume any kind of alcohol beverages, for 3 weeks |
Who may qualify
- Ages
- 45 to 70 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Men, 45-70 years
- Established atherosclerotic diseases defined as:
- Previous history of CAD: angina or acute myocardial infarction (AMI), myocardial revascularization or angioplasty, angiographic evidence of stenosis ≥50% in at least one of the major coronary arteries B. Cerebrovascular disease: transient ischemic stroke or cerebrovascular accident C. Peripheral arterial disease: clinical evidence of extracoronary atherosclerosis
Key exclusion criteria (11 listed)
- Acute events in the last 30 days (AMI, troponin elevation, coronary angioplasty or coronary artery bypass grafting)
- Heart Failure (NYHA functional class ≥ II)
- Renal Failure (clearance creatinine <30 mL / min by the Cockcroft-Gault formula)
- Hepatic Failure
- Gastro-intestinal cancer
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Red Wine consumptionAfter a two weeks washout period,in the intervening period with red wine, patients will receive 250 mL / day of red wine per Day, 5 days a week, for 3 weeks. | Dietary supplement | Red Wine group (RW) |
| Period without alcohol consumptionAlso: Abstain PeriodAfter a two weeks washout period,in the Abstemious period, patients should not consume any kind of alcohol beverages, for 3 weeks | Other | Abstemious |
Primary outcome
Gut flora modification assessed by 16S ribosomal rNA gene sequencing and plasma concentration of TMAO changes measured by liquid chromatography coupled to mass spectrometry in 42 patients after ingestion 250 mL of Red Wine 5 days/week, for 3 weeks
Time frame: up to 10 weeks
Patients will be divided into 2 groups: A and B. In the first intervention stage, after 2 weeks of washout for all patients , group A receives Red Wine (RW) and group B is the control, abstemious. In the 2nd stage of intervention, after 2 weeks of washout for all patients the groups are inverted: group B receives RW; and group A will be abstemious. In the period with wine intervention, patients will receive 250 mL/day of red wine per day, for 5 days of the week, for 3 weeks. Patients will maintain their usual diet without the use of prebiotics or probiotics, or other polyphenolic derivatives. At the beginning and at the end of each stage, patients will be submitted to serum TMAO and intestinal microbiota evaluation. For the intestinal microbiota evaluation, the new generation sequencing will be used in the highly preserved portion of the 16S subunit of the rRNA gene. The determination of TMAO in plasma will be by liquid chromatography coupled to mass spectrometry
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2021.
- Background: PubMed 23614584Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.1056/NEJMoa1109400.
- Background: PubMed 14747690Zoetendal EG, Collier CT, Koike S, Mackie RI, Gaskins HR. Molecular ecological analysis of the gastrointestinal microbiota: a review. J Nutr. 2004 Feb;134(2):465-72. doi: 10.1093/jn/134.2.465.
- Background: PubMed 15831718Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005 Jun 10;308(5728):1635-8. doi: 10.1126/science.1110591. Epub 2005 Apr 14.
- Background: PubMed 18665274Andersson AF, Lindberg M, Jakobsson H, Backhed F, Nyren P, Engstrand L. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS One. 2008 Jul 30;3(7):e2836. doi: 10.1371/journal.pone.0002836.
- Background: PubMed 25587655Brown JM, Hazen SL. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med. 2015;66:343-59. doi: 10.1146/annurev-med-060513-093205.
- Background: PubMed 24009397Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013 Sep 6;341(6150):1241214. doi: 10.1126/science.1241214.
- Background: PubMed 23482058Caricilli AM, Saad MJ. The role of gut microbiota on insulin resistance. Nutrients. 2013 Mar 12;5(3):829-51. doi: 10.3390/nu5030829.
- Derived from this study: PubMed 36205549Haas EA, Saad MJA, Santos A, Vitulo N, Lemos WJF, Martins AMA, Picossi CRC, Favarato D, Gaspar RS, Magro DO, Libby P, Laurindo FRM, Da Luz PL; WineFlora Study. A red wine intervention does not modify plasma trimethylamine N-oxide but is associated with broad shifts in the plasma metabolome and gut microbiota composition. Am J Clin Nutr. 2022 Dec 19;116(6):1515-1529. doi: 10.1093/ajcn/nqac286.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Protasio L da Luz, Professor study chair
Instituto do Coração - InCor - University of Sao Paulo General Hospital
Elisa A Haas, MD principal investigator
Instituto do Coração - InCor - University of Sao Paulo General Hospital
Questions about this trial
What is this clinical trial studying?
A study testing Red Wine consumption and Period without alcohol consumption in people with Trimethylamine-N-oxide and Gut Microbiota, run by University of Sao Paulo General Hospital.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Gut flora modification assessed by 16S ribosomal rNA gene sequencing and plasma concentration of TMAO changes measured by liquid chromatography coupled to mass spectrometry in 42 patients after ingestion 250 mL of Red Wine 5 days/week, for 3 weeks (time frame: up to 10 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03232099, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2021.