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CYP17A1 is a cytochrome P450 enzyme that has 17-alpha-hydroxylase and C17,20-lyase activities. <i>Cyp17a11</i> deficiency is associated with high body mass and visceral fat deposition in atherosclerotic female ApoE knockout (KO, d/d or −/−) mice. In the present study, we aimed to investigate the effects of diet and <i>Cyp17a1</i> genotype on the gut microbiome. Female <i>Cyp17a1</i> (d/d) × ApoE (d/d) (DKO) and ApoE (d/d) (controls) were fed either standard chow or a Western-type diet (WTD), and we demonstrated the effects of genetics and diet on the body mass of the mice and composition of their gut microbiome. We found a significantly lower alpha diversity after accounting for the ecological network structure in DKO mice and WTD-fed mice compared with chow-fed ApoE(d/d). Furthermore, we found a strong significant positive association of the <i>Firmicutes</i> vs. <i>Bacteroidota</i> ratio with body mass and the circulating total cholesterol and triglyceride concentrations of the mice when feeding the WTD, independent of the <i>Cyp17a1</i> genotype. Further pathway enrichment and network analyses revealed a substantial effect of <i>Cyp17a1</i> genotype on associated cardiovascular and obesity-related pathways involving aspartate and L-arginine. Future studies are required to validate these findings and further investigate the role of aspartate/L-arginine pathways in the obesity and body fat distribution in our mouse model.