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

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ClinicalTrials.gov Identifier: NCT04753359
Recruitment Status : Not yet recruiting
First Posted : February 15, 2021
Last Update Posted : April 27, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Lisa Tussing-Humphreys, University of Illinois at Chicago

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, propose to conduct a four-arm RCT in which 200 obese AAs, 45-75 years old complete one of the following 8-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-4) 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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Diet Habit Other: Med Other: WL Not Applicable

Detailed Description:
Colorectal cancer (CRC) is associated with multiple risk factors including, obesity, low fiber diets, and diets high in animal protein and saturated fat (SFat). African Americans (AAs) have a higher prevalence of these risk factors and they have the highest incidence of CRC and related mortality. These multiple risk factors are also linked to higher circulating and fecal bile acids (BA) and a shift in BA amino acid conjugation from glycine to taurine. These BA-related changes can alter the composition, structure, and metabolic activity of the gut microbiota, fostering conditions for gut bacteria to expand and metabolize taurine-conjugated BAs to genotoxic hydrogen sulfide (H2S) and the tumor promoter, deoxycholic acid (DCA); a colonic milieu conducive to the formation of CRC. The investigators have shown that the abundance of H2S-producing bacteria is significantly higher in the colon of AAs compared to non-Hispanic whites (NHWs) and is a defining feature among AA CRC cases implicating these bacteria as contributors to CRC development in a race-dependent manner. Moreover, the microbial difference is associated with higher intake of SFat and animal protein in AAs, providing a pivotal intervention target. The investigators hypothesize that targeting the BA-gut microbiome axis to suppress abundance, growth and metabolic activity of H2S and DCA producing bacteria through diet and weight loss (WL) may reduce CRC risk, especially among AAs. 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. Our multidisciplinary team combining expertise in psychology, nutrition, microbiology, molecular cell biology, computational biology, medicine and biostatistics, propose to conduct a four-arm RCT in which 200 obese AAs, 45-75 years old complete one of the following 8-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-4) 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. The investigators approach is strong given the multidisciplinary team, use of evidence-based lifestyle interventions, and sophisticated -omics analyses to examine crosstalk between diet/WL, gut microbiome, and host intestinal physiology. If successful, this study could have profound public health impact on CRC risk among AAs and other high-risk populations, that would translate into timely dissemination opportunities.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 232 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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 4) and post-intervention (month 8) assessments.
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Mediterranean Diet and Weight Loss: Targeting the Bile Acid/Gut Microbiome Axis to Reduce Colorectal Cancer
Estimated Study Start Date : September 2021
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Med-A

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 group sessions. 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 in-person session, subjects will meet for 26 group sessions (1-hour, held approximately weekly) over the remaining 7.5 months.

The Med-A group will be asked to maintain their usual physical activity pattern.

Other: Med
Mediterranean diet

Experimental: WL-A

WL-A will attend a one-hour, in-person individual session with a registered dietitian (RD) during the two weeks prior to the start of group sessions. For subjects randomized to 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 8 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 in-person session, subjects will meet for 26 group sessions (1-hour, held approximately weekly) over the remaining 7.5 months.

The WL-A group will be prescribed an activity program with an initial recommendation of 100 min/week progressing to 150 min/week within 6 weeks. Subjects will also participate in 30 minutes of supervised physical activity during the group sessions

Other: WL
Measuring change in weight

Experimental: WL-Med

WL-Med will attend a one-hour, in-person individual session with a registered dietitian (RD) during the two weeks prior to the start of group sessions. The study RD will instruct on adoption of an eating pattern consistent with a MedDiet using an individualized exchange list and companion guide. Recommended daily 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 8 months). 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 in-person session, subjects will meet for 26 group sessions (1-hour, held approximately weekly) over the remaining 7.5 months.

Physical activity. Participants will be prescribed an activity program and will also participate in 30 minutes of supervised physical activity during the group sessions

Other: Med
Mediterranean diet

Other: WL
Measuring change in weight

No Intervention: Control
The study RD will meet individually with the Control group subjects for 1-hour at the start of the 8-month intervention. Control participants will be instructed to maintain current eating and activity patterns and weight over the next 8 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-4 and post-intervention (month-8) research visits and during monthly phone calls to collect data pertaining to recent diet intake. At the month-4 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 8-month intervention.



Primary Outcome Measures :
  1. Circulating and fecal bile acids [ Time Frame: baseline ]
    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.

  2. Circulating and fecal bile acids [ Time Frame: 4 month ]
    Absolute measurement of BAs in stool and serum obtained at mid-study (4 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. Circulating and fecal bile acids [ Time Frame: 8 month ]
    Absolute measurement of BAs in stool and serum obtained at post-intervention (8 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.

  4. Gut microbiota for metabolic function [ Time Frame: baseline ]
    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.

  5. Gut microbiota for metabolic function [ Time Frame: 4 month ]
    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. Gut microbiota for metabolic function [ Time Frame: 8 month ]
    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.

  7. Gene expression [ Time Frame: baseline ]
    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.

  8. Gene expression [ Time Frame: 4 month ]
    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.

  9. Gene expression [ Time Frame: 8 month ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   45 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Men and women 45-75 years of age
  • Self-identify as AA
  • BMI 30-50 kg/m2
  • Up to date with CRC screening (confirmed via EMR) or if not up to date, negative fecal immunochemical test (FIT) (UI Health can offer FIT to all eligible patients, and navigate those with positive results to direct access colonoscopy)
  • Willingness to participate in all procedures including maintaining weight/current physical activity if randomized to Med-A/Control
  • Willingness 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.

Exclusion Criteria:

  • 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
  • positive FIT at the time of screening (subject can participate in a later wave pending results of direct access colonoscopy)
  • history of CRC
  • genetic predisposition to CRC (e.g., Lynch syndrome)
  • gait disorder
  • weight > 450 lbs. (weight limitation of the DXA scanner)
  • currently adhering to a MedDiet based on a diet screener
  • self-reported WL > 3% in the past 12 months
  • currently on a WL diet or actively involved in a formal WL program (e.g., Weight Watchers)
  • food allergies that would interfere with adopting a MedDiet
  • antibiotic use in the past 3 months
  • night-shift work
  • regular use (i.e., ≥ 3 times per week) of prebiotics/probiotics/synbiotics, dietary fiber supplements, or laxatives,

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 ClinicalTrials.gov identifier (NCT number): NCT04753359


Contacts
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Contact: Alyshia Hamm 19702508462 ahamm6@uic.edu

Sponsors and Collaborators
University of Illinois at Chicago
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Lisa Tussing-Humphreys, PhD, RD University of Illinois at Chicago
Principal Investigator: Marian Fitzgibbon, PhD University of Illinois at Chicago
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Responsible Party: Lisa Tussing-Humphreys, Assistant Professor of Medicine, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT04753359    
Other Study ID Numbers: 2020-1342
1R01CA250390-01A1 ( U.S. NIH Grant/Contract )
First Posted: February 15, 2021    Key Record Dates
Last Update Posted: April 27, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Weight Loss
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Body Weight Changes
Body Weight