Aconitate Decarboxylase 1 Deficiency Exacerbates Mouse Colitis Induced by Dextran Sodium Sulfate.

Area of Science:

• Immunology
• Gastroenterology
• Metabolomics

Background:

• Ulcerative colitis (UC) is a prevalent inflammatory bowel disease (IBD) with complex genetic underpinnings.
• Itaconate, an immune-modulating metabolite synthesized from cis-aconitic acid, has recently gained attention.
• The role of the Aconitate decarboxylase 1 (Acod1)-itaconate pathway in UC pathogenesis remains largely unexplored.

Purpose of the Study:

• To investigate the association between the Acod1-itaconate axis and the development of ulcerative colitis.
• To evaluate the therapeutic potential of itaconate in a colitis model.

Main Methods:

• Established a DSS-induced colitis model using Acod1-deficient and wild-type mice.
• Assessed colitis severity through body weight, colon length, and histological analysis.
• Measured cytokine and chemokine levels in colon tissues.

Main Results:

• Acod1 expression was upregulated in DSS-induced colitis.
• Acod1 deficiency worsened colitis symptoms, including increased weight loss, disease activity, and colon shortening.
• Acod1-deficient mice exhibited greater intestinal barrier dysfunction, immune cell infiltration, and pro-inflammatory mediator expression.
• Administration of 4-octyl itaconate (4-OI) ameliorated DSS-induced colitis and reduced inflammatory markers in Acod1-deficient mice.

Conclusions:

• Acod1 plays a protective role in DSS-induced colitis.
• Acod1 deficiency exacerbates intestinal inflammation and barrier defects.
• The Acod1-itaconate pathway represents a potential therapeutic target for ulcerative colitis, with 4-OI showing promise.