Clinical trial NCT02016430: Gut Flora Metabolite Reduction After Dietary Intervention (GRADY)
Official title: Gut Flora Metabolite Reduction After Dietary Intervention (GRADY)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Dietary Modification
Cardiovascular Risk Factor
Keywords: TMAO
Gut Flora
Dietary Intervention
Choline
Carnitine
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
First posted: 2013-12-20
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Change in TMAO level
timeFrame: From baseline to 12 weeks follow-up
Secondary outcomes:
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: W. H. Wilson Tang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Stanley L. Hazen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.