Colorectal Cancer, Diet Habit
Conditions
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.
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 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.
Sponsors
National Cancer Institute (NCI)
University of Illinois at Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
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 3) and post-intervention (month 6) assessments.
Eligibility
Sex/Gender
ALL
Age
45 Years to 75 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gene expression | 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. |
| Gut microbiota for metabolic function | 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. |
| Exfoliated intestinal epithelial cell transcriptomics | Baseline | Exfoliated intestinal epithelial cells separated from stool with gene expression analysis |
| Circulating and fecal bile acids | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mediterranean Diet Adherance | Month 3 | Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score |
| Total and regional body composition (fat and muscle) | baseline | DXA whole-body composition scan to measure total body composition fat% vs bone% vs lean% |
| Circulating cytokines | Baseline | Measured from serum using a commercial multiplex kit |
| Fasting glucose | Baseline | Measured from plasma at a local commercial lab |
| Fasting insulin | Baseline | Measured from plasma at a local commercial lab |
| Physical activity | Baseline | Number of steps measured for 7-days with FitBit wearable tracker |
| Body weight | baseline | Body weight will be measured with a digital scale |
| Body mass index | baseline | Calculated from measured weight and height |
| Mediterranean Diet Adherence | Baseline | Measured with a food frequency questionnaire, 24-hour diet recalls, and screener which will be aggregated to evaluate a total adherence score |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Through study completion, an average of 6 months | Obtained via interview |
| Bowel habits | baseline | survey |
| Medication use | baseline | Survey, interview |
| Psychosocial health | Baseline | survey |
Countries
United States
Contacts
Primary ContactLara Blumstein
Outcome results
None listed