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Ellagic Acid, Urolithin and Colonic Microbial Communities Affected by Walnut Consumption

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04066816
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : March 19, 2021
American Institute for Cancer Research
California Walnut Commission
The Jackson Laboratory
Information provided by (Responsible Party):
Daniel Rosenberg, UConn Health

Brief Summary:
Briefly, this is a 28-day dietary intervention study participants will be asked to eat 2 ounces (52 grams) of walnuts every day for 3 weeks, and at the end of the study period they will come in for a colonoscopy. Participants will first start a 1-week run-in period where they will be asked to avoid foods high in ellagic acid. In addition, they will be asked to complete food surveys and two sets of 3-day dietary records, and to provide colon biopsies for this study during their routine colonoscopy, as well as a blood, and two urine and stool samples. Urine samples will be used for analysis of urolithin, ellagic acid metabolites. Stool samples will be used to assess gut microbiota changes after walnut consumption. Dietary records will be used for compliance and Food Frequency Questionnaire will be used to assess dietary habits. Lastly, the biopsy samples will be used for analysis of biomarkers and anti-inflammatory in the colon, as well as adherent microbiome to the colonic tissue. Data will be analyzed based on the urolithin phenotypes.

Condition or disease Intervention/treatment Phase
Colo-rectal Cancer Colon Cancer Diet Habit Other: Walnuts Not Applicable

Detailed Description:
The investigators propose to address the influence of ellagic acid obtained from walnuts and its microbial-derived metabolites (urolithin) on the gut microbiome and inflammation-related biomarkers in a human clinical study. Patients will be enrolled and detailed demographic and dietary information, biopsy specimens through colonoscopies, as well as fecal, blood and urine samples will be collected. The wide range of gut urolithin levels provides the rationale for our proposed studies. Will the specific urolithin phenotypes show a disparate range of chemopreventive (anti-inflammatory) response to walnut consumption? The hypothesis is that walnut ingestion in "Phenotype A" participants (producing the highest levels of urolithin) will be associated with a beneficial anti-inflammatory response as tested in colonic mucosa and a higher abundance of bacterial species associated with ellagic acid metabolism. Although 16S ribosomal ribonucleic acid gene (rRNA) sequencing allows inexpensive bacterial identification at the genus/species level, a whole genome sequencing (mWGS) will be employed to achieve finer classification (strain level), and identify other microbes (e.g., viruses, fungi, small eukaryotes). Furthermore, mWGS targets the entire genome of each microbe (not just the 16S rRNA gene), allowing for construction of a microbial gene catalogue, including a metabolic pathway description for each sample. This will characterize the functional potential of the microbial community. Ultimately, the proposed studies will inform the application of prebiotic to enhance the formation of urolithin metabolites from ellagic acid for the prevention of inflammation-associated Colorectal Cancer, a development that would have significant translational implications.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Ellagic Acid, Urolithin and Colonic Microbial Communities Affected by Walnut Consumption
Actual Study Start Date : May 20, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : June 30, 2022

Arm Intervention/treatment
Experimental: Walnut Consumption
After screening, participants will avoid foods high in ellagic acid. These foods include pomegranates, hazelnuts, pistachios, strawberries, raspberries, blackberries, oak-aged wines, spirits, and walnuts (besides the ones given by researchers); a complete list will be provided to the subjects. Participants will then return to research facility and provide urine and stool samples, as well as a set of 3-day dietary records. Then, they will start to consume 2 ounces of walnuts per day for 21 days with their usual diet. At the end, they will collect another urine and stool sample as well as another set of dietary records, and then come in for the scheduled colonoscopy where they will be asked to provide biopsy specimens. That completes the intervention and participation in the study.
Other: Walnuts
Participants will consume 2 ounces of walnuts for 21 days

Primary Outcome Measures :
  1. Leve of Urolithin of this Population [ Time Frame: 28 days post walnuts ]
    Urolithin will be measure in urine using a mass spectrometer to characterize this population into three know urolithin phenotypes, Uro-A, Uro-B and Uro-0, after walnut consumption.

  2. Urolithin Phenotype and Colonic Health [ Time Frame: 28 days post walnuts ]
    Assess biomarkers in colonic mucosa from biopsy samples collected at colonoscopy that are associated with the three different urolithin metabotype following walnut consumption. This biomarkers is a total of 287 genes involved in cellular apoptosis and proliferation, inflammation and senescence, including TIMP1 (used for power calculations), cytokine and T cell and B cell signaling genes, as well as markers of lymphocyte subsets and immune checkpoint pathways and targets, providing a wide range of functional annotation groups.

Secondary Outcome Measures :
  1. Identify Changes in Microbiota and Microbes Responsible for Urolithin Formation Followed by Walnuts Consumption using Metagenomics Sequencing [ Time Frame: Day 7 to Day 28 ]
    Microbiome will be analyzed before and after walnut consumption with the goal to identify microbes responsible for urolithins production. DNA will be extracted from fecal samples and the V1-3 hyper-variable region of bacterial 16S rRNA genes will be sequenced to analyze bacterial community structure. Although 16S rRNA gene sequencing allows inexpensive bacterial identification to the genus/species level, mWGS will be employed in order to achieve finer classification (strain level), and identify other microbes, including viruses, fungi and small eukaryotes.

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Men or women between the ages of 50-65 years old who are scheduled to undergo a routine screening colonoscopy
  • English speaking/reading patients willing and able to provide written informed consent for study participation
  • Patients willing to consume walnuts for 3 weeks
  • Willingness to comply with all study requirements

Exclusion Criteria:

  • Current active malignancy, previous history of gastrointestinal malignancy, or altered gastrointestinal anatomy
  • Current evidence or previous history of ulcerative colitis or Crohn's disease
  • HIV infection, chronic viral hepatitis
  • Allergy to walnuts or hypersensitivity to tree nuts
  • Use of antibiotics within the past month
  • Individuals with blood coagulation disorders or on anti-coagulant therapy
  • Treated with steroids, immunosuppressive agents or other anti-inflammatory drugs one week prior to starting intervention
  • Non-English-speaking patients who require an interpreter to give consent
  • Patients residing in the Department of Correction
  • Inability to comply with the protocol requirements
  • Any other condition that, in the opinion of the PI, might interfere with study objectives

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 identifier (NCT number): NCT04066816

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Contact: MEG TORO 860.679.8175
Contact: AIYANA CALLAS 860.679.7640

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United States, Connecticut
University of Connecticut Health Center Recruiting
Farmington, Connecticut, United States, 06030
Contact: MEG TORO    860-679-8175   
Principal Investigator: Daniel W Rosenberg, PhD         
Sponsors and Collaborators
UConn Health
American Institute for Cancer Research
California Walnut Commission
The Jackson Laboratory
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Study Chair: JOHN BIRK, MD UConn Health
Principal Investigator: DANIEL W ROSENBERG, PhD UConn Health
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Responsible Party: Daniel Rosenberg, Professor, UConn Health Identifier: NCT04066816    
Other Study ID Numbers: 19-121JS-1
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: March 19, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daniel Rosenberg, UConn Health:
Colorectal cancer
Additional relevant MeSH terms:
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Rectal Neoplasms
Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Colonic Diseases