Campylobacter jejuni and Mycobacterium paratuberculosis have been implicated in the pathogenesis of Crohn's disease. The presence of bacterial metabolites in the colonic lumen causing a specific breakdown of fatty acid oxidation ill colonic epithelial cells has been suggested as an initiating event in inflammatory bowel disease (IBD). L-Carnitine is a small highly polar zwitterion that plays all essential role in fatty acid oxidation and ATP generation in intestinal bioenergetic metabolism. The organic cation/carnitine transporters, OCTN1 and OCTN2. function primarily in the transport oft.-carnitine and elimination of cationic drugs ill the intestine. High-resolution linkage disequilibrium mapping has identified a region of about 250 kb in size at 5q31 (1131)5) encompassing the OCTN1 and -2 genes, to confer susceptibility to Crohn's disease. Recently, two variants in the OCTN1 and OCTN2 genes have been shown to form a haplotype which is associated with susceptibility to Crohn's. We show that OCTNI and OCTN2 are strongly expressed in target areas for I BE) such Lis ileum and colon. Further, we have now identified a nine amino acid epitope shared by this functional variant of OCTN1 (Leu503Phe) (which decreases the efficiency of carnitine transport), and by C.jejuni (9 aa) and M. paramberculosis (6 aa). The prevalence of this variant of OCTN1 (Phe503:Leu503) is 3-fold lower ill unaffected individuals or Jewish origin (1:3.44) compared to unaffected individuals Of non-Jewish origin (1:1). We hypothesize that a specific antibody raised to this epitope during C jejuni or M. paratuberculosis enterocolitis would cross-react with the intestinal epithelial cell functional variant of OCTN1, all already less efficient carnitine transporter, leading to all impairment of mitochondrial beta-oxidation which may then serve Lis all initiating event in IBD. This impairment Of L-carnitine transport by OCTN1 may respond to high-dose L-carnitine therapy. (c) 2005 Elsevier Inc. All rights reserved.