Gut Flora Metabolite Reduction After Dietary Intervention (GRADY)

Overview

Our group has recently identified the association between gut-flora-mediated carnitine and phosphatidylcholine metabolism, specifically trimethylamine-N-oxide (TMAO), and cardiovascular risk. This study investigates the ability for dietary intervention to modulate TMAO levels.

Detailed description

This is a pilot human study to characterize the relationship between gut flora-associated TMAO generation and dietary intervention. The investigators hypothesize that tailored dietary interventions may help to reduce the ability for gut flora to generate TMAO in individuals with elevated TMAO levels. Specific aims include:

1. To investigate the proportion of subjects with persistently elevated circulating TMAO levels. 2. To compare the amount of TMAO generated from gut flora using stable-isotope-labelled choline, carnitine, and betaine in subjects with elevated versus normal circulating TMAO levels. 3. To evaluate the effect of dietary interventions on the amount of TMAO generated from gut flora using stable-isotope-labelled choline, carnitine, and betaine in subjects with elevated circulating TMAO levels.

Interventions

• Behavioral MeLT Dietary intervention
  Mediterranean diet containing food with low TMAO content.
• Behavioral TLC Dietary intervention
  Standard American Heart Association (AHA) recommendations for dietary counseling.
• Behavioral MeLT dietary intervention with TMAO
  Mediterranean diet containing food with low TMAO content with TMAO levels provided to the subject for guidance.

Primary outcome measures

• Change in TMAO level [Time frame: From baseline to 12 weeks follow-up]

Eligibility criteria

Inclusion criteria

Cohort 1 Inclusion criteria:

• Men and women age 18 years or above.
• Elevated TMAO metabolizers (>5 µM) based on screening test and/or eGFR < 60 at most recent measurement.
• Willing to remain on aspirin or able to be off aspirin or aspirin products for 1 week prior to starting the study and staying on the same aspirin regimen during the duration of the study.
• Willing to sign the consent form and follow the study protocol, which includes a 12-week dietary modification.

Cohort 2 Inclusion criteria:

• Men and women age 18 years or above.
• Willing to remain on aspirin or able to be off aspirin or aspirin products for 1 week prior to starting the study and staying on the same aspirin regimen during the duration of the study.
• Willing to sign the consent form and follow the study protocol.
• eGFR values ranging from 16-59

Cohort 3 Inclusion criteria:

• Men and women age 18 years or above.
• Willing to remain on aspirin or able to be off aspirin or aspirin products for 1 week prior to starting the study and staying on the same aspirin regimen during the duration of the study.
• Willing to sign the consent form and follow the study protocol.

Exclusion Criteria (all cohorts):

• Significant chronic illness or end-organ dysfunction, including known history of uncompensated heart failure, renal failure, pulmonary disease, hematologic diseases.
• Active infection or received antibiotics within 2 months of study enrollment
• Use of over-the-counter probiotic within past month, or ingestion of yogurt within past 7 days
• Having undergone bariatric procedures or surgeries such as gastric banding or bypass.
• Pregnancy.
• Any condition which, in the judgment of the Investigator, would place a patient at undue risk by being enrolled in the trial, or cause inability to comply with the trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Cleveland Clinic — Cleveland

Publications

• Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011 Apr 7;472(7341):57-63. doi: 10.1038/nature09922. PMID 21475195
• Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 May;19(5):576-85. doi: 10.1038/nm.3145. Epub 2013 Apr 7. PMID 23563705
• Dalmeijer GW, Olthof MR, Verhoef P, Bots ML, van der Schouw YT. Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women. Eur J Clin Nutr. 2008 Mar;62(3):386-94. doi: 10.1038/sj.ejcn.1602725. Epub 2007 Mar 21. PMID 17375117
• Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G. Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc Disord. 2007 Jul 13;7:20. doi: 10.1186/1471-2261-7-20. PMID 17629908
• 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. PMID 23614584

Identifiers

NCT: NCT02016430 · 13-863

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