Genetically modified mice have been successfully used as models for inflammatory bowel diseases; however, dietary effects were poorly examined. Here, we studied the impact of particular nutrients and supplements on gut functions related to the knockout of the epithelial caspase-8 gene. Caspase-8 knockout (Casp8^∆IEC) and control (Casp8^fl) mice were fed for 4 wk a control diet (CD) enriched with 10% inulin (CD-Inu) or 5% sodium butyrate (CD-But) while having free access to plain water or water supplemented with 30% fructose (+F). Body weight changes, intestinal inflammation, and selected markers for barrier function and of liver steatosis were assessed. Casp8^∆IECmice developed ileocolitis accompanied by changes in intestinal barrier morphology and reduced expression of barrier-related genes such as mucin-2 ( Muc2) and defensins in the ileum and Muc2 in the colon. Casp8^∆IECmice fed a CD also showed impaired body weight gain compared with Casp8^flmice, which was even more pronounced in mice receiving water supplemented with fructose. Furthermore, we observed a marked liver steatosis and inflammation in some but not all Casp8^∆IECmice under a CD, which was on average similar to that observed in control mice under a fructose-rich diet. Hepatic lipid accumulation, as well as markers of ileal barrier function, but not intestinal pathohistology or body weight loss, were attenuated by diets enriched with inulin or butyrate, especially in the absence of fructose supplementation. Our data show that ileocolitis, barrier dysfunction, and malassimilation in Caspase-8 knockout mice can be partially attenuated by oral inulin or butyrate supplementation.NEW & NOTEWORTHY Genetic mouse models for ileocolitis are important to understand inflammatory bowel disease in humans. We examined dietetic factors that might aggravate or attenuate ileocolitis and related pathologies in such a model. Deletion of the caspase-8 gene results not only in ileocolitis but also in gut barrier dysfunction, liver steatosis, and malassimilation, which can be partially attenuated by oral inulin or sodium butyrate. Our data indicate that diet modifications can contribute to disease variability and therapy.