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Title: Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice

Author
item BENIGHT, NANCY - Children'S Nutrition Research Center (CNRC)
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)
item Burrin, Douglas - Doug

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/29/2012
Publication Date: 5/3/2012
Citation: Benight, N.M., Stoll, B., Marini, J.C., Burrin, D.G. 2012. Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice. American Journal of Physiology - Gastrointestinal and Liver Physiology. 303(1):G71-G82.

Interpretive Summary: Inflammatory bowel disease (IBD) is a disease of the intestine that often starts in adolescents and results in a substantial health care burden in the U.S. We wanted to understand whether the severity of IBD could be influenced by the intestinal metabolism of specific dietary amino acids, such as methioine, since it is involved in many important cells functions. Our previous studies showed that accumulation of the methionine metabolite methylthioadenosine (MTA) was associated with reduced injury and inflammation of the large intestine or colon in our experimental mouse model of IBD. In this study, we tested whether dietary supplementation with MTA either as a prevention or as a treatment remedy would reduce the incidence and severity of disease in the mouse model of IBD. Our results first showed that dietary MTA is rapidly absorbed into the blood and worked effectively to prevent inflammation and tissue injury in the large intestine in the mouse IBD model. In contrast, a second study found that supplementing dietary MTA after inducing colitis was less effective in treatment of IBD. Our studies are the first animal studies to show the therapeutic benefit of MTA in a condition of IBD and opens the possibility that MTA may be a useful dietary supplement to prevent IBD in adolescents and adult.

Technical Abstract: Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesized that orally administered MTA would be bioavailable and reduce morbidity associated with experimental colitis. We examined clinical, histological, and molecular markers of disease in mice provided oral MTA before (preventative) or after (therapy) the induction of colitis with 3% dextran sulfate sodium (DSS). We found a reduction in disease activity, weight loss, myeloperoxidase activity, and histological damage inmice given preventative MTA compared with DSS alone. We also found that equivalent supplementation with methionine could not reproduce the anti-inflammatory effects of MTA, and that MTA had no detectable adverse effects in control or DSS mice. Expression microarray analysis of colonic tissue showed several dominant pathways related to inflammatory cytokines/chemokines and extracellular matrix remodeling were upregulation by DSS and suppressed in MTA-supplemented mice. MTA is rapidly absorbed in the gastrointestinal tract and disseminated throughout the body, based on a time course analysis of an oral bolus of MTA. This effect is transient, with MTA levels falling to near baseline within 90 min in most organs. Moreover, MTA did not lead to increased blood or tissue methionine levels, suggesting that its effects are specific. However, MTA provided limited therapeutic benefit when administered after the onset of colitis. Our results show that oral MTA supplementation is a safe and effective strategy to prevent inflammation and tissue injury associated with DSS colitis in mice. Additional studies in chronic inflammatory models are necessary to determine if MTA is a safe and beneficial option for the maintenance of remission in human inflammatory bowel disease.