Walnuts and Colon Health

NCT05195970 | Completed DMC

• 2 other identifiers: 21-167JS-11R01CA252045-01A1
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 2

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.

Conditions

Colorectal Cancer; Diet Habit

Keywords

Colorectal cancer; Microbiome; Urolithin; Walnuts; Diet habit; Inflammatory markers; Colon inflammation

Outcome Measures

Primary Outcomes (8)

• Bacterial composition and taxonomy changes in the fecal microbiome

  Bacterial composition and taxonomy changes in the fecal microbiome will be assessed using 16 Svedberg unit (16S) ribosomal ribonucleic acid (rRNA) sequencing, at day 7 (post-washout/pre-walnut supplementation) and at day 28 (post-walnut supplementation).

  Day 7 and Day 28

• Bacterial diversity changes and strain-level variations in the fecal microbiome

  Bacterial diversity/abundance changes and strain-level variations in the fecal microbiome will be assessed using metagenomic shotgun sequencing at day 7 (post-washout/pre-walnut supplementation) and at day 28 (post-walnut supplementation).

  Day 7 and Day 28

• Bacterial gene expression profile changes in the fecal microbiome

  Bacterial gene expression profile changes in the fecal microbiome will be assessed using metagenomic ribonucleic acid (RNA) sequencing at day 7 (post-washout/pre-walnut supplementation) and at day 28 (post-walnut supplementation).

  Day 7 and Day 28

• Urolithin levels in urine

  Urolithin levels will be measured in urine by ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry at day 0 (baseline/pre-washout), day 7 (post-washout/pre-walnut supplementation) and day 30 (post-walnut supplementation/end of study).

  Day 0, Day 7 and Day 30

• Association of urolithin levels with presence (and type) of colonic lesions

  Baseline urolithin levels measured in the urine by ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry will be associated with the presence (and type) of colonic lesions (e.g., advanced adenomas (AAs) or sessile serrated adenomas/polyps (SSA/Ps)) detected during the colonoscopy procedure at the end of the study (day 30).

  Day 30

• Correlation of urolithin levels with fecal microbiome composition

  Detailed statistical analyses will be used to correlate urolithin formation with the composition of the fecal microbiome at day 7 (post-washout/pre-walnut supplementation) and at day 28 (post-walnut supplementation).

  Day 7 and Day 28

• Correlation of colonic lesion gene expression with urolithin production

  Colonic lesion (AAs and SSA/Ps) biopsies obtained at the end of the study (day 30) during the colonoscopy procedure will undergo DNA sequence-based analysis to determine gene expression profiling. These results will be compared to urinary urolithin levels measured at baseline to establish correlations between urolithin production and colorectal cancer risk markers.

  Day 30

• Association of urolithin levels with the immune composition of the tumor microenvironment

  FFPE colon polyp tissue sections will be analyzed by the NCI Imaging Core (Frederick, MD) using imaging mass cytometry (IMC) to determine immune cell populations present within the tumor microenvironment. This data will be used to establish correlations with urolithin production.

  Day 30

Secondary Outcomes (6)

• Short-chain fatty acid composition in stool

  Day 7 and Day 30

• Bile acid metabolism in stool

  Day 7 and Day 30

• Inflammatory markers in blood

  Day 7 and Day 30

• Correlation of dietary behavior with presence (or absence) of colonic polyps

  Day 7 and Day 30

• Correlation of dietary behavior with fecal microbiome composition and diversity

  Day 7 and Day 30

Study Arms (1)

Walnut Consumption

EXPERIMENTAL

Following enrollment, participants will start a 7-day wash-out period where they will be asked to avoid foods and beverages high in ellagitannins. These include pomegranates, hazelnuts, pistachios, walnuts (besides the samples given by the researchers), strawberries, raspberries, blackberries, oak-aged wines and spirits; a full list of foods and beverages to avoid will be provided. Then, participants will consume 2 ounces of walnuts daily with their usual diet while continuing to avoid ellagitannins for 21 days prior to their routine colonoscopy.

Other: Walnuts

Interventions

Walnuts OTHER

Participants consume 2 ounces of walnuts daily for 21 days

Walnut Consumption

Eligibility Criteria

• Age: 39 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• 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
• 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
• Individuals who have a personal history of colon polyps
• Willing and able to provide written informed consent for study participation
• Willing to consume 2 ounces (56 grams) of walnuts daily for 3 weeks
• 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)
• Willing to stop taking dietary supplements, including probiotics
• Willing to have two separate blood draws, as well as urine and stool collections
• Willingness to comply with all study requirements

You may not qualify if:

• Individual has a personal history of CRC, or a history of any malignancy (other than skin cancer) within the past 5 years
• Individual meets the Amsterdam criteria for Lynch Syndrome or has a history of familial adenomatous polyposis (FAP)
• 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
• Use of antibiotics at least one month prior to the Screening Visit and for the duration of the study
• Patients with severe medical illness or those at high risk for anesthesia, as determined by good clinical practice
• Current evidence or previous history of ulcerative colitis or Crohn's disease
• Colonoscopy performed for reasons other than screening or surveillance for CRC
• HIV infection, chronic viral hepatitis
• Allergy to walnuts or hypersensitivity to tree nuts
• Peri-menopausal women with any chance or plan of pregnancy
• Individuals with blood coagulation disorders or on anti-coagulant therapy
• Any other condition that, in the opinion of the PI, might interfere with study objectives

Sponsors & Collaborators

• UConn Health: lead
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator
• Weill Medical College of Cornell University: collaborator
• University of Connecticut: collaborator
• California Walnut Commission: collaborator
• Spanish National Research Council: collaborator
• University of Florida: collaborator

Study Sites (2)

UConn Health

Farmington, Connecticut, 06032, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Related Publications (8)

• 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.

  PMID: 37237848 BACKGROUND

• 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.

  PMID: 39548408 BACKGROUND

• 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.

  PMID: 39995164 BACKGROUND

• 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.

  PMID: 31137456 BACKGROUND

• 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.

  PMID: 31818852 BACKGROUND

• 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.

  PMID: 27215566 BACKGROUND

• 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.

  PMID: 31754633 BACKGROUND

• 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.

  PMID: 27158799 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms; Feeding Behavior; Colitis

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Behavior, Animal; Behavior; Gastroenteritis

Study Officials

• Daniel W. Rosenberg, Ph.D.

  UConn Health

  PRINCIPAL INVESTIGATOR

• Christian Jobin, Ph.D.

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: November 24, 2021
• First Posted: January 19, 2022
• Study Start: January 24, 2022
• Primary Completion: January 30, 2026
• Study Completion: January 30, 2026
• Last Updated: April 17, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)