A novel cholesterol dehydrogenase from Limosilactobacillus fermentum catalyzes the direct conversion of cholesterol to coprostanol

Abstract

AbstractThe gut microbiome harbors enzymes that can transform dietary cholesterol. Understanding this interaction can help tailor the diet to modulate host lipid homeostasis. Despite being exploited commercially as a probiotic, including a role in cholesterol reduction, the molecular mechanism of cholesterol transformation by lactobacilli still needs to be discovered. Herein, we elucidate the role of a novel microbial 3β-OH-Δ5–6-cholesterol-5β-reductase fromLimosilactobacillus fermentumNKN51, which directly converts cholesterol to coprostanol. Protein engineering provides insights into the catalytic mechanism of 5βChR. Phylogenetic studies indicate an abundance of 5βChR in gut commensal lactobacilli, which shares a common ancestor with plant 5β reductases. Meta-analysis of healthy participants microbiomes highlights the significance of the 5βChR homologs, and shotgun data analysis establishes an association between higher 5βChR abundance in diabetic patients (p-0.0213). The discovery and elucidation of the role of lactobacillus 5βChR in cholesterol metabolism may lead to designing functional foods tailored to ameliorate dyslipidemia.