| Summary: | Abstract Bile acids are natural detergents that aid in the absorption of dietary lipids. Fatty acid binding protein 6 (Fabp6) is a component of the bile acid recovery system that operates in the small intestine. The aim of this study was to determine if Fabp6 deficiency causes dietary fat malabsorption. Wild‐type and Fabp6‐deficient mice were fed a Western‐style diet (WSD) or a reference low‐fat diet (LFD) for 10 weeks. The body weight gain, bile acid excretion, fat excretion, energy metabolism, and major gut microbial phyla of the mice were assessed at the end of the controlled diet period. Fabp6−/− mice exhibited enhanced excretion of both bile acids and fat on the WSD but not on the LFD diet. Paradoxically, male Fabp6−/− mice, but not female Fabp6−/− mice, had greater adiposity despite increased fat excretion. Analysis of energy intake and of expenditure by indirect calorimetry revealed sex differences in physical activity level and respiratory quotient, but these did not account for the enhanced adiposity displayed by male Fabp6−/− mice. Analysis of stool DNA showed sex‐specific changes in the abundance of major phyla of bacteria in response to Fabp6 deficiency and WSD feeding. The results obtained indicate that the malabsorption of bile acids that occurs in Fabp6−/− mice is associated with dietary fat malabsorption on the high‐fat diet but not on the low‐fat diet. The WSD induced a sexually dimorphic increase in adiposity displayed by Fabp6−/− mice and sexually distinct pattern of change in gut microbiota composition.
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