Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice.
Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice.
复制标题
表征选择性抑制小鼠肠道微生物β-葡萄糖醛酸苷酶的代谢效应。
DOI：
10.1038/s41598-022-21518-4
复制
发表时间：
2022-10-19
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
肠道细菌葡萄糖醛酸苷酶对异生素葡萄糖醛酸苷的水解使先前解毒的化合物重新活化，导致对宿主的严重肠道毒性。选择性细菌β-葡萄糖醛酸酶抑制剂可以减轻这种毒性，但尚未研究其对更广泛的宿主代谢过程的影响。为了研究这一点，向小鼠给予抑制剂4-（8-（哌嗪-1-基）-1，2，3，4-四氢-[1，2，3]三嗪并[4′，5 ′：4，5]噻吩并[2，3-c]异喹啉-5-基）吗啉（UNC 10201652，Inh 9），以选择性抑制肠道中范围较窄的细菌β-葡萄糖醛酸苷酶。测定了肠内容物、生物液体和参与肝肠循环的几种组织的代谢组学特征，并与对照动物进行了比较。在血浆、肝脏或胆囊中未观察到生化干扰。相反，与对照组相比，尿液、结肠内容物、粪便和肠壁的代谢产物谱发生了改变。变化主要限于肠道微生物代谢产生的化合物。这项工作确定了靶向细菌β-葡萄糖醛酸苷酶的抑制剂调节肠道微生物群的功能，而不会对宿主代谢系统产生不利影响。
The hydrolysis of xenobiotic glucuronides by gut bacterial glucuronidases reactivates previously detoxified compounds resulting in severe gut toxicity for the host. Selective bacterial β-glucuronidase inhibitors can mitigate this toxicity but their impact on wider host metabolic processes has not been studied. To investigate this the inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4′,5′:4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine (UNC10201652, Inh 9) was administered to mice to selectively inhibit a narrow range of bacterial β-glucuronidases in the gut. The metabolomic profiles of the intestinal contents, biofluids, and several tissues involved in the enterohepatic circulation were measured and compared to control animals. No biochemical perturbations were observed in the plasma, liver or gall bladder. In contrast, the metabolite profiles of urine, colon contents, feces and gut wall were altered compared to the controls. Changes were largely restricted to compounds derived from gut microbial metabolism. This work establishes that inhibitors targeted towards bacterial β-glucuronidases modulate the functionality of the intestinal microbiota without adversely impacting the host metabolic system.
登录
查看更多内容
影响因子：
4.4
作者：
Posma JM;Garcia-Perez I;Ebbels TMD;Lindon JC;Stamler J;Elliott P;Holmes E;Nicholson JK
通讯作者：
Nicholson JK
DOI：
10.1016/j.str.2017.05.003
发表时间：
2017-07-05
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Pollet RM;D'Agostino EH;Walton WG;Xu Y;Little MS;Biernat KA;Pellock SJ;Patterson LM;Creekmore BC;Isenberg HN;Bahethi RR;Bhatt AP;Liu J;Gharaibeh RZ;Redinbo MR
通讯作者：
Redinbo MR
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
18.2
作者：
Pellock SJ;Creekmore BC;Walton WG;Mehta N;Biernat KA;Cesmat AP;Ariyarathna Y;Dunn ZD;Li B;Jin J;James LI;Redinbo MR
通讯作者：
Redinbo MR
影响因子：
4.6
作者：
Biernat, Kristen A.;Pellock, Samuel J.;Redinbo, Matthew R.
通讯作者：
Redinbo, Matthew R.