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Consumption of food-borne bioactive compounds can protect against human diseases such as cancer, inflammation, birth defects, and microbial infection. We will determine the mechanisms by which selected compounds exert their protective action. <P>
The overall goal of this component of the research is to find simple intervention(s) that can reshape the gut microbial communities of obese individuals such that they resemble those of lean individuals. The desired outcome of the interventions is an increase in Bacteroidetes bacteria and a reduction of Firmicutes in the gut microbiota. <P>Specific Aim Year 1: Protocol design, set-up of mouse breeding, baseline characterization of gut microbiotas, induction of obesity by high-fat diet. Initial diet intervention studies. <P>Specific Aim Year 2: Diet, probiotic and antibiotic supplements in obese vs. lean mice. <P>Specific Aim Year 3: Bioinformatic analysis of data, manuscript preparation and publishing.
NON-TECHNICAL SUMMARY: Obesity rates amongst the adult and child population in New York State exceed 25% and continuing to rise, and are highest in upstate counties. Obesity is associated with chronic diseases such as Type 2 diabetes and heart disease, which impose suffering, reduced lifespan as well as a financial burden to the state. Although obesity is largely a lifestyle disease, where energy intake exceeds expenditure, diet and exercise are generally not successful at reducing obesity rates. My past research has shown that the microbes that normally inhabit the gut can contribute to obesity. In studies of mice and humans, the gut microbes of obese individuals were more efficient as energy extraction from the diet than microbes of lean individuals. Thus, manipulation of the gut microbiota is a promising avenue in the search for simple interventions. The goals of this research are to determine in a mouse model of obesity simple interventions (dietary, antibiotic, probiotic, or combinations) that can reshape over the long term the gut microbial communities of obese individuals to resemble those of lean individuals, and process the diet in a less efficient manner. This research will provide guideline for simple, affordable therapies to be tested in human volunteers. The results of the study could potentially impact the health of more than a quarter of the New York State population, which is obese. <P>
APPROACH: We will use mice for these studies, because our past research with obese mouse models, both genetic and diet-induced, have shown them to be very good models for humans. The composition of the gut microbes will be monitored from analyses of fecal samples and cecal contents upon sacrifice of the animals. Obesity will be induced in the mice (inbred strain C56Bl/6J) by transferring them to a high fat/high sugar diet upon weaning. Control mice will be fed standard polysaccharide-rich mouse chow. Obese (> 35 g) and lean (20-25g) mice will be randomly assigned to interventions consisting of supplementation by gavage with 1) soluble fiber (inulin, pectin or beta-glucans), 2) a probiotic bacterium (Lactobacillus reuteri), 3) antibiotics (ciprofloxacin). A second round of interventions will consist of combinations: (1+2), (3 then 1), (3 then 2), (3 then 1+2). To survey the overall composition of samples, we will analyze the DNA present in the samples for the diversity of 16S rRNA genes (the bacterial barcode of life). We will use recently developed massively parallel pyrosequencing to survey many samples at once (i.e., hundreds, funds for 2 machine runs are requested). We have an established track record for this type of study, including publications in Nature (4) and Science (1).