Liver-specific knockdown of ANGPTL8 alters the structure of the gut microbiota in mice

Yinlong Cheng,Yixin Zou,Siyu Chen,Wenxiang Zhang,Yonghong Xiong,Yining Li,Yujie Shi,Chang Liu

doi:10.1186/s13213-020-01599-0

Abstract

PurposeTo investigate the effect of liver-specific knockdown of ANGPTL8 on the structure of the gut microbiota.MethodsWe constructed mice with liver-specific ANGPTL8 knockdown by using an adeno-associated virus serotype 8 (AAV8) system harbouring an ANGPTL8 shRNA. We analysed the structure and function of the gut microbiome through pyrosequencing and KEGG (Kyoto Encyclopedia of Genes and Genomes) functional prediction.ResultsCompared with controls, ANGPTL8 shRNA reduced the Simpson index and Shannon index (p < 0.01) of the gut microbiota in mice. At the phylum level, the sh-ANGPTL8 group showed a healthier gut microbiota composition than controls (Bacteroidetes: controls 67.52%, sh-ANGPTL8 80.75%; Firmicutes: controls 10.96%, sh-ANGPTL8 8.58%; Proteobacteria: controls 9.29%, sh-ANGPTL8 0.98%; F/B ratio: controls 0.16, sh-ANGPTL8 0.11). PCoA and UPGMA analysis revealed a significant difference in microbiota composition, while KEGG analysis revealed a significant difference in microbiota function between controls and the sh-ANGPTL8 group.ConclusionOur results revealed that inhibition of ANGPTL8 signalling altered the structure of the gut microbiome, which might further affect the metabolism of mice. We have thus identified ANGPTL8 as a novel hepatogenic hormone potentially involving the liver-gut axis and regulating the structure of the gut microbiota.

Highlights

Incredible amounts of microorganisms exist in the human intestinal tract, the population of which reaches 100 trillion, far more than other microorganisms on the human surface, approximately 10 times the sum of both somatic cells and germ cells (Backhed et al 2005)
Mice were transduced with an associated virus serotype 8 (AAV8) system carrying shRNA against scramble or ANGPTL8 into mice at a dose of 1 × 1012 vg for 45 days to knock down ANGPTL8 expression in the liver through tail-vein injection
Our previous research showed that AAV8-mediated knockdown of ANGPLT8 blocked its expression and secretion (Chen et al 2019)

Summary

Introduction

Incredible amounts of microorganisms exist in the human intestinal tract, the population of which reaches 100 trillion, far more than other microorganisms on the human surface, approximately 10 times the sum of both somatic cells and germ cells (Backhed et al 2005). Treatment with progesterone in ovariectomized (OVX) mice has been reported to change the gut microbiota composition significantly (Sovijit et al 2019). It is noteworthy that the GI tract is unable to secrete sex hormones, which indicates that the gut microbiota potentially respond to the hormones secreted from remote organs. As microbial products and gut-derived toxins can enter hepatocytes through the portal vein, the abnormal composition changes the gut microbiota, contributing to CLD, especially non-alcoholic fatty liver disease (NAFLD) and hepatic encephalopathy (Minemura and Shimizu 2015). Previous studies have shown that the liver tissue influences the structure of the gut microbiota through secreting bile acids. Abnormal secretion of bile acids plays an important role in the dysbiosis of gut microbiota (Quesada-Vazquez et al 2020)

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