Mediterranean Diet and Weight Loss: Targeting the Bile Acid/Gut Microbiome Axis to Reduce Colorectal Cancer

NCT04753359 | Recruiting DMC

• 2 other identifiers: 2020-13421R01CA250390-01A1
• Study Type: interventional
• Target: 232
• Locations: 1 country
• Sites: 1

Brief Summary

A Mediterranean Diet (MedDiet), a largely plant-based dietary pattern, is relevant to CRC prevention and microbial production of anti-cancer metabolites in observational studies. A MedDiet can shift BA metabolism as shown in primates and when combined with calorie restriction, shows superior adherence and weight control in humans, given its palatability. To date, no studies have tested in an RCT the effects of a MedDiet alone (MedA), WL through lifestyle intervention (WL-A) or a calorie-restricted MedDiet for WL (WL-Med) on the BA-gut microbiome axis and its relevance to CRC prevention among AAs. A multidisciplinary team combining expertise in psychology, nutrition, microbiology, molecular cell biology, computational biology, medicine and biostatistics, proposes to conduct a four-arm RCT in which 232 obese AAs, 45-75 years old complete one of the following 6-month interventions: Med-A, weight stable; WL-A, calorie restriction with no diet pattern change; WLMed; or Control. The investigators will use samples and data collected at baseline, mid-study (month-3) and post-intervention to compare the effects of the interventions on 1) Concentration and composition of circulating and fecal BAs; 2) Gut microbiota and metabolic function; and 3) Gene expression profiles of exfoliated intestinal epithelial cells.

Conditions

Colorectal Cancer; Diet Habit

Outcome Measures

Primary Outcomes (12)

• Circulating and fecal bile acids

  Absolute measurement of BAs in stool and serum obtained at baseline will be performed under the direction of Co-I Ridlon. Samples will be extracted, and supernatants will be dried and resuspended for LC/MS analysis following validated and published methods. We will quantify all major primary and secondary BAs (e.g., DCA) and glycine and taurine conjugates and their ratios, as well as total BAs and total unconjugated BAs. Authentic reference BAs will be purchased from Sigma-Aldrich and Steraloids. Blind duplicate samples will be used to assess inter- and intra-batch precision.

  baseline

• Circulating and fecal bile acids

  Absolute measurement of BAs in stool and serum obtained at mid-study (3 month follow up) will be performed under the direction of Co-I Ridlon. Samples will be extracted, and supernatants will be dried and resuspended for LC/MS analysis following validated and published methods. We will quantify all major primary and secondary BAs (e.g., DCA) and glycine and taurine conjugates and their ratios, as well as total BAs and total unconjugated BAs. Authentic reference BAs will be purchased from Sigma-Aldrich and Steraloids. Blind duplicate samples will be used to assess inter- and intra-batch precision.

  3 month

• Circulating and fecal bile acids

  Absolute measurement of BAs in stool and serum obtained at post-intervention (6 month follow up) will be performed under the direction of Co-I Ridlon. Samples will be extracted, and supernatants will be dried and resuspended for LC/MS analysis following validated and published methods. We will quantify all major primary and secondary BAs (e.g., DCA) and glycine and taurine conjugates and their ratios, as well as total BAs and total unconjugated BAs. Authentic reference BAs will be purchased from Sigma-Aldrich and Steraloids. Blind duplicate samples will be used to assess inter- and intra-batch precision.

  6 month

• Gut microbiota for metabolic function

  The UIC Genomics core will PCR amplify genomic DNA with primers CS1\_515F and CS2\_806R (modified from the set used by the Earth Microbiome Project) targeting the V4 region of microbial small subunit ribosomal RNA genes. Amplicons will be generated using a two-stage PCR protocol. The V4 region of the 16S rRNA gene will be sequenced with the Illumina MiSeq platform to generate 2x250 bp paired end reads per sample. Environmental controls will be included in the sequences to distinguish from any contaminants in reagents or the lab environment.

  baseline

• Gut microbiota for metabolic function

  The UIC Genomics core will PCR amplify genomic DNA with primers CS1\_515F and CS2\_806R (modified from the set used by the Earth Microbiome Project) targeting the V4 region of microbial small subunit ribosomal RNA genes. Amplicons will be generated using a two-stage PCR protocol. The V4 region of the 16S rRNA gene will be sequenced with the Illumina MiSeq platform to generate 2x250 bp paired end reads per sample. Environmental controls will be included in the sequences to distinguish from any contaminants in reagents or the lab environment.

  3 month

• Gut microbiota for metabolic function

  The UIC Genomics core will PCR amplify genomic DNA with primers CS1\_515F and CS2\_806R (modified from the set used by the Earth Microbiome Project) targeting the V4 region of microbial small subunit ribosomal RNA genes. Amplicons will be generated using a two-stage PCR protocol. The V4 region of the 16S rRNA gene will be sequenced with the Illumina MiSeq platform to generate 2x250 bp paired end reads per sample. Environmental controls will be included in the sequences to distinguish from any contaminants in reagents or the lab environment.

