The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.

人类微生物组编码广泛的代谢能力，但我们对将肠道微生物与人类代谢联系起来的机制的理解仍然有限。在这里，我们专注于通过肠道微生物群将胆固醇转化为吸收不良的甾醇coprostanol，以开发用于识别功能性酶和微生物的框架。通过将来自现有队列的配对宏基因组学和代谢组学数据与生化知识和实验相结合，我们预测并验证了一组有助于形成粪前列烷醇的微生物胆固醇脱氢酶。这些酶由ismA编码未培养微生物进化枝中的基因，这些微生物在地理上不同的人类群体中普遍存在。携带可形成粪前列烷醇的微生物的个体具有显着降低的粪便胆固醇水平和血清总胆固醇水平，其影响与脂质稳态基因变化的影响相当。因此，这些微生物的胆固醇代谢可能在降低肠道和血清胆固醇浓度方面发挥重要作用，直接影响人类健康。