Kara M. McNamara , Yvonne L. Latour , Caroline V. Hawkins , Kamery J. Williams , Daniel P. Barry , Margaret M. Allaman , Alberto G. Delgado , Sergei V. Chetyrkin , M Wade Calcutt , M. Blanca Piazuelo , M. Kay Washington , Shilin Zhao , Lori A. Coburn , Alain P. Gobert , Keith T. Wilson
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引用次数: 0
Abstract
Background & Aims
Aconitate decarboxylase 1 (ACOD1) is implicated in innate immunity and inflammatory responses. We determined the role of ACOD1 in colon inflammation and colitis-associated carcinoma (CAC).
Methods
Human inflammatory bowel disease transcriptomic datasets and banked RNA samples were interrogated. C57BL/6 wild-type (WT) and Acod1–/– mice were infected with Citrobacter rodentium or given one or two cycles of 4% dextran sulfate sodium (DSS) as models of colitis. For CAC, mice were given 12.5 mg/kg azoxymethane (AOM) followed by 3 cycles of 4% DSS. Clinical and histological parameters were assessed. Tissues and stool were used for metabolomic and 16S microbiome analyses, respectively.
Results
ACOD1 expression is increased in ulcerative colitis (UC) and Crohn’s disease (CD) tissues compared to controls. C. rodentium infection caused body weight loss only in Acod1–/– mice, which had increased histologic injury versus wild-type. In DSS colitis, we observed decreased colon length and increased histologic injury in Acod1–/– versus wild-type mice. AOM-DSS-treated Acod1–/– animals exhibited more inflammation and injury but no difference in tumorigenesis. There was an altered metabolome in Acod1–/– versus wild-type colon tissues, and during colitis, purine metabolism was most markedly affected. 16S microbiome analysis revealed significant differences in phyla and genera; notably an increase in Bacteroidetes and decrease in Proteobacteria in Acod1–/– mice, indicating a dysbiotic state.
Conclusions
While ACOD1 is increased in human inflammatory bowel disease (IBD) tissues, our data indicate that this enzyme has a protective role in acute and chronic experimental colitis and is associated with prevention of intestinal dysbiosis and stabilization of the metabolome.