Metagenomic shotgun sequencing in cecal contents of mice with loss of CYP7A1

Intestinal fat absorption requires the coordinated actions of bile acids and lipases, but the specificity of this process remains poorly defined. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, Cyp7a1, using liver-directed gene editing in mice. Compared to lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones (GLP-1), suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively decreased absorption of saturated fatty acids, but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake using human enteroids. Our studies demonstrate a substantial potential in leveraging bile acids to regulate dietary fat absorption for health and disease.