Genetically Obese Human Gut Microbiota Induces Liver Steatosis in Germ-Free Mice Fed on Normal Diet.

Ruirui Wang,Xinhe Xue,Xin Yang,Jian Shen,Liman Deng,Chenhong Zhang,Liping Zhao,Menghui Zhang,Hui Li

doi:10.3389/fmicb.2018.01602

Ruirui Wang, Xinhe Xue + Show 7 more

Open Access

https://doi.org/10.3389/fmicb.2018.01602

Copy DOI

Abstract

Dysbiotic gut microbiota contributes to genetically obese phenotype in human. However, the effect of genetic obesity-associated gut microbiota on host hepatic metabolic deteriorations remains largely unknown. Gut microbiota from a genetically obese human donor before and after a dietary weight loss program was transplanted into germ-free C57BL/6J male mice, grouped as PreM and PostM groups, respectively. The gut microbiome, liver pathology and transcriptome response in the gnotobiotic mice were evaluated. After being fed on normal chow diet for 4 weeks, PreM group developed liver macrovesicular steatosis accompanied with higher concentrations of hepatic triglyceride and cholesterol, while PostM group exhibited normal hepatic physiology. The gut microbiota in PreM and PostM groups was significantly different from each other and was more resembling with their respective donor. RNA-sequencing revealed that, in comparison with PostM group, PreM group showed a foregoing pro-steatotic transcriptional response in liver featuring by the repression of lipid beta-oxidation and the activation of lipid absorption and cholesterol uptake before the pathology of liver steatosis. Moreover, peroxisome proliferator-activated receptor alpha (PPARα), which was repressed in PreM group, may act as crucial regulator of the hepatic transcriptional profile of lipid metabolism between two groups. Our results show that gut microbiota from a genetically obese human promotes the onset of liver steatosis by impacting hepatic transcriptional profile of lipid metabolism in mice. This adds new evidence that gut microbiota may play a causative role in the development of non-alcoholic fatty liver disease.

Highlights

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prevalent chronic liver diseases along with the worldwide epidemic of obesity (Bedogni et al, 2005; Younossi et al, 2016)
Our results show that gut microbiota from a genetically obese human promotes the onset of liver steatosis by impacting hepatic transcriptional profile of lipid metabolism in mice
In our previous cohort study of children with Prader−Willi syndrome (PWS), one of the most common human genetic diseases leading to obesity (Butler, 2011), we showed that a diet rich in non-digestible carbohydrates could modulate the structure and function of gut microbiota in PWS children and improve their obesity-related phenotypes (Zhang et al, 2015)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prevalent chronic liver diseases along with the worldwide epidemic of obesity (Bedogni et al, 2005; Younossi et al, 2016). Fat accumulation in liver induced by diet could be transferred to germ-free (GF) animal through gut microbiota transplantation (Le Roy et al, 2012; Duca et al, 2014). The persistent activation of genes involved in fatty acid oxidation in liver and skeletal muscle was speculated to be one of the crucial reasons for the resistance to diet-induced obesity in GF mice (Backhed et al, 2007). Murakami et al (2016) found that in response to a high-fat diet, gut microbiota could drive the peroxisome proliferator-activated receptor gamma (PPARγ)-mediated activation of hepatic transcriptional circadian oscillation. Gut microbiota may contribute to the onset of diet-induced obesity and NAFLD through distal regulation of the host hepatic transcriptional response related with lipid metabolism

Methods

Results

Discussion

Conclusion