RNA-Seq Profiling of Intestinal Expression of Xenobiotic Processing Genes in Germ-Free Mice
RNA-Seq Profiling of Intestinal Expression of Xenobiotic Processing Genes in Germ-Free Mice
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DOI：
10.1124/dmd.117.077313
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发表时间：
2017-12-01
影响因子：
3.9
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
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作者：
Fu, Zidong Donna;Selwyn, Felcy P.;Klaassen, Curtis D.
肠道细菌可以通过直接的细菌酶催化修饰外生物和间接的改变宿主基因的表达来影响外生物的代谢。为了确定肠道细菌如何影响宿主异种生物加工基因（XPGs）的表达，通过RNA测序对4个肠道切片的303个XPGs的mRNA谱进行了表征，并与成年雄性常规（CV）和无菌（GF）小鼠肝脏中的mRNA谱进行了比较。54个xpg在CV和GF小鼠的肠道中均未表达。GF至少改变了116个xpg在一个肠段的表达，但对133个xpg没有影响。许多细胞色素P450家族成员，如Cyp1a、Cyp2b10、Cyp2c和大多数Cyp3a成员，以及羧酸酯酶（Ces） 2a在GF小鼠肠道中的表达低于CV小鼠。与此相反，GF小鼠肠道中部分ⅰ期氧化酶（醇脱氢酶1、醛脱氢酶a1l1和4a1以及黄素单加氧酶5）和ⅱ期偶联酶（udp -葡萄糖醛基转移酶1a1、硫转移酶1c2、1d1和2b1）表达较高。肠内多种转运蛋白，如胆汁酸转运蛋白（胆汁酸转运蛋白、有机溶质转运蛋白a和b）、肽转运蛋白1、多药和毒素挤出蛋白1在GF小鼠中表达较高。综上所述，肠道细菌的缺乏改变了宿主肠道中大量xpg的表达，其中一些是切片特异性的。Cyp3a在GF小鼠的肝脏和肠道中均下调，这可能导致了外源代谢的改变。
Intestinal bacteria can affect xenobiotic metabolism through both direct bacterial enzyme-catalyzed modification of the xenobiotics and indirect alterations of the expression of host genes. To determine how intestinal bacteria affect the expression of host xenobiotic-processing genes (XPGs), the mRNA profiles of 303 XPGs were characterized by RNA sequencing in four intestinal sections and compared with that in the liver from adult male conventional (CV) and germ-free (GF) mice. Fifty-four XPGs were not expressed in the intestine of either CV or GF mice. The GF condition altered the expression of 116 XPGs in at least one intestinal section but had no effect on 133 XPGs. Many cytochrome P450 family members such as Cyp1a, Cyp2b10, Cyp2c, and most Cyp3a members, as well as carboxylesterase (Ces) 2a were expressed lower in the intestine of GF than CV mice. In contrast, GF mice had higher intestinal expression of some phase I oxidases (alcohol dehydrogenase 1, aldehyde dehydrogenase a1l1 and 4a1, as well as flavin monooxygenase 5) and phase II conjugation enzymes (UDP-glucuronosyltransferase 1a1, and sulfotransferase 1c2, 1d1, and 2b1). Several transporters in the intestine, such as bile acid transporters (apical sodium-dependent bile acid transporter, organic solute transporter a and b), peptide transporter 1, and multidrug and toxin extrusion protein 1, exhibited higher expression in GF mice. In conclusion, lack of intestinal bacteria alters the expression of a large number of XPGs in the host intestine, some of which are section specific. Cyp3a is down-regulated in both the liver and intestine of GF mice, which probably contributes to altered xenobiotic metabolism.