PDF(Pubmed)
Abstract：
Members of the human gut microbiome enzymatically process many bioactive molecules in the gastrointestinal tract. Most gut bacterial modifications characterized so far are hydrolytic or reductive in nature. Here we report that abundant human gut bacteria from the phylum Bacteroidetes perform conjugative modifications by selectively sulfonating steroidal metabolites. While sulfonation is a ubiquitous biochemical modification, this activity has not yet been characterized in gut microbes. Using genetic and biochemical approaches, we identify a widespread biosynthetic gene cluster that encodes both a sulfotransferase (BtSULT, BT0416) and enzymes that synthesize the sulfonate donor adenosine 3\'-phosphate-5\'-phosphosulfate (PAPS), including an APS kinase (CysC, BT0413) and an ATP sulfurylase (CysD and CysN, BT0414-BT0415). BtSULT selectively sulfonates steroidal metabolites with a flat A/B ring fusion, including cholesterol. Germ-free mice monocolonized with Bacteroides thetaiotaomicron ΔBT0416 exhibited reduced gastrointestinal levels of cholesterol sulfate (Ch-S) compared with wild-type B. thetaiotaomicron-colonized mice. The presence of BtSULT and BtSULT homologues in bacteria inhibited leucocyte migration in vitro and in vivo, and abundances of cluster genes were significantly reduced in patients with inflammatory bowel disease. Together, these data provide a mechanism by which gut bacteria sulfonate steroidal metabolites and suggest that these compounds can modulate immune cell trafficking in the host.
摘要：
人类肠道微生物组的成员酶促处理胃肠道中的许多生物活性分子。迄今为止表征的大多数肠道细菌修饰本质上是水解性或还原性的。在这里，我们报道了来自拟杆菌门的大量人类肠道细菌通过选择性磺化类固醇代谢物进行共轭修饰。虽然磺化是一种无处不在的生化修饰，这种活性尚未在肠道微生物中表征。使用遗传和生化方法，我们确定了一个广泛的生物合成基因簇，该基因簇既编码磺基转移酶（BtSULT，BT0416）和合成磺酸盐供体腺苷3'-磷酸-5'-磷酸（PAPS）的酶，包括APS激酶（CysC，BT0413）和ATP硫酸化酶（CysD和CysN，BT0414-BT0415）。BtSULT选择性磺化甾体代谢物与平坦的A/B环融合，包括胆固醇.与野生型B.thetaiotaomicron定植的小鼠相比，用拟杆菌属细菌ΔBT0416单株的无菌小鼠表现出降低的胃肠道胆固醇硫酸盐（Ch-S）水平。细菌中BtSULT和BtSULT同源物的存在在体外和体内抑制了白细胞的迁移，炎症性肠病患者的簇基因丰度显著降低。一起,这些数据提供了肠道细菌磺酸甾体代谢物的机制，并表明这些化合物可以调节宿主中的免疫细胞运输。
