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Microbiota, Metabolites and Colon Neoplasia
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21-167JS-1
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Microbiota, Metabolites and Colon Neoplasia
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Dr. Daniel Rosenberg
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Dr. Daniel W. Rosenberg and his project Co-Investigators are conducting a research study called ";Microbiota, Metabolites, and Colon Neoplasia"; to examine whether eating walnuts can have a beneficial effect on the gut bacteria population and the tissue that lines the inside of the colon in healthy individuals. Background & Hypothesis The human diet can positively or negatively impact cancer incidence, with plant-derived compounds - such as polyphenols - often exhibiting antioxidant cancer-preventive properties. Walnuts are an exceptional source of polyphenolic ellagitannins (ETs) that are converted to ellagic acid and various urolithins by gut microbiota in the colon. Urolithin A (UroA) is of particular interest for its potent anti-cancer, anti-inflammatory, and prebiotic activities. However, UroA production in individuals can vary significantly, likely based on differences in gut microbiota. We will substantiate the anti-cancer benefits of a prebiotic/probiotic complex derived from consuming walnuts and determine the basis of human inter-individual variability in UroA formation. Our overall hypothesis is that walnut supplementation improves colonic health and lowers colorectal cancer (CRC) risk through UroA formation. Study Design This is a controlled clinical trial to examine the effects of walnuts on CRC risk factors. Rationale While gut associated microbial metabolism of food-derived ETs is correlated with cardiovascular risk biomarkers, ET metabolism and how it relates to CRC risk has not been evaluated. Urolithins affect numerous cell signaling pathways relevant to cancer. The wide range of urolithin bioactivity provides the rationale for studying their potential cancer preventive properties. As part of an ongoing clinical study of early colonic neoplasia, our laboratory optimized ultra-sensitive analytical pipelines to perform a wide range of 'omics' analyses on human mucosal biopsies. This includes our recent study of the 'adherent' microbiome, raising the possibility that microbiota influence early CRC development, a time when prevention strategies are most efficacious. Our newly published findings demonstrate the feasibility of our analytical pipeline and our ability to associate molecular changes in the host colonic mucosa with the microbiota. Ultimately, these human and preclinical mouse studies may lead to the application of prebiotics and probiotics that enhance formation of protective urolithins for CRC prevention. These studies are of high significance as they will test the ability of the microbiota to generate agents (e.g., UroA) protective of the colonic mucosa. It is possible that high-risk patients can be efficiently converted to a protective state by taking probiotics to realize the full benefits of ET-rich foods. Study Population and Sample Size Men or women between the ages of 45-75 years who are scheduled to undergo a routine screening or surveillance colonoscopy for CRC. A total of 1,200 subjects will be enrolled across two sites (UConn Health and Weill Cornell Medicine). Major Study Interventions Subjects will be asked to consume 2 ounces of walnuts daily for 3 weeks prior to their routine colonoscopy. Food surveys, and blood, urine and stool samples will be collected at 2 time points over the course of study participation. A total of 8-10 colon biopsy specimens will be collected during a subject's colonoscopy procedure for the purposes of this study. Main Outcome Measures/Analyses 1) Association of the presence of colon lesions (AAs or SSA/Ps) with UroA production to assess whether UroA is associated with at-risk patients. 2) Identification and isolation of specific bacteria in the microbiome that either promote or impair urolithin synthesis and metabolism, and determine whether they have probiotic activity. 3) We will test whether the consumption of walnuts can elicit beneficial changes to host microbiota and associated functional metabolites (e.g., bile acids [BAs], SCFAs) in human colon. 4) Fecal (or bacterial) microbiome transplants will test for a causal link between UroA formation and cancer protection.
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Bacterial and Fungal
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Nutrition/Metabolism/Exercise
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Check with study contact
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Amy Pallotti. Telephone: 860-679-3878. Email: apallotti@uchc.edu
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Enrolling/recruiting. For current recruitment status, please check with study contact.
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