A DIET HIGH IN FIBER IS THOUGHT TO INHIBIT ULCERATIVE COLITIS. IN CONTRAST, FIBER IS ALSO KNOWN TO EXACERBATE THE SYMPTOMS ASSOCIATED WITH ULCERATIVE COLITIS. THIS PARADOX OF WHY FIBER BENEFITS SOME ULCERATIVE COLITIS PATIENTS IS NOT CLEAR. BUTYRATE, A METABOLITE FROM THE BREAKDOWN OF FIBER IN THE COLON BY BACTERIA, IS AN IMPORTANT PLAYER. COLONOCYTES THAT NORMALLY USE BUTYRATE AS THEIR PRIMARY ENERGY SOURCE (OVER GLUCOSE) BECOME UNABLE TO USE BUTYRATE PROPERLY IN ULCERATIVE COLITIS. SINCE BUTYRATE IS NOT USED ITS LEVELS BECOME ELEVATED, AND THIS RESULTS IN A DIMINISHED ABILITY FOR THE COLON TO REPAIR DURING INFLAMMATION AND IN ULCERATIVE COLITIS. THE REASON BEHIND THIS IS THAT ELEVATED BUTYRATE LEVELS (COMING FROM A HIGH FIBER DIET) CAUSE STEM CELLS IN THE COLON, WHICH ARE NEEDED TO PRODUCE NEW COLONIC CELLS FOR REPAIR, TO UNDERGO APOPTOSIS, AND THEREFORE HINDER THE HEALING PROCESS OF THE COLON. PRELIMINARY DATA SUGGESTS THAT AN INFLAMMATORY MOLECULE, OR CYTOKINE CALLED INTERLEUKIN-1BETA, WHICH IS ELEVATED IN ULCERATIVE COLITIS, CAUSES THE DECREASE IN BUTYRATE UTILIZATION IN THE COLON CELLS. INTERLEUKIN-1BETA ELICITS ITS EFFECT THROUGH A RECEPTOR ON THESE COLON CELL CALLED THE INTERLEUKIN-1 RECEPTOR. BLOCKING THIS RECEPTOR INHIBITS INTERLEUKIN-1BETA AND RESTORES BUTYRATE UTILIZATION IN THE COLON CELL. MOREVER, INHIBITING A MOLECULE THAT WORKS DOWNSTREAM OF THE INTERLEUKIN-1 RECEPTOR CALLED P38 BLOCKS THE ABILITY OF INTERLEUKIN-1BETA TO DECREASE BUTYRATE UTILIZATION. P38 APPEARS TO BE AN IMPORTANT COMPONENT IN THE MECHANISM THAT REGULATES BUTYRATE METABOLISM. THE HYPOTHESIS IS THAT IT IS THE CAPACITY OF COLONOCYTES TO OXIDIZE BUTYRATE IS A FACTOR IN THE RESPONSE OF A BUTYRATE-ENHANCING DIET TOWARD THE COLONIC REPAIR PROCESS IN ULCERATIVE COLITIS. TO ADDRESS THIS HYPOTHESIS, IT WILL BE DETERMINED HOW VARIOUS FIBER DIETS THAT INCREASE BUTYRATE LEVELS MODULATE THE COLONIC REPAIR PROCESS IN THE PRESENCE OR ABSENCE OF THE IL-1 RECEPTOR (AIM 1) OR P38 (AIM 2) IN A MODELOF COLONIC INJURY AND REPAIR. THIS RESEARCH WILL LEAD TO THERAPEUTIC STRATEGIES TO RESTORE BUTYRATE UTILIZATION IN THE COLONOCYTE AND ULTIMATELY TREAT ULCERATIVE COLITIS. THIS PROJECT WILL ALSO ENHANCE OUR UNDERSTANDING OF HOW A HIGH FIBER DIET IMPACTS COLONIC HEALTH AND DISEASE DURING INFLAMMATORY STATES SUCH AS ULCERATIVE COLITIS.