Metabolic Regulation of Mucosal Inflammation

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The Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, are among the most debilitating inflammatory disorders of the western world. It is estimated that more than 3 million Americans suffer with IBD, with incidence rates on the rise in many populations. A recent study of more than 100,000 military service members estimated the incidence of IBD to be 2-10 times greater than non-service members, with a striking relationship between IBD incidence and the number of life stressors. The precise etiology of IBD is currently unknown. Our interest is focused on the identification of inflammation-associated changes in tissue metabolsim during flares of active inflammation. Our ongoing studies are founded on the observation that active intestinal inflammation is characterized by significant shifts in tissue metabolism that can influence cell and tissue function in fundamentally important ways. Under such conditions, epithelial cells have the capacity to dynamically control mucosal resolution and do so with a high degree of fidelity. The precise mechanisms by which metabolic pathways control resolution, however, have yet to be elucidated. Our work in progress has conclusively revealed that energy utilization becomes compromised during active inflammation and that creatine and its associated creatine kinase (CK) family of enzymes are fundamental in shuttling of high energy phosphates in the form of phosphocreatine between sites of ATP generation. Moreover, we have shown that double-mutant mice lacking the brain and mitochondrial isoforms of CK (termed the CK dKO) are significantly more susceptible to acute colitis as measured by multiple disease parameters. In addition to impaired barrier function, CK dKO mice showed defective inflammatory responses underscored by nearly non-existent levels of colonic IFN. In this proposal, we will define how creatine metabolism molds the mucosal tissue environment during inflammation. Three synergistic specific aims are directed at testing the hypothesis that CK expression and activity within the epithelia and immune cells are fundamental in inflammatory resolution responses in the mucosa. Aim 1 will elucidate how creatine kinase(s) ultimately influence tissue metabolism during active inflammation. Aim 2 will define the regulation of IFN by CK enzymes. Specific Aim 3 will illuminate the relationship between IFN and CK metabolism in the regulation of intestinal inflammation. It is our hope that these results will reveal new insights into innate regulation of mucosal inflammatory resolution and that extensions of this work will lead to targets for experimental therapeutics.