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<p>Our long-term goal is to understand the mechanisms which may explain the decreased prevalence of insulin resistance phenotypes (systemic inflammation, hypertension, dyslipidemia, insulin insensitivity, obesity) observed in populations consuming a healthy dietary pattern rich in fruits, vegetables and whole grains. In support of this goal, we have developed the following hypothesis: Dietary polyphenols alter intestinal microbiota composition and metabolic activity resulting in changes in intestinal inflammation and permeability, and secondarily, changes in systemic inflammation and insulin sensitivity. To test this hypothesis, we propose to recruit 30 overweight/obese participants and provide them well-controlled diets which differ markedly in their polyphenol content so that we can achieve the following objectives: Objective 1. Determine the effects of a high polyphenol diet on intestinal microbiota and metabolic capabilities. Objective 2. Determine polyphenol-mediate deffects on intestinal inflammation and permeability. Objective 3. Determine the consequences of polyphenol-mediated changes in intestinal microbiota and inflammation on systemic inflammation and insulin sensitivity. </p>
<p>NON-TECHNICAL SUMMARY: A healthy dietary pattern, almost uniformly characterized as being rich in fruits, vegetables and whole grains (among other components), has been repeatedly associated with a decreased prevalence of obesity and type 2 diabetes. Recent studies have begun to consider whether the dietary polyphenol components may underlie the suggested favorable effects of a healthy dietary pattern. Based on our preliminary data as well as published observations, we hypothesized that polyphenols alter intestinal bacteria content, composition and metabolic activity resulting in decreased intestinal and systemic inflammation and improvements in insulin sensitivity. To test this idea, we will feed 30 overweight volunteers two diets which differ substantially in plant polyphenol levels. After six weeks on each diet, we will take samples of blood and stools and determine if plant polyphenols affect gut bacteria composition, gut "leakiness", and markers of pre-diabetes. If our hypothesis is proven correct, then this would provide an additional explanation for the decreased rate of obesity and type 2 diabetes in people consuming a healthy dietary pattern rich in fruits, vegetables and whole grains. </p>
<p>APPROACH: We will recruit 30 overweight/obese participants and provide them well-controlled diets which differ markedly in polyphenol content. For this study, all menus will be prepared by the Center for Human Nutrition Studies Research Kitchen and provided to our participants for consumption. Diets will be fed for 6 weeks each in arandomized cross-over design with fecal and blood samples collected during the last week of each diet period. From the collected samples will determine the effects of a high polyphenol diet on: 1) intestinal microbiota and metabolic capabilities by assessing changes in fecal microbiota subpopulations (454 pyrosequencing) and short chain fatty acid content; 2) intestinal inflammation and permeability by assessing changes in fecal markers associated with intestinal inflammation (calprotectin, myeloperoxidase, eosinophil protein X) by ELISA, measuring intestinal permeability with partially absorbed sugar probes, and assaying for plasma endotoxin levels by ELISA; and 3) systemic inflammation and insulin sensitivity by assessing circulating levels of inflammatory cytokines (interleukin-6, C-reactive protein, soluble TNFαreceptors), adipokines (resistin, adiponectin, leptin), and metabolic regulatory hormones (insulin, C-peptide) employing multiplexed assays. </p>