Intestinal Microbiota and Development of NAFLD
Intestinal Microbiota and Development of NAFLD
Objective Non-alcoholic fatty liver disease (NAFLD) is prevalent among obese people and is considered the hepatic manifestation of metabolic syndrome. However, not all obese individuals develop NAFLD. Our objective was to demonstrate the role of the gut microbiota in NAFLD development using transplantation experiments in mice.
Design Two donor C57BL/6J mice were selected on the basis of their responses to a high-fat diet (HFD). Although both mice displayed similar body weight gain, one mouse, called the 'responder', developed hyperglycaemia and had a high plasma concentration of pro-inflammatory cytokines. The other, called a 'non-responder', was normoglycaemic and had a lower level of systemic inflammation. Germ-free mice were colonised with intestinal microbiota from either the responder or the non-responder and then fed the same HFD.
Results Mice that received microbiota from different donors developed comparable obesity on the HFD. The responder-receiver (RR) group developed fasting hyperglycaemia and insulinaemia, whereas the non-responder-receiver (NRR) group remained normoglycaemic. In contrast to NRR mice, RR mice developed hepatic macrovesicular steatosis, which was confirmed by a higher liver concentration of triglycerides and increased expression of genes involved in de-novo lipogenesis. Pyrosequencing of the 16S ribosomal RNA genes revealed that RR and NRR mice had distinct gut microbiota including differences at the phylum, genera and species levels.
Conclusions Differences in microbiota composition can determine response to a HFD in mice. These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity.
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and is commonly associated with insulin resistance. NAFLD affects 20–30% of western countries' population and more than 80% of obese people. It refers to a spectrum of liver damage ranging from simple steatosis to non-alcoholic steatohepatitis, advanced fibrosis, cirrhosis or even hepatocellular carcinoma. An increasing body of literature has recently been generated identifying gut microbiota as a new environmental factor contributing to obesity and NAFLD. First, Bäckhed and colleagues showed that germ-free (GF) C57BL/6J mice gained less weight than conventional mice when given a sugar and lipids-rich diet despite greater food consumption. Moreover, Rabot et al observed that GF mice receiving a high-fat diet (HFD) showed enhanced insulin sensitivity with improved glucose tolerance and reduced insulinaemia. Concurrently, colonisation of GF mice by a gut microbiota from conventional mice produced an increase in body fat content. More recently, an association between the human gut microbiota and the development of fatty liver due to choline deficiency has been identified. Moreover, it was revealed that changes in the gut microbiota associated with inflammasome defects regulates the progression of NAFLD.
HFD feeding is widely used in rodents to study the onset and progression of obesity and associated metabolic disorders. However, the high-fat-induced phenotype varies distinctly, even within a group of animals with the same genetic background, and it has recently been demonstrated that disctinct gut microbiota profiles are associated with different metabolic phenotypes. Gut microbiota of humans and mice are more than 95% made up of three phyla: Firmicutes, Bacteroidetes and Actinobacteria. In contrast to the poor diversity at the phylum level, the species level displays a high diversity, with an average human microbiota estimated at 200 prevalent bacterial species and up to 1000 less common species. Importantly, in humans but also in mice, the bacterial species profiles are unique for each individual. We therefore hypothesised that the gut microbiota modulates the effect of a HFD challenge and that the variability of the composition of this microbiota could explain the diversity of responses to HFD.
In the present work, we developed a strategy based on gut microbiota transfer to establish whether we can transmit the different propensity to develop NAFLD in response to HFD by means of gut microbiota transplant.
Abstract and Introduction
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is prevalent among obese people and is considered the hepatic manifestation of metabolic syndrome. However, not all obese individuals develop NAFLD. Our objective was to demonstrate the role of the gut microbiota in NAFLD development using transplantation experiments in mice.
Design Two donor C57BL/6J mice were selected on the basis of their responses to a high-fat diet (HFD). Although both mice displayed similar body weight gain, one mouse, called the 'responder', developed hyperglycaemia and had a high plasma concentration of pro-inflammatory cytokines. The other, called a 'non-responder', was normoglycaemic and had a lower level of systemic inflammation. Germ-free mice were colonised with intestinal microbiota from either the responder or the non-responder and then fed the same HFD.
Results Mice that received microbiota from different donors developed comparable obesity on the HFD. The responder-receiver (RR) group developed fasting hyperglycaemia and insulinaemia, whereas the non-responder-receiver (NRR) group remained normoglycaemic. In contrast to NRR mice, RR mice developed hepatic macrovesicular steatosis, which was confirmed by a higher liver concentration of triglycerides and increased expression of genes involved in de-novo lipogenesis. Pyrosequencing of the 16S ribosomal RNA genes revealed that RR and NRR mice had distinct gut microbiota including differences at the phylum, genera and species levels.
Conclusions Differences in microbiota composition can determine response to a HFD in mice. These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity.
Introduction
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and is commonly associated with insulin resistance. NAFLD affects 20–30% of western countries' population and more than 80% of obese people. It refers to a spectrum of liver damage ranging from simple steatosis to non-alcoholic steatohepatitis, advanced fibrosis, cirrhosis or even hepatocellular carcinoma. An increasing body of literature has recently been generated identifying gut microbiota as a new environmental factor contributing to obesity and NAFLD. First, Bäckhed and colleagues showed that germ-free (GF) C57BL/6J mice gained less weight than conventional mice when given a sugar and lipids-rich diet despite greater food consumption. Moreover, Rabot et al observed that GF mice receiving a high-fat diet (HFD) showed enhanced insulin sensitivity with improved glucose tolerance and reduced insulinaemia. Concurrently, colonisation of GF mice by a gut microbiota from conventional mice produced an increase in body fat content. More recently, an association between the human gut microbiota and the development of fatty liver due to choline deficiency has been identified. Moreover, it was revealed that changes in the gut microbiota associated with inflammasome defects regulates the progression of NAFLD.
HFD feeding is widely used in rodents to study the onset and progression of obesity and associated metabolic disorders. However, the high-fat-induced phenotype varies distinctly, even within a group of animals with the same genetic background, and it has recently been demonstrated that disctinct gut microbiota profiles are associated with different metabolic phenotypes. Gut microbiota of humans and mice are more than 95% made up of three phyla: Firmicutes, Bacteroidetes and Actinobacteria. In contrast to the poor diversity at the phylum level, the species level displays a high diversity, with an average human microbiota estimated at 200 prevalent bacterial species and up to 1000 less common species. Importantly, in humans but also in mice, the bacterial species profiles are unique for each individual. We therefore hypothesised that the gut microbiota modulates the effect of a HFD challenge and that the variability of the composition of this microbiota could explain the diversity of responses to HFD.
In the present work, we developed a strategy based on gut microbiota transfer to establish whether we can transmit the different propensity to develop NAFLD in response to HFD by means of gut microbiota transplant.
