Cell Mol Gastroenterol Hepatol. 2021;11(4):973-997. doi: 10.1016/j.jcmgh.2020.10.011. Epub 2020 Oct 23.
Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling.
Cellular and molecular gastroenterology and hepatology
Shengmin Yan, Bilon Khambu, Xiaoyun Chen, Zheng Dong, Grace Guo, Xiao-Ming Yin
Affiliations
Affiliations
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia; Charlie Norwood VA Medical Center, Augusta, Georgia.
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey.
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: [email protected].
PMID: 33127558
PMCID: PMC7898036 DOI: 10.1016/j.jcmgh.2020.10.011
Abstract
BACKGROUND & AIMS: 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.
METHODS: 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.
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, antibiotics 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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Keywords: Autophagy; FGF15; Gut Dysbiosis; Liver Injury
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