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ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Research Project #426494

Research Project: Regulatory Mechanisms Induced by Health-Promoting Bioactive Food Components on Sex Steroid Hormone-Dependent Pathways, Cancer Cell-Stromal Cell Interactions, and the Gut Microbiome

Location: Diet, Genomics and Immunology Laboratory

2014 Annual Report

The overall goal of the project is to elucidate the molecular and cellular mechanisms that respond to selected food components to reduce the risk of chronic diseases such as cancer and obesity, with a focus on immune modulation in relation to obesity. A secondary aim is to further develop the utility of a porcine model to test the effect of probiotics and prebiotics on health maintenance through modulation of the gut microbiome and metabolome. Objective 1. Validate protective effects of bioactive food components such as glyceollins, indoles, and isothiocyanates on development of prostate cancer, and elucidate the regulation of sex steroid hormone-dependent pathways and cancer cell-stromal cell interactions as mechanisms of action by these bioactive food components. (NP107; C3, PS3B, C4, PS 4B) Objective 2. Study, in a swine model or other models as approriate, diet and gut microbiome interactions, focusing on the role of Lactobacillus, Bifidobacterium, and Bacteroides species, for the prevention of obesity and obesity-related metabolic syndrome. (NP107; C3, PS3B, C4, PS 4B)

For Objective 1, a complementary cell culture and tumor xenograft model will be used to test and identify efficacies of bioactive compounds from the diet and elucidate the mechanisms of how these bioactive food components act. The research is expected to identify mechanisms where food components alter biological processes such as proliferation, apoptosis, cell cycles, intracellular cell signaling, inflammation, metastasis, and post-transcriptional message regulation from both cell culture and whole animal studies. Genes involved in pathways mediated by the sex steroid hormones estrogen and androgen, orphan receptors, and cytokine-mediated pathways will be characterized. The conditions that modulate these pathways will include the use of plants with different phytochemical composition to delineate the role of specific compounds along with related food matrix effects. For Objective 2, a juvenile porcine animal model as a surrogate model for humans will be used to validate the effect of selected prebiotics and probiotics on the modulation of the host immune and metabolic responses to an obesogenic diet. The research will use a whole nutrigenomic approach where transcriptomics, metabolomic and metagenomic changes are integrated to identify biomarkers associated with health and disease that can be used as targets for nutritional interventions. Data generated from these studies is expected to reveal mechanisms of action of prebiotic and probiotic products added to the diet.

Progress Report
This project plan replaces and expands upon previous project plan # 1235-51530-053-00D. The efforts to identify active components in the diet that may contribute to the protective effects of chronic diseases including cancer, obesity, and inflammation were continued. The hypothesis that the cruciferous-derived compound phenethylisothiocyanate protects against prostate cancer (PEITC) using a rodent model of cancer development were tested. The animal feeding portion of the study using human prostate cancer LNCaP xenograft in nude mice on the effect of PEITC was completed. Nude mice were fed with and without PEITC. Animals were injected in their flanks with the human prostate cancer cell LNCaP. Tumor sizes, food intake, and animal weight were measured. Animals were on the experimental diet for 8 weeks after the tumor cell injection. PEITC fed-animal tumor volumes were significantly lower than control diet animals. These data support a cancer protective effect by PEITC. Molecular analysis will be performed and the molecular marker for cell proliferation, androgen-dependent pathway (including IGFBP-3), angiogenesis, and immune responses (including IL-6) will be determined to elucidate the effects of PEITC in-vivo. Consumption of probiotics starting at an early age, ameliorate the onset of dietary-induced obesity and its consequences in the juvenile pig. To test this hypothesis we have initiated pig selection, synchronization, and breeding. The polyphenol content of cocoa is high and its consumption is associated with benefits to human health. To determine the metabolites of cocoa-derived flavanols after consumption, five-month old conventional crossbred pigs were fed 5, 10, and 20 g of flavanol-enriched cocoa powder per day for 26 days. The total flavanol content in the cocoa powder was 20.5 mg/g and the major flavanols detected were epicatechin, (+) catechin, and procyanidin C1. Serum, urine, liver tissue, and proximal colon contents were collected 14 hours after the final consumption of cocoa powder. Metabolite analysis was conducted using a high-performance liquid chromatography tandem with accurate mass spectrometry (HPLC-HRM) on a Q-exactive high-resolution mass spectrometer. Epicatechin or catechin-glucuronide conjugates were the major metabolites found in the serum, urine, and liver. The urine had more diverse metabolites than the serum and liver, whereas proximal colon contents had fewer metabolites. The concentration of total epicatechin-glucronide in the serum and urine was higher than in the liver. Products of microbial metabolism such as vanillic acid and 3-hydroxyphenylpropionic acid were also detected. Changes in intestinal microbiota indicate an increase in the abundance of inherent porcine Bifidobacterium and Lactobacillus species with a high dose of cocoa powder. This study showed that flavanol metabolites were detectable in serum, urine, liver, and proximal colon content after consumption of cocoa powder for 26 days, and the concentration of flavanol metabolites and changes in microbiota composition were dependent on the dose of cocoa powder ingested.