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

ABSTRACT: 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.

DISEASE(S): Diet Habit,Weight Loss,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2367279 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Moderate weight loss can ameliorate adverse health effects associated with obesity, reflected by an improved adipose tissue (AT) gene expression profile. However, the effect of rate of weight loss on the AT transcriptome is unknown. Objective: We investigated the global AT gene expression profile before and after two different rates of weight loss that resulted in similar total weight loss, and after a subsequent weight stabilization period. Design: In this randomized controlled trial, 25 male and 28 female individuals (BMI: 28-35 kg/m2) followed either a low-calorie diet (LCD; 1250 kcal/d) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal/d) for 5 weeks (weight loss (WL) period) and a subsequent weight stable (WS) period of four weeks. The WL period and WS period together is termed dietary intervention (DI) period. Abdominal subcutaneous AT biopsies were collected for microarray analysis, and gene expression changes were calculated for all three periods in the LCD group, VLCD group and between diets (ΔVLCD-ΔLCD). Results: Weight loss was similar between groups during the WL period (LCD: -8.1±0.5 kg, VLCD: -8.9±0.4 kg, difference p=0.25). Overall, more genes were significantly regulated and changes in gene expression were more extreme in the VLCD group compared to the LCD group. Gene sets related to mitochondrial function, adipogenesis and immunity/inflammation were more strongly upregulated on a VLCD compared to a LCD during the DI period (positive ΔVLCD-ΔLCD). Neuronal- and olfactory-related gene sets were decreased during the WL period and DI period in the VLCD group. Conclusions: The rate of weight loss (LCD vs. VLCD), with similar total weight loss, strongly regulates AT gene expression. Increased mitochondrial function and adipogenesis on a VLCD compared to a LCD reflect potential beneficial diet-induced changes in AT, while differential neuronal and olfactory regulation suggest functions of these genes beyond the current paradigm.

Project description:We investigated the regulation of adipose tissue (AT) gene expression during different phases of a dietary weight loss program and its relationship with insulin sensitivity. Obese women followed a weight reduction program composed of an energy restriction phase (ER) with a 4-week very-low-calorie diet and a weight stabilization period (WS) composed of a 2-month low-calorie diet followed by 3 to 4 months of a weight maintenance diet. At each time point, body composition, plasma parameters and glucose disposal rate were assessed and subcutaneous AT biopsies were performed. Variations in mRNA levels were determined using DNA microarrays and reverse transcription-quantitative PCR. Distinct sets of AT genes are regulated during calorie restriction and weight stabilization revealing an unexpected temporal pattern in the link between AT and insulin sensitivity during weight loss. Experiment Overall Design: Fifteen obese premenopausal women were recruited at the Third Faculty of Medicine of Charles University and at the Institute for Mother and Child Care in Prague, Czech Republic. During the first four weeks of the dietary intervention program, the subjects received an energy restricted diet of 800 kcal/day (liquid formula diet, Redita, Promil). During the next two months, a low-calorie diet was designed to provide 600 kcal/day less than the individually estimated energy requirement based on an initial resting metabolic rate multiplied by 1.3. Following this, subjects entered a weight maintenance phase for a period of 3 to 4 months, during which the patients were instructed to keep their weight stable. A complete clinical investigation in the fasting state was realized before and at the end of each phase. Needle microbiopsy of subcutaneous AT was performed under local anesthesia (1% Xylocaine) from the abdominal region (14â20 cm lateral to the umbilicus). Total RNA were isolated from AT samples with Qiagen RNeasy kit. RNA quantity and quality were checked with the Experion automated electrophoresis system (BioRad laboratories). We performed a whole transcriptome analysis comparing 1) before vs. after the initial 4 weeks severe energy restriction (ER), 2) after energy restriction vs. after weight stabilization (WS) and 3) before dietary intervention vs. after weight stabilization (DI). Eight subjects representative of the cohort were selected, matched for high quality of total RNA samples, insulin sensitivity and weight changes during the study. Targets for microarray experiments were generated from 500 ng of total RNA with Agilent low RNA input amplification kit (Agilent Technologies) and hybridized to whole genome 44k oligonucleotide arrays (Agilent Technologies). Each combination of samples was analyzed twice using a dye swap design (i.e., a total of 48 hybridizations). Data acquisition from microarrays was obtained with a GenePix 4000B scanner (Axon instruments) and image processing was performed with Feature Extraction 8.5 (Agilent Technologies). Raw data were normalized with a global Lowess procedure and filtered with R package LIMMA (Bioconductor). Outlier replicates and spots with a signal to noise ratio lesser than 2 on both red and green channel were eliminated from our analyses. Mean log ratios were calculated from paired duplicates before normalization. Differentially expressed genes were identified with Significance Analysis of Microarray (SAM) procedure.

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

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