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

Colorectal Cancer Clinical Trial

— Bridge CRC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04753359
• Other study ID #: 2020-1342
• Secondary ID: 1R01CA250390-01A
• Status: Recruiting
• Phase: N/A
• Start date: February 1, 2022
• Est. completion date: March 31, 2025

Study information

• Verified date: April 2023
• Source: University of Illinois at Chicago
• Contact: Alyshia Hamm
• Phone: 19702508462
• Email: ahamm6[@]uic.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 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. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 232
• Est. completion date: March 31, 2025
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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.

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
• history of CRC
• genetic predisposition to CRC (e.g., Lynch syndrome)
• 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,
• Gait disorder
• currently pregnant
• active Covid-19 infection within 6 weeks of recruitment/data collection.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Diet Habit
• Weight Loss

Intervention

Other:
• Med
Mediterranean diet
• WL
Measuring change in weight

Locations

Country	Name	City	State
United States	University of Illinois at Chicago	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
University of Illinois at Chicago	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse events	Obtained via interview	Through study completion, an average of 6 months
Other	Psychosocial health	survey	Baseline
Other	Psychosocial health	survey	3 month
Other	Psychosocial health	survey	6 month
Other	Medication use	Survey, interview	baseline
Other	Medication use	Survey, interview	3 month
Other	Medication use	Survey, interview	6 month
Other	Bowel habits	survey	baseline
Other	Bowel habits	survey	3 month
Other	Bowel habits	survey	6 month
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Exfoliated intestinal epithelial cell transcriptomics	Exfoliated intestinal epithelial cells separated from stool with gene expression analysis	Baseline
Primary	Exfoliated intestinal epithelial cell transcriptomics	Exfoliated intestinal epithelial cells separated from stool with gene expression analysis	3 months
Primary	Exfoliated intestinal epithelial cell transcriptomics	Exfoliated intestinal epithelial cells separated from stool with gene expression analysis	6 months
Secondary	Body weight	Body weight will be measured with a digital scale	baseline
Secondary	Body weight	Body weight will be measured with a digital scale	3 month
Secondary	Body weight	Body weight will be measured with a digital scale	6 month
Secondary	Body mass index	Calculated from measured weight and height	baseline
Secondary	Body mass index	Calculated from measured weight and height	3 month
Secondary	Body mass index	Calculated from measured weight and height	6 month
Secondary	Mediterranean Diet Adherence	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Baseline
Secondary	Mediterranean Diet Adherence	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Month 1
Secondary	Mediterranean Diet Adherence	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Month 2
Secondary	Mediterranean Diet Adherance	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Month 3
Secondary	Mediterranean Diet Adherence	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Month 4
Secondary	Mediterranean Diet Adherence	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Month 5
Secondary	Mediterranean Diet Adherence	Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score	Month 6
Secondary	Physical activity	Number of steps measured for 7-days with FitBit wearable tracker	Baseline
Secondary	Physical activity	Number of steps measured for 7-days with FitBit wearable tracker	3 month
Secondary	Physical activity	Number of steps measured for 7-days with FitBit wearable tracker	6 month
Secondary	Total and regional body composition (fat and muscle)	DXA whole-body composition scan to measure total body composition fat% vs bone% vs lean%	baseline
Secondary	Total and regional body composition (fat and muscle)	DXA whole-body composition scan to measure total body composition fat% vs bone% vs lean%	3 month
Secondary	Total and regional body composition (fat and muscle)	DXA whole-body composition scan to measure total body composition fat% vs bone% vs lean%	6 month
Secondary	Circulating cytokines	Measured from serum using a commercial multiplex kit	Baseline
Secondary	Circulating cytokines	Measured from serum using a commercial multiplex kit	3 month
Secondary	Circulating cytokines	Measured from serum using a commercial multiplex kit	6 month
Secondary	Fasting glucose	Measured from plasma at a local commercial lab	Baseline
Secondary	Fasting glucose	Measured from plasma at a local commercial lab	3 month
Secondary	Fasting glucose	Measured from plasma at a local commercial lab	6 month
Secondary	Fasting insulin	Measured from plasma at a local commercial lab	Baseline
Secondary	Fasting insulin	Measured from plasma at a local commercial lab	3 month
Secondary	Fasting insulin	Measured from plasma at a local commercial lab	6 month