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Protective Role of Spermidine in Colitis and Colon Carcinogenesis

结肠炎 偶氮甲烷 化学 癌变 癌症研究 溃疡性结肠炎 炎症性肠病 免疫学 医学 内科学 生物化学 疾病 基因
作者
Alain P. Gobert,Yvonne L. Latour,Mohammad Asim,Daniel P. Barry,Margaret M. Allaman,Jordan L. Finley,Thaddeus M. Smith,Kara M. McNamara,Kshipra Singh,Johanna C. Sierra,Alberto Delgado,Paula B. Luis,Claus Schneider,M. Kay Washington,M. Blanca Piazuelo,Shilin Zhao,Lori A. Coburn,Keith T. Wilson
出处
期刊:Gastroenterology [Elsevier]
卷期号:162 (3): 813-827.e8 被引量:44
标识
DOI:10.1053/j.gastro.2021.11.005
摘要

Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis.SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed.SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd.Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.
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