PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice
PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice
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DOI：
10.1124/dmd.118.081547
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发表时间：
2018-08-01
影响因子：
3.9
通讯作者：
Cui, Julia Yue
中科院分区：
文献类型：
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作者：
Li, Cindy Yanfei;Dempsey, Joseph L.;Cui, Julia Yue
多溴联苯醚（PBDEs）是一种持久性环境污染物，在宿主器官中具有明确的毒性。肠道微生物组越来越被认为是异生物质生物转化的重要调节器;然而，人们对其与多溴二苯醚的相互作用知之甚少。初级胆汁酸（BA）被肠道微生物组代谢成更亲脂的次级BA，其可以被吸收并与某些宿主受体相互作用。本研究的目的是测试我们的假设，多溴联苯醚造成的生态失调和异常调节BA的稳态。9周龄雄性C57 BL/6常规（CV）和无菌（GF）小鼠连续4天每天一次经口灌胃玉米油（10毫克/千克）、BDE-47（100微摩尔/千克）或BDE-99（100微摩尔/千克）（每组n = 3-5）。使用CV小鼠中大肠内容物的16 S rRNA测序来表征肠道微生物组。BDE-47和BDE-99都显著降低了肠道微生物组的α多样性，并对45种细菌物种进行了差异调节。两种多溴联苯醚同系物都增加了嗜粘蛋白阿克曼氏菌和丹毒丝菌Allobaculum spp.，据报道其具有抗炎和抗肥胖功能。在CV和GF小鼠的血清、肝脏、小肠和大肠内容物中进行了56种BA的靶向代谢组学研究。BDE-99以依赖肠道微生物群的方式增加了多个生物区室中的许多未结合的BA。这与微生物7 α-脱羟基酶的增加，用于次级BA合成和宿主肠道转运蛋白的表达增加，用于BA吸收有关。靶向蛋白质组学研究表明，多溴联苯醚下调宿主BA合成酶和转运蛋白在CV，但没有GF小鼠的肝脏。总之，多溴联苯醚和内源性BA信号之间存在一种新的相互作用，通过修改“肠道-肝脏轴”。
Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants with well characterized toxicities in host organs. Gut microbiome is increasingly recognized as an important regulator of xenobiotic biotransformation; however, little is known about its interactions with PBDEs. Primary bile acids (BAs) are metabolized by the gut microbiome into more lipophilic secondary BAs thatmay be absorbed and interact with certain host receptors. The goal of this study was to test our hypothesis that PBDEs cause dysbiosis and aberrant regulation of BA homeostasis. Nine-week-old male C57BL/6 conventional (CV) and germ-free (GF) mice were orally gavaged with corn oil (10 mg/kg), BDE-47 (100 mu mol/kg), or BDE-99 (100 mu mol/kg) once daily for 4 days (n = 3-5/group). Gut microbiome was characterized using 16S rRNA sequencing of the large intestinal content in CV mice. Both BDE-47 and BDE-99 profoundly decreased the alpha diversity of gut microbiome and differentially regulated 45 bacterial species. Both PBDE congeners increased Akkermansia muciniphila and Erysipelotrichaceae Allobaculum spp., which have been reported to have anti-inflammatory and antiobesity functions. Targeted metabolomics of 56 BAs was conducted in serum, liver, and small and large intestinal content of CV and GF mice. BDE-99 increased many unconjugated BAs in multiple biocompartments in a gut microbiota-dependent manner. This correlated with an increase in microbial 7 alpha-dehydroxylation enzymes for secondary BA synthesis and increased expression of host intestinal transporters for BA absorption. Targeted proteomics showed that PBDEs downregulated host BA-synthesizing enzymes and transporters in livers of CV but not GF mice. In conclusion, there is a novel interaction between PBDEs and the endogenous BA-signaling through modification of the "gut-liver axis".