Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level.

Efforts to investigate how gut microbes influence human metabolism are critical to understand how this microbial community impacts human health and disease. For example, while the metabolism of cholesterol to the poorly absorbed sterol coprostanol by the human gut microbiota is hypothesized to play a role in modulating human serum cholesterol concentrations, there is a gap in knowledge regarding which enzymes and microbes are responsible for this metabolism in the human gut. Here we identify a novel group of cholesterol oxidoreductase enzymes in the gut that are involved in the metabolism of cholesterol to cholestenone, an on-pathway intermediate to the final product coprostanol. These enzymes are prevalent in geographically diverse gut microbiota and are encoded by a clade of uncultured microorganisms. Individuals with coprostanol-forming microbes have significantly lower concentrations of fecal cholesterol and lower concentrations of serum total cholesterol (-0.14 mmol/L in TC; 95% CI: -0.27, -0.02) and triglycerides. Thus, the metabolism of cholesterol by an uncultured clade of microorganisms may play an important role in modulating both intestinal and serum cholesterol concentrations, directly impacting human health.

探究肠道微生物如何影响人体代谢的相关研究，对于阐明该微生物群落对人类健康与疾病的调控作用至关重要。例如，尽管有假说认为人体肠道菌群将胆固醇代谢为难吸收的粪甾醇（coprostanol）这一过程，可调控人体血清胆固醇水平，但目前学界仍不清楚究竟是哪些酶与微生物在肠道内介导了这一代谢过程。本研究首次在肠道中鉴定出一类新型胆固醇氧化还原酶（cholesterol oxidoreductase），其参与将胆固醇代谢为胆甾烯酮（cholestenone）——这是终产物粪甾醇合成通路中的关键中间产物。这类酶在地理分布各异的肠道菌群中广泛存在，其编码基因来自一类未培养微生物进化枝。携带能合成粪甾醇的微生物的个体，其粪便胆固醇浓度显著更低，血清总胆固醇（TC：-0.14 mmol/L；95%置信区间：-0.27, -0.02）与甘油三酯水平也更低。综上，一类未培养微生物进化枝介导的胆固醇代谢，或可同时调控肠道与血清胆固醇水平，进而直接影响人类健康。