Gastro hep advances · 2025
Aconitate Decarboxylase 1 Downregulates Colitis and Maintains Homeostasis of the Gut Metabolome and Microbiome.
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McNamara Kara M, Latour Yvonne L, Hawkins Caroline V, Williams Kamery J, Barry Daniel P, Allaman Margaret M, Delgado Alberto G, Chetyrkin Sergei V, Calcutt M Wade, Piazuelo M Blanca, Washington M Kay, Zhao Shilin, Coburn Lori A, Gobert Alain P, Wilson Keith T
Аннотация
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.
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.