Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling
Authors: Yan Shengmin , Khambu Bilon , Chen Xiaoyun , Dong Zheng , Guo Grace , Yin Xiao-Ming 
Published: May 2020

Objective

The gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury.

Design

Fecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5Δhepmice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice. 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 given a fibroblast growth factor receptor 4 (FGFR4) inhibitor.

Results

The composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria inAtg5Δhepmice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice.

Conclusion

Gut dysbiosis can remedy liver injury inAtg5Δhepmice through the FXR-FGF15 signaling. Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gut-liver axis.

SHORT SUMMARY

What is already known about this subject?

Gut microbiota (GM) can be altered during hepatic pathogenesis.

GM are involved in bile acid (BA) metabolism.

Autophagy deficiency in the liver disrupts BA homeostasis and causes cholestatic injury.

What are the new findings?

Deficiency of autophagy in the liver causes alteration of GM, which leads to a higher proportion of BA-metabolizing bacteria.

GM contribute to the activation of ileal farnesoid X receptor (FXR) and a higher expression of fibroblast growth factor 15 (FGF15) in autophagy deficient condition in the liver, which is associated with decreased levels of conjugated BAs and increased levels of unconjugated BAs in the intestine.

Manipulations that lead to GM alteration, intestinal BA signaling, or FGF15 signaling can all modulate the liver phenotype.

BA and GM together can act as a sensor to liver injury to trigger FGF15-mediated protective mechanism.

How might it impact on clinical practice in the foreseeable future?

These findings indicate that gut dysbiosis in the scenario of liver disease can be beneficial, suggesting cautions should be exercised in the use of antibiotics during specific liver diseases.

If antibiotics need to be used in patients with liver diseases it may be beneficial to enhance the FXR-FGF15 feedback signaling to retain the protective effect of GM.