Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling.
Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling.
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肝自噬缺乏通过FGF15-FGFR4信号重塑肠道微生物群的适应性保护
DOI：
10.1016/j.jcmgh.2020.10.011
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发表时间：
2021
影响因子：
7.2
通讯作者：
Yin XM
中科院分区：
文献类型：
--
作者：
Yan S;Khambu B;Chen X;Dong Z;Guo G;Yin XM
肝脏和肠道的功能在生理和病理条件下都是密切相关的。肠道微生物区系(GM)在肝脏发病过程中经常产生有害影响。自噬对肝脏内环境的稳定至关重要，但自噬功能对肝脏-肠道相互作用的影响尚不清楚。在这里，我们研究了肝脏自噬缺陷(ATG5，Δ，HEP)对GM的影响，进而研究了GM对肝脏病理的影响。通过16S测序分析粪便微生物区系。抗生素被用来调节GM。应用胆碱乙胺降低肠-肝胆汁酸(BA)水平。在过量表达成纤维细胞生长因子15基因的小鼠和给予成纤维细胞生长因子受体4(FGFR4)抑制剂的小鼠中，研究了成纤维细胞生长因子15(FGF15)和回肠法兰样X受体(FXR)的功能作用。Δ-HEP可引起肝脏损伤和肠道BA组成的改变，结合型BA所占比例较低，未结合型BA所占比例较高。随着BA代谢细菌数量的增加，GM的组成发生了显著变化，导致FXR驱动的回肠FGF15表达增加，FXR对未结合BA具有更高的亲和力。值得注意的是，抗生素或氯氰菊酯治疗减少了FGF15的表达，并加剧了肝脏损伤。一直以来，抑制肝脏中的FGF15信号会增强肝脏损伤。肝脏自噬功能的缺陷会影响肠道环境，导致肠道生物失调。令人惊讶的是，这些变化通过FGF15-FGFR4信号对肝脏损伤提供了适应性保护。因此，在肝脏受损的情况下使用抗生素可能会通过肠道-肝脏轴产生意想不到的不良后果。
The functions of the liver and the intestine are closely tied in both physiological and pathologic conditions. The gut microbiota (GM) often cause deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here we investigated the effect of hepatic autophagy deficiency (Atg5Δhep) on GM and in turn the effect of GM on the liver pathology. Fecal microbiota were analyzed by 16S sequencing. Antibiotics were used to modulate GM. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor. Atg5Δhep causes liver injury and alterations of intestinal BA composition, with a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs. The composition of GM is significantly changed with an increase in BA-metabolizing bacteria, leading to an increased expression of ileal FGF15 driven by FXR that has a higher affinity to unconjugated BAs. Notably, antibiotics or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury. Deficiency of autophagy function in the liver can affect intestinal environment, leading to gut dysbiosis. Surprisingly, such changes provide an adaptive protection against the liver injury through the FGF15-FGFR4 signaling. Antibiotics use in the condition of liver injury may thus have unexpected adverse consequences via the gut-liver axis.
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影响因子：
--
作者：
Dawson, Paul A
通讯作者：
Dawson, Paul A
影响因子：
3.7
作者：
Li Z;Lin B;Lin G;Wu Y;Jie Y;Li X;Ko B;Chong Y;Luo J
通讯作者：
Luo J
影响因子：
8.3
作者：
Kennedy, DJ;Vetteth, S;Shapiro, JI
通讯作者：
Shapiro, JI
DOI：
10.1002/hep.29676
发表时间：
2018-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hartmann P;Hochrath K;Horvath A;Chen P;Seebauer CT;Llorente C;Wang L;Alnouti Y;Fouts DE;Stärkel P;Loomba R;Coulter S;Liddle C;Yu RT;Ling L;Rossi SJ;DePaoli AM;Downes M;Evans RM;Brenner DA;Schnabl B
通讯作者：
Schnabl B
影响因子：
20.8
作者：
Gadaleta, Raffaella Maria;Moschetta, Antonio
通讯作者：
Moschetta, Antonio