In conclusion, by unveiling an unrecognized impact of Acod1 loss on diet-induced gut microbiota alterations, this study has uncovered a novel role for itaconate biosynthesis in obesity and major associated inflammatory outcomes induced by fat overnutrition, paving the way for the development and utilization of synthetic small-molecule inhibitors targeting ACOD1 activity for treatment of metabolic disease. Here, ACOD1 is linked to obesity disorder.