Clinical trial NCT05195970: Walnuts and Colon Health
Official title: Microbiota, Metabolites and Colon Neoplasia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Colorectal Cancer
Diet Habit
Keywords: Colorectal cancer
Microbiome
Urolithin
Walnuts
Diet habit
Inflammatory markers
Colon inflammation
Lead sponsor: UConn Health
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Cancer Institute (NCI)
name: Weill Medical College of Cornell University
name: University of Connecticut
name: California Walnut Commission
name: Spanish National Research Council
name: University of Florida
First posted: 2022-01-19
Enrollment: 200
Sex: ALL
Minimum age (years): 39
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: The purpose of this research study is to examine whether adding walnuts to your diet can have a beneficial effect on the gut bacteria population, inflammatory markers in the blood, and the tissue that lines the inside of the colon.

Detailed description: This is a 30-day dietary intervention study where participants will be asked to consume 2 ounces of walnuts daily for 21 days, and at the end of the study period they will come in for a routine colonoscopy. After being informed about the study and potential risks, participants giving written informed consent will first start a 7-day wash-out period where they will be asked to avoid foods high in ellagitannins for the duration of the study. In addition, participants will be asked to complete food and activity questionnaires, a walnut consumption log, and two sets of 3-day dietary records during their participation in the study. Participants will also be asked to provide three urine samples, two blood samples, and two stool samples at multiple time points, and 8-10 colon tissue specimens (biopsies) will be collected during their colonoscopy procedure for the purposes of this study.

Eligibility criteria: Inclusion Criteria:

1. Men and women between the ages of 39-75 years old who meet the criteria of one of the following groups and are eligible to undergo a routine screening or surveillance colonoscopy for colorectal cancer (CRC):

   1. Individuals who have a family history of colon polyps or CRC in a first-degree relative diagnosed with CRC under the age of 65 years, or
   2. Individuals who are referred for colonoscopy following a positive fecal immunochemical test (FIT) or a positive Cologuard screening test and have not had a high-quality colonoscopy in the past 3 years, or
   3. Individuals who have a personal history of colon polyps
2. Willing and able to provide written informed consent for study participation
3. Willing to consume 2 ounces (56 grams) of walnuts daily for 3 weeks
4. Willing to avoid intake of EA/ET-rich foods and beverages (e.g., pomegranates, hazelnuts, pistachios, strawberries, raspberries, blackberries, oak-aged wines, and other items on a list given by researchers) and fermented dairy products containing viable Bifidobacteria or Lactobacilli)
5. Willing to stop taking dietary supplements, including probiotics
6. Willing to have two separate blood draws, as well as urine and stool collections
7. Willingness to comply with all study requirements

Exclusion Criteria:

1. Individual has a personal history of CRC, or a history of any malignancy (other than skin cancer) within the past 5 years
2. Individual meets the Amsterdam criteria for Lynch Syndrome or has a history of familial adenomatous polyposis (FAP)
3. Individual has been treated with immunosuppressive agents or systemic steroids, excluding inhalers, at least two weeks prior to the Screening Visit and for the duration of the study
4. Use of antibiotics at least one month prior to the Screening Visit and for the duration of the study
5. Patients with severe medical illness or those at high risk for anesthesia, as determined by good clinical practice
6. Current evidence or previous history of ulcerative colitis or Crohn's disease
7. Colonoscopy performed for reasons other than screening or surveillance for CRC
8. HIV infection, chronic viral hepatitis
9. Allergy to walnuts or hypersensitivity to tree nuts
10. Peri-menopausal women with any chance or plan of pregnancy
11. Individuals with blood coagulation disorders or on anti-coagulant therapy
12. Any other condition that, in the opinion of the PI, might interfere with study objectives
13. No race/ethnicity, language or gender exclusions for this study

