人类肠道细菌选择性磺化类固醇代谢物的生物合成途径
Nature Microbiology
(
IF
19.4
)
Pub Date : 2022-08-18
, DOI:
10.1038/s41564-022-01176-y
Lina Yao
1
,
Gabriel D D'Agostino
1
,
Jinseok Park
2
,
Saiyu Hang
2
,
Arijit A Adhikari
1
,
Yancong Zhang
3,
4
,
Wei Li
1
,
Julian Avila-Pacheco
3
,
Sena Bae
4,
5
,
Clary B Clish
3
,
Eric A Franzosa
4,
5
,
Curtis Huttenhower
3,
4,
5
,
Jun R Huh
2
,
A Sloan Devlin
1
Affiliation
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
人类肠道微生物组的成员在胃肠道中酶促处理许多生物活性分子。迄今为止，惠阳月嫂13825404095大多数肠道细菌修饰本质上都是水解或还原性的。在这里，我们报告来自拟杆菌门的丰富的人类肠道细菌通过选择性磺化类固醇代谢物来进行接合修饰。虽然磺化是一种普遍存在的生化修饰，但这种活性尚未在肠道微生物中得到表征。利用遗传和生化方法，我们鉴定了一个广泛存在的生物合成基因簇，该基因簇编码磺基转移酶（BtSULT、BT0416）和合成磺酸盐供体腺苷 3'-磷酸-5'-磷酸硫酸盐（PAPS）的酶，包括 APS 激酶（CysC） ，BT0413）和 ATP 硫酸化酶（CysD 和 CysN，BT0414–BT0415）。 BtSULT 选择性磺化具有平坦 A/B 环融合的类固醇代谢物，包括胆固醇。与野生型多形拟杆菌定植的小鼠相比，单定殖多形拟杆菌ΔBT0416的无菌小鼠表现出胃肠道硫酸胆固醇(Ch-S)水平降低。细菌中 BtSULT 和 BtSULT 同源物的存在抑制了白细胞在体外和体内的迁移，并且炎症性肠病患者中簇基因的丰度显着降低。总之，这些数据提供了肠道细菌磺化类固醇代谢物的机制，并表明这些化合物可以调节宿主中的免疫细胞运输。
A biosynthetic pathway for the selective sulfonation of steroidal metabolites by human gut bacteria
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.
