PR002297 (Project)

Description: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. There was an altered metabolome in Acod1–/– versus wild-type colon tissues, and during colitis, purine metabolism was most markedly affected. AOM-DSS-treated Acod1–/– animals exhibited more inflammation and injury but no difference in tumorigenesis. 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.