Primary outcomes:
measure: Bacterial composition and taxonomy changes in the fecal microbiome
timeFrame: Day 7 and Day 28
measure: Bacterial diversity changes and strain-level variations in the fecal microbiome
timeFrame: Day 7 and Day 28
measure: Bacterial gene expression profile changes in the fecal microbiome
timeFrame: Day 7 and Day 28
measure: Urolithin levels in urine
timeFrame: Day 0, Day 7 and Day 30
measure: Association of urolithin levels with presence (and type) of colonic lesions
timeFrame: Day 30
measure: Correlation of urolithin levels with fecal microbiome composition
timeFrame: Day 7 and Day 28
measure: Correlation of colonic lesion gene expression with urolithin production
timeFrame: Day 30
measure: Association of urolithin levels with the immune composition of the tumor microenvironment
timeFrame: Day 30
Secondary outcomes:
measure: Short-chain fatty acid composition in stool
timeFrame: Day 7 and Day 30
measure: Bile acid metabolism in stool
timeFrame: Day 7 and Day 30
measure: Inflammatory markers in blood
timeFrame: Day 7 and Day 30
measure: Correlation of dietary behavior with presence (or absence) of colonic polyps
timeFrame: Day 7 and Day 30
measure: Correlation of dietary behavior with fecal microbiome composition and diversity
timeFrame: Day 7 and Day 30
measure: Correlation of dietary behavior with urolithin production
timeFrame: Day 7 and Day 30
Other outcomes:
Locations:
city: Farmington
country: United States
facility: UConn Health
state: Connecticut
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
Study officials:
affiliation: UConn Health
name: Daniel W. Rosenberg, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Christian Jobin, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fan N, Fusco JL, Rosenberg DW. Antioxidant and Anti-Inflammatory Properties of Walnut Constituents: Focus on Personalized Cancer Prevention and the Microbiome. Antioxidants (Basel). 2023 Apr 22;12(5):982. doi: 10.3390/antiox12050982.
citation: Liu H, Birk JW, Provatas AA, Vaziri H, Fan N, Rosenberg DW, Gharaibeh RZ, Jobin C. Correlation between intestinal microbiota and urolithin metabolism in a human walnut dietary intervention. BMC Microbiol. 2024 Nov 15;24(1):476. doi: 10.1186/s12866-024-03626-5.
citation: Moussa MR, Fan N, Birk J, Provatas AA, Mehta P, Hatano Y, Chun OK, Darooghegi Mofrad M, Lotfi A, Aksenov A, Motta VN, Zenali M, Vaziri H, Grady JJ, Nakanishi M, Rosenberg DW. Systemic Inflammation and the Inflammatory Context of the Colonic Microenvironment Are Improved by Urolithin A. Cancer Prev Res (Phila). 2025 Apr 1;18(4):235-250. doi: 10.1158/1940-6207.CAPR-24-0383.
citation: Nakanishi M, Matz A, Klemashevich C, Rosenberg DW. Dietary Walnut Supplementation Alters Mucosal Metabolite Profiles During DSS-Induced Colonic Ulceration. Nutrients. 2019 May 20;11(5):1118. doi: 10.3390/nu11051118.
citation: Chen Y, Nakanishi M, Bautista EJ, Qendro V, Sodergren E, Rosenberg DW, Weinstock GM. Colon Cancer Prevention with Walnuts: A Longitudinal Study in Mice from the Perspective of a Gut Enterotype-like Cluster. Cancer Prev Res (Phila). 2020 Jan;13(1):15-24. doi: 10.1158/1940-6207.CAPR-19-0273. Epub 2019 Dec 9.
citation: Nakanishi M, Chen Y, Qendro V, Miyamoto S, Weinstock E, Weinstock GM, Rosenberg DW. Effects of Walnut Consumption on Colon Carcinogenesis and Microbial Community Structure. Cancer Prev Res (Phila). 2016 Aug;9(8):692-703. doi: 10.1158/1940-6207.CAPR-16-0026. Epub 2016 May 23.
citation: Hong BY, Ideta T, Lemos BS, Igarashi Y, Tan Y, DiSiena M, Mo A, Birk JW, Forouhar F, Devers TJ, Weinstock GM, Rosenberg DW. Characterization of Mucosal Dysbiosis of Early Colonic Neoplasia. NPJ Precis Oncol. 2019 Nov 14;3:29. doi: 10.1038/s41698-019-0101-6. eCollection 2019.
citation: Tomas-Barberan FA, Gonzalez-Sarrias A, Garcia-Villalba R, Nunez-Sanchez MA, Selma MV, Garcia-Conesa MT, Espin JC. Urolithins, the rescue of "old" metabolites to understand a "new" concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res. 2017 Jan;61(1). doi: 10.1002/mnfr.201500901. Epub 2016 Jun 20.