Clinical trial NCT04160481: A Pilot Study to Investigate the Effect of Water-soluble Tomato Extract on TMAO
Official title: A Randomised, Double-blinded, Cross-over, Placebo- Controlled Pilot Study to Investigate the Effect of Tomato Extract on TMAO in Overweight or Obese Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cardiovascular Risk Factor
Keywords: gut microbiome
carciovascular risk factor
Lead sponsor: DSM Nutritional Products, Inc.
Sponsor class: INDUSTRY
First posted: 2019-11-13
Enrollment: 37
Sex: ALL
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, double-blind, placebo-controlled, cross-over
Primary purpose: BASIC_SCIENCE

Brief summary: To determine the effect of 4 weeks daily consumption of Fruitflow on changes in plasma levels of fasting Trimethylamine N-oxide concentrations (TMAO)

Detailed description: Tomatoes contain a range of polyphenols that are of low bioavailability and reach the colon. Data from animal studies suggest that certain polyphenols are extensively metabolized by the gut microbiota which may impact bioactivity including TMA/TMAO production. It was previously shown that a polyphenol-rich cranberry extract attenuated diet-induced metabolic syndrome in mice in a gut microbiota-dependent manner. In another mouse study the polyphenol resveratrol attenuated TMAO-induced atherosclerosis by decreasing TMAO levels and increasing hepatic bile acid neosynthesis via gut microbiota remodelling. However, human studies on polyphenol effect on TMAO levels and the gut microbiome are sparse. In a recent study TMAO serum levels were reduced in healthy subjects upon supplementation with a grape pomace polyphenolic extract.

This clinical study will provide new insight into the effect of tomato extract on TMAO levels and the gut microbiota composition and thus potential new mechanisms responsible for the cardiovascular protective effects.

Eligibility criteria: Inclusion Criteria:

1. Be able to give written informed consent;
2. Be between 35 and 65 years of age;
3. Has a BMI between 28 - 35 Kg/m2;
4. Has a stable body weight (≤5% change) over the past 3-months;
5. Is in general good health, as determined by the investigator;
6. Avoid consuming dietary supplements (prebiotic, probiotic, fibre, resveratrol, fish oil, seed oils, ginkgo biloba, ginseng, fruit powder extracts and DHA) within 4 weeks prior to baseline visit, until the end of the study;
7. Avoid consuming seafood or fish 24h prior to each visit;
8. Maintain current level of physical activity;
9. Willing to consume the investigational product daily for the duration of the study.

