Bile Salt Hydrolase: From Basic Science to Translational Innovation

Bile salt hydrolase (BSH) is an intestinal bacterial enzyme that catalyzes deconjugation of conjugated bile acids, an essential gateway reaction in the metabolism of bile acids. Therefore, BSH is a key mechanism through which the microbiota modulates host lipid metabolism and energy harvest. Recent studies have shown that BSH is a promising microbiome target for developing novel alternatives to antibiotic growth promoters (AGPs) for animal industry and new measures to control obesity in humans. However, research on BSH is still in its infancy in terms of both basic science and translational innovation. In this dissertation study, multidisciplinary approaches in conjunction with two animal model systems (rat and chicken) were used to examine the impact of BSH on host physiology, to understand the BSH structure-function relationship, and to evaluate in vivo efficacy of three identified BSH inhibitors with potential as novel alternatives to AGPs. Large quantities of recombinant BSH were purified and encapsulated using a novel encapsulation system. Oral administration of rats with the encapsulated BSH did not significantly affect host growth performance, lipid metabolism, and energy harvest although intestinal bile profile was significantly changed in response to BSH treatment. The crystal structure of the BSH from Lactobacillus salivarius NRRL B-30514 was elucidated. Comparative structural analysis identified the residues and domains that are critical for catalysis and substrate specificity of BSH, which was subsequently validated by site-directed mutagenesis as well as comparative BSH activity examination. The in vivo efficacies of three BSH inhibitors caffeic acid phenethylester, riboflavin, and carnosic acid were evaluated using chicken model. Dietary supplementation of the BSH inhibitors in broilers (25 mg/kg body weight/day) enhanced body weight gain/feed efficiency, and significantly changed host bile acid and transcriptome profiles at both local and systemic levels, which provided physiological, metabolomics, and molecular evidence demonstrating in vivo efficacies of the tested BSH inhibitors.