Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level.. human gut metagenome

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调控人体代谢，对于阐明该微生物群落与人类健康和疾病的关联至关重要。例如，尽管有假说提出，人体肠道菌群将胆固醇代谢为吸收性极差的甾醇类物质粪甾烷醇（coprostanol）这一过程，可调节人体血清胆固醇浓度，但目前学界仍不清楚究竟是哪些酶与微生物介导了人体肠道内的这一代谢过程，相关知识存在空白。本研究在肠道中鉴定出一类新型胆固醇氧化还原酶（cholesterol oxidoreductase），该类酶参与将胆固醇代谢为胆甾烯酮（cholestenone）——这是生成终产物粪甾烷醇的代谢途径中间产物。这类酶在地理分布各异的肠道菌群中广泛存在，且由一类未培养微生物演化支所编码。携带能生成粪甾烷醇的微生物的个体，其粪便胆固醇浓度显著更低，血清总胆固醇（TC）水平亦显著降低（总胆固醇均值差值为-0.14 mmol/L；95%置信区间：-0.27~-0.02），甘油三酯浓度也有所降低。因此，一类未培养微生物演化支介导的胆固醇代谢过程，或许在调节肠道与血清胆固醇浓度方面发挥着重要作用，进而直接影响人类健康。