   Exclusion Criteria:
10. Pregnant or breastfeeding women; women planning to become pregnant during the study;
11. Are hypersensitive to any of the components of the test product;
12. Has taken antibiotics within the previous 3 months;
13. Has taken hypolipidemic agents or any treatment for diabetes (type I or II) within the previous 6 months;
14. Has a history of drug and/or alcohol abuse at the time of enrolment;
15. Consumes greater than 2 servings/day of alcohol (e.g. \>28 g ethanol/day);
16. Is a smoker;
17. Has made any major dietary changes in the past 3 months;
18. Planned major changes in life style (i.e. diet, dieting, exercise level, travelling) during the duration of the study;
19. Has an eating disorder;
20. Is vegetarian/vegan diet or has food allergies or other issues with foods that would preclude intake of the study products;
21. Is using fibre supplements or enemas;
22. Has any health conditions that would prevent from fulfilling the study requirements, put the subject at risk or would confound the interpretation of the study results as judged by the investigator on the basis of medical history and routine laboratory test results;
23. Have a significant acute or chronic coexisting illness such as cardiovascular disease, chronic kidney or liver disease, gastrointestinal disorder, endocrinological disorder, immunological disorder, metabolic disease or any condition which contraindicates, in the investigator's judgement, entry to the study;
24. Current hepatic failure, renal failure, bleeding disorder (haemophilia, Von Willebrand disease, oesophageal varicoses);
25. Having a condition or taking a medication that the investigator believes would interfere with the objectives of the study, pose a safety risk or confound the interpretation of the study results; to include Statins (including atorvastatin (Lipitor and Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor, Altoprev), pitavastatin (Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor, Lipex)), Cholesterol Absorption Inhibitors (including Zetia (ezetimibe)), Niacin (nicotinic acid), Fibric acid derivatives (including Atromid-S (clofibrate), Lopid (gemfibrozil), and Tricor (fenofibrate)), Bile Acid Sequestrants (including cholestyramine, sold under the brand names Questran, Prevalite, and LoCholest, and colestipol (Colestid)) or have taken them in the past 28 days;
26. Taking a cholesterol lowering supplement, including, example Plant sterols/stanols, Fish Oil supplements, vitamin B supplements (e.g. Niacin and Niacinamide), red rice yeast extract, oat beta glucan, pharmaceutical garlic or have taken them in the past month;
27. Has an active gastrointestinal disorder or previous gastrointestinal surgery;
28. If taking chronic medications (e.g., anti-hypertensive medications), they must have been taking the product for at least two months prior to screening and agree to maintain the same dosage throughout the study;
29. Has a gastrointestinal or chronic infective disease (i.e., diarrhoea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diverticulosis, stomach or duodenal ulcers, hepatitis, HIV, cancer, etc.), with a history of such diseases;
30. Are severely immunocompromised (HIV positive, transplant patient, on antirejection medications, on a steroid for \>30 days, or chemotherapy or radiotherapy within the last year);
31. Experiences alarm features such as weight loss, rectal bleeding, recent change in bowel habit (\<3 months) or abdominal pain;
32. Have a malignant disease or any concomitant end-stage organ disease;
33. Individuals who, in the opinion of the investigator, are considered to be poor attendees or unlikely for any reason to be able to comply with the trial;
34. Subjects may not be receiving treatment involving experimental drugs. If the subject has been in a recent experimental trial, these must have been completed not less than 60 days prior to this study;
35. High habitual intake of tomatoes, and tomato-based products confirmed by FFQ.
36. Known history of allergies to tomatoes or tomato-based products;

Primary outcomes:
measure: Change in TMAO concentrations
timeFrame: 4 weeks
Secondary outcomes:
measure: Changes in the relative abundance of common human gut microbes in stool samples
timeFrame: 4 weeks
measure: Urinary TMAO
timeFrame: 4 weeks
measure: LPS
timeFrame: 4 weeks
measure: Stool consistency
timeFrame: 4 weeks
measure: Stool microbiota composition alpha diversity
timeFrame: 4 weeks
measure: Stool microbiota composition beta diversity
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Cork
country: Ireland
facility: Atlantia Food Clinical Trials
Study officials:
References:
citation: Miller CA, Corbin KD, da Costa KA, Zhang S, Zhao X, Galanko JA, Blevins T, Bennett BJ, O'Connor A, Zeisel SH. Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr. 2014 Sep;100(3):778-86. doi: 10.3945/ajcn.114.087692. Epub 2014 Jun 18.
citation: Annunziata G, Maisto M, Schisano C, Ciampaglia R, Narciso V, Tenore GC, Novellino E. Effects of Grape Pomace Polyphenolic Extract (Taurisolo(R)) in Reducing TMAO Serum Levels in Humans: Preliminary Results from a Randomized, Placebo-Controlled, Cross-Over Study. Nutrients. 2019 Jan 10;11(1):139. doi: 10.3390/nu11010139.
citation: Bergeron N, Williams PT, Lamendella R, Faghihnia N, Grube A, Li X, Wang Z, Knight R, Jansson JK, Hazen SL, Krauss RM. Diets high in resistant starch increase plasma levels of trimethylamine-N-oxide, a gut microbiome metabolite associated with CVD risk. Br J Nutr. 2016 Dec;116(12):2020-2029. doi: 10.1017/S0007114516004165. Epub 2016 Dec 20.
citation: Cassidy A, Minihane AM. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr. 2017 Jan;105(1):10-22. doi: 10.3945/ajcn.116.136051. Epub 2016 Nov 23.
citation: Cardona F, Andres-Lacueva C, Tulipani S, Tinahones FJ, Queipo-Ortuno MI. Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem. 2013 Aug;24(8):1415-22. doi: 10.1016/j.jnutbio.2013.05.001.