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53

THE NUTRIENT AND OCTN LIGAND L-CARNITINE INDUCES REMISSION IN EXPERIMENTAL MODELS OF IBD

G Fortin, C Collette, I Elimrani, C Villani, A Bitton, G Wild, E Seidman, D Franchimont
Department of Experimental Medicine, McGill University, Montreal, Quebec

L-carnitine (vitamin B_t) is consumed in the diet, biosynthesized and available as an over-the-counter nutritional supplement. Interestingly, it has been shown to have immunosuppressive effects, possibly as an allosteric regulator of the glucocorticoid receptor. Additionally, it was recently confirmed that the causative mutation at the IBD5 locus is in the OCTN (L-carnitine transporter) gene, leading to an increased susceptibility to Crohn's disease (CD). We therefore decided to investigate the expression of OCTN1 and OCTN2 in colonic biopsies of CD patients. We also evaluated the therapeutic efficacy of L-carnitine in mouse models of CD.
METHODS: Human study: Intestinal biopsies were taken from healthy subjects (HS) (n=4), and patients with CD (n=7). OCTN1 and OCTN2 expression were determined by quantitative real-time PCR. Animal study: Balb/C mice were administered either 1) 100 mg/kg trinitrobenzene sulfonic acid (TNBS) dissolved in 50% ethanol intra-rectally, treated intra-peritoneally with either L-carnitine (n=6) or saline (n=6) and euthanized after five days of treatment, or 2) 5% dextran sulfate sodium (DSS) in their drinking water as a model of chronic colitis, with or without L-canitine as above, and sacrificed after 26 days.
RESULTS: Human study: OCTN1 expression was not statistically different between CD patients and HS. However, OCTN2 expression was found to be significantly diminished in patients with CD (2.4-fold, P<0.05) compared with healthy controls. Mouse study: There was a significant amelioration of TNBS colitis in L-carnitine-treated mice versus control colitic mice in all of the following parameters (P<0.05): body weight (97.5%±4.4% vs 85.2%±5.5%), Wallace score (2.8±2.7 vs 8.7±3.3), serum levels of IL-1b (18.5±9.3 pg/mL vs 37.5±7.5 pg/mL) and IL-6 (53.5±26.8 pg/mL vs 128.7±73.7 pg/mL), as well as colonic expression of IL-1b (2.7-fold decrease in treated mice) and IL-6 (4.8-fold decrease in treated mice). L-carnitine was also effective in treating mice with DSS colitis: there was a decrease in the expression of IL-1b by 2.3-fold, and of IL-6 by 15.5-fold.
CONCLUSION: L-carnitine therapy is effective in treating experimental IBD and could represent a novel and safe alternative therapeutic strategy in CD. This study sheds light on the potential beneficial impact of diet on disease activity in CD.

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