  6 month

• Gene expression

  From stool preserved in Ambion Denaturation Solution, eukaryotic polyA+ RNA will be isolated using the Active Motif mTRAP Maxi kit followed by DNA removal with DNAFree (Invitrogen). Libraries will be quantified using the Library Quantification kit (Kapa Biosystems), and sequencing will be performed on an Illumina HiSeq 2500 platform using standard Illumina protocols. RNA reads will be mapped with the STAR aligner using the default parameters to the Ensembl GRCh38 human reference. Reads will be examined for quality control using FastQC and quantified using HTSeq-count. Sequencing reads will be filtered to remove genes present in low abundance. For stool exfoliated cells, the RNA-seq gene count matrix is very sparse, with most entries corresponding to zero transcripts; thus, genes in stool will be removed if \>33% of the samples contain only 0 or 1 read.

  baseline

• Gene expression

  From stool preserved in Ambion Denaturation Solution, eukaryotic polyA+ RNA will be isolated using the Active Motif mTRAP Maxi kit followed by DNA removal with DNAFree (Invitrogen). Libraries will be quantified using the Library Quantification kit (Kapa Biosystems), and sequencing will be performed on an Illumina HiSeq 2500 platform using standard Illumina protocols. RNA reads will be mapped with the STAR aligner using the default parameters to the Ensembl GRCh38 human reference. Reads will be examined for quality control using FastQC and quantified using HTSeq-count. Sequencing reads will be filtered to remove genes present in low abundance. For stool exfoliated cells, the RNA-seq gene count matrix is very sparse, with most entries corresponding to zero transcripts; thus, genes in stool will be removed if \>33% of the samples contain only 0 or 1 read.

  3 month

• Gene expression

  From stool preserved in Ambion Denaturation Solution, eukaryotic polyA+ RNA will be isolated using the Active Motif mTRAP Maxi kit followed by DNA removal with DNAFree (Invitrogen). Libraries will be quantified using the Library Quantification kit (Kapa Biosystems), and sequencing will be performed on an Illumina HiSeq 2500 platform using standard Illumina protocols. RNA reads will be mapped with the STAR aligner using the default parameters to the Ensembl GRCh38 human reference. Reads will be examined for quality control using FastQC and quantified using HTSeq-count. Sequencing reads will be filtered to remove genes present in low abundance. For stool exfoliated cells, the RNA-seq gene count matrix is very sparse, with most entries corresponding to zero transcripts; thus, genes in stool will be removed if \>33% of the samples contain only 0 or 1 read.

  6 month

• Exfoliated intestinal epithelial cell transcriptomics

  Exfoliated intestinal epithelial cells separated from stool with gene expression analysis

  Baseline

• Exfoliated intestinal epithelial cell transcriptomics

  Exfoliated intestinal epithelial cells separated from stool with gene expression analysis

  3 months

• Exfoliated intestinal epithelial cell transcriptomics

  Exfoliated intestinal epithelial cells separated from stool with gene expression analysis

  6 months

Secondary Outcomes (28)

• Body weight

  baseline

• Body weight

  3 month

• Body weight

  6 month

• Body mass index

  baseline

• Body mass index

  3 month

Other Outcomes (10)

• Adverse events

  Through study completion, an average of 6 months

• Psychosocial health

  Baseline

• Psychosocial health

  3 month

Study Arms (4)

Med-A

EXPERIMENTAL

Med-A will attend a one-hour, in-person individual session with a registered dietitian (RD) during the two weeks prior to the start of the intervention. For subjects randomized to Med-A the study RD will instruct on adoption of an eating pattern consistent with a MedDiet using an individualized MedDiet exchange list and companion guide. Recommended daily exchanges are based on individual caloric needs to maintain weight. We will not ask subjects to abstain from alcohol during the trial despite its known effects on BA metabolism, but we will recommend that only 5% of calories come from alcohol taken with meals. Following the initial session, subjects will meet for 24 individual sessions (1-hour, held approximately weekly) in-person or virtually over the remaining 6 months. Additional asynchronous learning materials will be distributed weekly through a private Facebook group. The Med-A group will be asked to maintain their usual physical activity.

Other: Med

WL-A

EXPERIMENTAL

WL-A will attend a one-hour, in-person individual session with a registered dietitian (RD) during the two weeks prior to the intervention. For WL-A, the focus will be on daily calorie restriction (-500-750 kcal/day) to achieve a 1-2 lb. per week WL and 5% WL from baseline at 6 months in the context of the subject's typical diet pattern. We will not ask subjects to abstain from alcohol during the trial despite its known effects on BA metabolism, but we will recommend that only 5% of calories come from alcohol taken with meals. Following the initial session, subjects will meet for 24 individual, virtual or in-person sessions (1-hour, held approximately weekly) over the remaining 6 months. Additional asynchronous learning materials will be distributed weekly through a private Facebook group. The WL-A group will be prescribed an activity program. Physical activity will be monitored via FitBit.

