Aconitate Decarboxylase 1 Downregulates Colitis and Maintains Homeostasis of the Gut Metabolome and Microbiome.

BACKGROUND AND 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.

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 1 or 2 cycles of 4% dextran sulfate sodium (DSS) as models of colitis. For colitis-associated carcinoma, mice were given 12.5 mg/kg azoxymethane 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 and Crohn's disease tissues compared to controls. C. rodentium infection caused body weight loss only in Acod1 -/- mice, which had increased histologic injury vs WT. In DSS colitis, we observed decreased colon length and increased histologic injury in Acod1 -/- vs WT mice. Azoxymethane-DSS-treated Acod1 -/- animals exhibited more inflammation and injury but no difference in tumorigenesis. There was an altered metabolome in Acod1 -/- vs WT 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.

CONCLUSION

While ACOD1 is increased in human inflammatory bowel disease 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.