肝脏自噬
[IF:7.076]
肝脏自噬缺陷通过FGF15-FGFR4信号重塑肠道菌群，获得适应性保护
10.1016/j.jcmgh.2020.10.011
10-23, Article
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Background & Aims: The functions of the liver and the intestine are closely tied in both physiological and pathological conditions. The gut microbiota (GM) often causes 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.
Methods: Fecal microbiota were analyzed by 16S sequencing. Antibiotics (ABX) was 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 over-expressing FGF15 gene, or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor.
Results: 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, ABX or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury.
Conclusions: 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.
First Authors:
Shengmin Yan
Correspondence Authors:
Xiao-Ming Yin
All Authors:
Shengmin Yan,Bilon Khambu,Xiaoyun Chen,Zheng Dong,Grace Guo,Xiao-Ming Yin