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Title: Anti-inflammatory properties of methylthioadenosine in experimental colitis

item BENIGHT, NANCY - Baylor College Of Medicine
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item BAUCHART-THEVRET, CAROLINE - Baylor College Of Medicine
item Burrin, Douglas - Doug

Submitted to: American Gastroenterological Association
Publication Type: Abstract Only
Publication Acceptance Date: 4/1/2010
Publication Date: 5/1/2010
Citation: Benight, N., Stoll, B., Bauchart-Thevret, C., Burrin, D.G. 2010. Anti-inflammatory properties of methylthioadenosine in experimental colitis [abstract]. American Gastroenterological Association. M1764.

Interpretive Summary:

Technical Abstract: The methionine (Met) metabolic cycle is critical for normal cell functions. Met cycle disruption has been implicated in disease, such as alcoholic liver disease (ALD) and multiple sclerosis (MS). Studies in animal models of ALD and MS have shown that the Met metabolite methylthioadenosine (MTA) has anti-inflammatory actions. Recent studies have shown that MTA’s action is mediated by changes in methylation of key pro-inflammatory genes. Met metabolism may also be disrupted in inflammatory bowel disease (IBD), as indicated by elevated levels of the Met metabolite homocysteine in IBD patients. However, the role of Met metabolism and its metabolites in IBD is poorly understood. We hypothesized that administration of MTA would reduce inflammation during experimental colitis. We designed a study to test the role of MTA supplementation in experimental colitis using mice treated with dextran sulfate sodium (DSS). Male C57Bl/6J mice divided into 3 groups; control (Con), DSS, and DSS+MTA. Con were healthy untreated mice. DSS and DSS+MTA received 3% DSS via the drinking water to induce colitis for 5 days. DSS+MTA also received MTA supplemented in the drinking water (150-mg/kg BW) for 2 day prior to and during all DSS days (7 days total). We measured daily weight change and scored a clinical disease activity index (cDAI). Plasma, colon, and liver collected at the end of the study and colon length was measured. Tissues and plasma were analyzed for Met metabolite levels, myeloperoxidase (MPO) activity, and global gene expression changes using microarray and qPCR, and histopathology. MTA supplementation prevented weight loss and reduced the cDAI in the DSS+MTA group compared to DSS. Supplementation improved colon length and reduced MPO activity compared to DSS. Histological damage was reduced with supplementation. Plasma, colon, and liver MTA concentrations did not differ between the groups. Colonic S-adenosylmethionine (SAM) was reduced in both DSS and DSS+MTA compared to control, but were not different from each other. Liver S-adenosylhomocysteine (SAH) followed the same pattern, while liver SAM was increased in both groups compared to control. Plasma Met levels were reduced with DSS and restored to control levels with MTA. Microarray results show that 1272 genes are up or down regulated at least 2 fold when compared to control. Specifically, expression levels of TNF-alpha, IL-10, and iNOS were reduced in DSS+MTA when compared to DSS. MTA supplementation was protective during colitis. We postulate that MTA is modulating colonic inflammation via changes in methylation status of key inflammatory genes.