Administration of antibiotics contributes to cholestasis in pediatric patients with intestinal failure via the alteration of FXR signaling.
Administration of antibiotics contributes to cholestasis in pediatric patients with intestinal failure via the alteration of FXR signaling.
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抗生素的使用通过 FXR 信号的改变导致肠衰竭儿科患者的胆汁淤积
DOI：
10.1038/s12276-018-0181-3
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发表时间：
2018-11-30
影响因子：
12.8
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Xiao Y;Zhou K;Lu Y;Yan W;Cai W;Wang Y
抗生素治疗和IF相关性肝病(IFALD)之间的联系尚不清楚。在这里，我们研究抗生素治疗对胆汁酸(BA)代谢的影响，并探讨其机制。结果显示，有胆汁淤积的儿童IF患者的BA-生物转化细菌丰度明显低于无胆汁淤积的患者。此外，胆汁淤积症患儿的血清、粪便和肝脏中的BA成分也发生了改变，反映在原发BAs比例的增加上。在回肠，法尼醇X受体(FXR)在胆汁淤积症患者的表达减少。相应地，胆汁淤积症患者血清FGF19水平显著降低。在肝脏中，胆汁淤积症患者肝脏中胆盐合成限速酶细胞色素P450 7A1的表达显著增加。在小鼠中，我们发现口服抗生素(庆大霉素、GM或万古霉素，VCM)降低了结肠微生物的多样性，同时减少了革兰氏阴性菌(GM影响优生菌和类杆菌)和革兰氏阳性菌(VCM影响梭状杆菌、双歧杆菌和乳杆菌)。同时，GM或VCM处理降低了结肠内容物中的继发性BAs，同时增加了血浆中的初级BAs。此外，结肠BA的变化，尤其是牛磺酸-β-鼠李酸(T-β-Mca)的变化，主要与抑制FXR有关，并进一步改变了BA的合成和运输。综上所述，抗生素的使用显著降低了肠道微生物区系多样性，进而改变了BA的组成。BA组分的改变通过调节FXR信号参与了IF患者的胆汁淤积。
The link between antibiotic treatment and IF-associated liver disease (IFALD) is unclear. Here, we study the effect of antibiotic treatment on bile acid (BA) metabolism and investigate the involved mechanisms. The results showed that pediatric IF patients with cholestasis had a significantly lower abundance of BA-biotransforming bacteria than patients without cholestasis. In addition, the BA composition was altered in the serum, feces, and liver of pediatric IF patients with cholestasis, as reflected by the increased proportion of primary BAs. In the ileum, farnesoid X receptor (FXR) expression was reduced in patients with cholestasis. Correspondingly, the serum FGF19 levels decreased significantly in patients with cholestasis. In the liver, the expression of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), increased noticeably in IF patients with cholestasis. In mice, we showed that oral antibiotics (gentamicin, GM or vancomycin, VCM) reduced colonic microbial diversity, with a decrease in both Gram-negative bacteria (GM affectedEubacteriumandBacteroides) and Gram-positive bacteria (VCM affectedClostridium,BifidobacteriumandLactobacillus). Concomitantly, treatment with GM or VCM decreased secondary BAs in the colonic contents, with a simultaneous increase in primary BAs in plasma. Moreover, the changes in the colonic BA profile especially that of tauro-beta-muricholic acid (TβMCA), were predominantly associated with the inhibition of the FXR and further altered BA synthesis and transport. In conclusion, the administration of antibiotics significantly decreased the intestinal microbiota diversity and subsequently altered the BA composition. The alterations in BA composition contributed to cholestasis in IF patients by regulating FXR signaling.
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影响因子：
64.8
作者：
Arumugam, Manimozhiyan;Raes, Jeroen;Pelletier, Eric;Le Paslier, Denis;Yamada, Takuji;Mende, Daniel R.;Fernandes, Gabriel R.;Tap, Julien;Bruls, Thomas;Batto, Jean-Michel;Bertalan, Marcelo;Borruel, Natalia;Casellas, Francesc;Fernandez, Leyden;Gautier, Laurent;Hansen, Torben;Hattori, Masahira;Hayashi, Tetsuya;Kleerebezem, Michiel;Kurokawa, Ken;Leclerc, Marion;Levenez, Florence;Manichanh, Chaysavanh;Nielsen, H. Bjorn;Nielsen, Trine;Pons, Nicolas;Poulain, Julie;Qin, Junjie;Sicheritz-Ponten, Thomas;Tims, Sebastian;Torrents, David;Ugarte, Edgardo;Zoetendal, Erwin G.;Wang, Jun;Guarner, Francisco;Pedersen, Oluf;de Vos, Willem M.;Brunak, Soren;Dore, Joel;Weissenbach, Jean;Ehrlich, S. Dusko;Bork, Peer
通讯作者：
Bork, Peer
影响因子：
25.7
作者：
Pereira-Fantini, Prue M.;Lapthorne, Susan;Bines, Julie E.
通讯作者：
Bines, Julie E.
DOI：
10.1016/j.jsbmb.2011.08.002
发表时间：
2012-03-01
影响因子：
4.1
作者：
Kisiela, Michael;Skarka, Adam;Maser, Edmund
通讯作者：
Maser, Edmund
DOI：
10.1111/j.1432-1033.1983.tb07550.x
发表时间：
1983-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BOTHAM, KM;BOYD, GS
通讯作者：
BOYD, GS
影响因子：
3.4
作者：
Gura, Kathleen M.;Mulberg, Andrew E.;Puder, Mark
通讯作者：
Puder, Mark