Other: WL

WL-Med

EXPERIMENTAL

WL-Med will attend a one-hour, in-person session with a registered dietitian (RD) prior to the intervention. The RD will instruct on an eating pattern consistent with a MedDiet using an individualized exchange list. Exchanges are based on individual caloric needs to lose weight (WL-Med, calorie restriction to achieve a 1-2 lb. per week WL and 5% WL from baseline at 6 months). We will not ask subjects to abstain from alcohol despite its known effects on BA metabolism, but we will recommend that only 5% of calories come from alcohol taken with meals. Following the initial session, subjects will meet remotely or in-person for 24 individual sessions (1-hour, held approximately weekly). Additional asynchronous learning materials will be distributed weekly through a private Facebook group. The WL-Med group will be prescribed an activity program. Some asynchronous lessons will contain information about physical activity. Physical activity will be monitored via FitBit.

Other: Med; Other: WL

Control

NO INTERVENTION

The study RD will meet individually with the Control group subjects in-person for 1-hour at the start of the 6-month intervention. Control participants will be instructed to maintain current eating and activity patterns and weight over the next 6 months. No dietary recommendations are provided, and they will receive weekly health newsletters that include non-diet related health topics (e.g., flu prevention). Contact will be made again at month-3 and post-intervention (month-6) research visits and during monthly phone calls to collect data pertaining to recent diet intake. At the month-3 assessment, weight will be checked and those with \>2.5% WL from baseline will receive additional instruction from the RD to maintain lifestyle patterns. All WL-Med materials are offered to the group in a self-guided format following the 6-month intervention.

Interventions

Med OTHER

Mediterranean diet

Med-A; WL-Med

WL OTHER

Measuring change in weight

WL-A; WL-Med

Eligibility Criteria

• Age: 45 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women 45-75 years of age
• Self-identify as AA
• BMI 30-50 kg/m2
• Willingness to participate in all procedures including maintaining weight/current physical activity if randomized to Med-A/Control
• Willingness and ability to provide informed consent
• Willingness to be randomized
• Understands English
• Has access to a phone
• Plans to reside in Chicago for the next 8-10 months.

You may not qualify if:

• renal disease
• autoimmune disorders
• immunodeficiency
• malabsorptive disorders
• significant gastrointestinal and/or hepatic diseases
• severe ischemic heart disease
• severe pulmonary disease
• history of bariatric surgery
• alcohol abuse (\> 50 grams/day)
• illicit drug abuse (other than marijuana based on self-report)
• combustible tobacco use
• uncontrolled diabetes based on HbA1c\>9.0%
• eating disorder
• cancer treatment within the past 12 months
• history of CRC

Sponsors & Collaborators

• University of Illinois at Chicago: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

RECRUITING

Related Publications (1)

• McLeod A, Wolf P, Chapkin RS, Davidson LA, Ivanov I, Berbaum M, Williams LR, Gaskins HR, Ridlon J, Sanchez-Flack J, Blumstein L, Schiffer L, Hamm A, Cares K, Antonic M, Bernabe BP, Fitzgibbon M, Tussing-Humphreys L. Design of the Building Research in CRC prevention (BRIDGE-CRC) trial: a 6-month, parallel group Mediterranean diet and weight loss randomized controlled lifestyle intervention targeting the bile acid-gut microbiome axis to reduce colorectal cancer risk among African American/Black adults with obesity. Trials. 2023 Feb 15;24(1):113. doi: 10.1186/s13063-023-07115-4.

  PMID: 36793105 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Feeding Behavior

Interventions

Matrilin Proteins

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

Intervention Hierarchy (Ancestors)

Extracellular Matrix Proteins; Scleroproteins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Lisa Tussing-Humphreys, PhD, RD

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

• Marian Fitzgibbon, PhD

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lara Blumstein

CONTACT

312-355-2328; lbb@uic.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: This study is a four-arm RCT designed to test the effect of a weight-stable MedDiet alone (Med-A) lifestyle intervention, calorie restriction for WL with no diet composition change (WL-A) intervention, a MedDiet WL lifestyle intervention (WL-Med) compared to Control on BA metabolism, the gut microbiome, and gene expression in exfoliated intestinal epithelial cells. The study includes 1) screening potential subjects; 2) baseline assessment of diet, lifestyle behaviors (e.g., physical activity), anthropometrics, and blood and fecal sampling; 3) a four-arm RCT; and 4) mid-(month 3) and post-intervention (month 6) assessments.

Study Record Dates

• First Submitted: January 29, 2021
• First Posted: February 15, 2021
• Study Start: February 1, 2022
• Primary Completion: March 31, 2025
• Study Completion: March 31, 2025
• Last Updated: August 21, 2024

Record last verified: 2024-08

Locations

US (1)