Colonic Bacterial Synthesis of Butyric Acid

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DESCRIPTION (provided by applicant): Colonic bacterial fermentation of carbohydrate will result in the colonic luminal synthesis of butyric acid (BA). A consistent supply of BA to the colonocyte is necessary to promote a normal balance of cell proliferation and apoptosis in this organ, but excessive BA may be toxic to the colonie mucosa. Little is known about how the production of BA in the colonic lumen is affected by fermentation of carbohydrate, especially in infants. Current understanding about colonic synthesis of BA is based either on incubations of substrates with colonic fluid or on measurements of luminal concentrations, neither of which may reflect actual synthesis. Based on preliminary data using a stable isotope technique, the investigators hypothesize that BA supply to the colon of the infant can be maintained by fermentation of disaccharides present in the feedings of such infants. Fructooligosaccharides such as inulin cause a beneficial increase in bifidobacteria in the colon (prebiotic effect), but it is not clear if feeding inulin enhances BA formation. The preliminary data suggest that inulin feeding may ameliorate some of the adverse effects of severe disaccharide malabsorption on colonic structure and function. it is hypothesized that moderate disaccharide malabsorption stimulates luminal BA synthesis in the cecum and cecal cell proliferation, but it is also hypothesized that severe disaccharide malabsorption depresses BA synthesis (and cell proliferation) and that inulin attenuates this effect. To assess these overall hypotheses, chronically catheterized piglets, aged 18-19 d, will be studied and colonic BA synthesis will be quantified in order to address three Specific Aims: Aim 1. To determine the effects of disaccharide malabsorption (0-5 g/hr) or inulin feeding on BA production and on cecal and distal left colonic luminal concentrations of BA. Aim 2. To determine whether disaccharide malabsorption or inulin feeding cause colonic inflammation or injury or affect cell kinetics (crypt cell proliferation rate and apoptosis) and the expression of Bax, a pro-apoptotic protein. Aim 3. To determine the effect of cecal infusion of BA on colonic structure and cell kinetics. Using data from Aim I on high and normal rates of BA production, the effects of a high rate of BA infusion will be evaluated, at two time points, in normal piglets and the effects of normalizing BA supply with a low rate of BA infusion in piglets during severe disaccharide malabsorption also will be studied.