Protective role of spermidine in colitis and colitis-associated carcinogenesis

BACKGROUND & AIMS: Because inflammatory bowel disease is increasing in the USA and worldwide, and risk for colitis-associated carcinogenesis (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX) can regulate colitis. Since SMOX generates the polyamine spermidine (Spd), we determined if Spd treatment reduces colitis and CAC. METHODS: SMOX was quantified in human colitis and associated dysplasia using RT-qPCR and immunohistochemistry. Wild-type and Smox-/- C57BL/6 mice were treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Animals were supplemented or not with Spd in the drinking water. Colonic polyamine concentrations, inflammation, tumorigenesis, and transcriptomes were assessed. RESULTS: SMOX mRNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. Both DSS-induced colitis and AOM-DSS-induced tumorigenesis were worsened in Smox-/- versus WT mice, and improved in both genotypes with Spd. Spd-treated mice exhibited less dysplasia. Spd levels were reduced Smox-/- tissues, and Spd supplementation reversed this alteration. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of alpha-defensins, which was reduced by Spd. A shift in the microbiome, characterized by reduced Prevotella and increased abundance of the pathobiont Mucispirillum schaedleri, occurred in Smox-/- mice, and was reversed with Spd. CONCLUSIONS: These studies implicate Spd in the regulation of the colonic microbiome. Spd has potential as an adjunctive treatment for colitis, and chemopreventive for CAC. A beneficial mechanism may be reduction of dysbiosis and the overzealous antimicrobial response that contributes to inflammation.