Protective Role of Spermidine in Colitis and Colon Carcinogenesis

被引:64
作者
Gobert, Alain P. [1 ,2 ,3 ]
Latour, Yvonne L. [1 ,4 ]
Asim, Mohammad [1 ]
Barry, Daniel P. [1 ]
Allaman, Margaret M. [1 ]
Finley, Jordan L. [1 ]
Smith, Thaddeus M. [1 ]
McNamara, Kara M. [1 ,3 ]
Singh, Kshipra [1 ,2 ]
Sierra, Johanna C. [1 ,2 ]
Delgado, Alberto G. [1 ]
Luis, Paula B. [5 ]
Schneider, Claus [2 ,5 ]
Washington, M. Kay [4 ]
Piazuelo, M. Blanca [1 ,2 ]
Zhao, Shilin [6 ]
Coburn, Lori A. [1 ,2 ,3 ,7 ]
Wilson, Keith T. [1 ,2 ,3 ,4 ,7 ]
机构
[1] Vanderbilt Univ, Dept Med, Med Ctr, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Ctr Mucosal Inflammat & Canc, Med Ctr, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Program Canc Biol, Med Ctr, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA
[5] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA
[6] Vanderbilt Univ, Dept Biostat, Med Ctr, Nashville, TN 37232 USA
[7] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA
基金
美国国家卫生研究院;
关键词
Inflammatory Bowel Disease; Colitis-Associated Carcinogenesis; Polyamines; Spermidine; a-Defensins; Chemo-prevention; Intestinal Microbiota; INFLAMMATORY-BOWEL-DISEASE; GASTRIC-CANCER RISK; MACROPHAGE ACTIVATION; INTESTINAL EPITHELIUM; PANETH CELLS; LIFE-SPAN; DIFLUOROMETHYLORNITHINE; EXPRESSION; CHEMOPREVENTION; METABOLISM;
D O I
10.1053/j.gastro.2021.11.005
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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(-/-) vsWT 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 alpha-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. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased alpha-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.
引用
收藏
页码:813 / +
页数:23
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