Abstract | BACKGROUND & AIMS: 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-/- 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. CONCLUSIONS: 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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Authors | 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 G Delgado, Paula B Luis, Claus Schneider, M Kay Washington, M Blanca Piazuelo, Shilin Zhao, Lori A Coburn, Keith T Wilson |
Journal | Gastroenterology
(Gastroenterology)
Vol. 162
Issue 3
Pg. 813-827.e8
(03 2022)
ISSN: 1528-0012 [Electronic] United States |
PMID | 34767785
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Published by Elsevier Inc. |
Chemical References |
- Adenomatous Polyposis Coli Protein
- DEFA5 protein, human
- DEFA6 protein, human
- RNA, Messenger
- adenomatous polyposis coli protein, mouse
- alpha-Defensins
- Dextran Sulfate
- Oxidoreductases Acting on CH-NH Group Donors
- polyamine oxidase
- Azoxymethane
- Spermidine
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Topics |
- Adenomatous Polyposis Coli Protein
(genetics)
- Animals
- Azoxymethane
- Carcinogenesis
(drug effects, genetics)
- Colitis
(chemically induced, enzymology, genetics, prevention & control)
- Colitis, Ulcerative
(enzymology, genetics)
- Colon
(enzymology, pathology)
- Colonic Neoplasms
(genetics, prevention & control)
- Dextran Sulfate
- Gastrointestinal Microbiome
(drug effects)
- Gene Expression Regulation
(drug effects)
- Humans
- Intestinal Mucosa
(enzymology, pathology)
- Male
- Mice
- Oxidoreductases Acting on CH-NH Group Donors
(genetics, metabolism)
- Precancerous Conditions
(enzymology)
- Protective Factors
- RNA, Messenger
(metabolism)
- Severity of Illness Index
- Spermidine
(metabolism, pharmacology, therapeutic use)
- Weight Loss
(drug effects)
- alpha-Defensins
(genetics, metabolism)
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