Characterization of the gut microbiome in non-alcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH.

Non-alcoholic steatohepatitis (NASH) is a serious liver disease associated with obesity. Characterized by metabolic syndrome, hepatic steatosis and liver inflammation, NASH is believed to be under the influence of the gut microflora. Here the composition of gut bacterial communities of NASH, obese and healthy children was determined by 16S rRNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of the patients and healthy controls. UniFrac based principle coordinates analysis indicated that most of the microbiome samples clustered by disease status. Each group was associated with a unique pattern of enterotypes. Differences were abundant at phylum, family and genus level between the healthy subjects and the obese patients (with or without NASH) and relatively fewer differences were observed between the obese and the NASH microbiomes. Among those taxa with greater than 1% representation in any of the disease groups, Proteobacteria, Enterobacteriaceae and Escherichia were the only phylum, family and genus exhibiting significant difference between the obese and the NASH microbiome. Similar blood ethanol concentration was observed between healthy subjects and obese non-NASH patients, but NASH patients exhibited significantly elevated blood ethanol level. CONCLUSIONS: The increased abundance of alcohol producing bacteria in NASH microbiome, the elevated blood ethanol concentration in NASH patients, and the well-established role of alcohol metabolism in oxidative stress and consequently liver inflammation suggest a role for alcohol producing microbiota in the pathogenesis of NASH. We postulatae that the distinct composition of the gut microbiome among NASH, obese and normals could offer a target for intervention or a marker for disease. (HEPATOLOGY 2012.).

Copyright © 2012 American Association for the Study of Liver Diseases.

Toll-like receptors 1-9 are elevated in livers with fructose-induced hepatic steatosis.

Studies in animals and human subjects indicate that gut-derived bacterial endotoxins may play a critical role in the development of non-alcoholic fatty liver disease (NAFLD). In the present study, we investigated if the liver is also sensitised by other microbial components during the onset of fructose-induced steatosis in a mouse model. C57BL/6 mice were either fed with 30 % fructose solution or tap water (control) with or without antibiotics for 8 weeks. Expression of toll-like receptors (TLR)1-9, TNF-α, inducible NO synthase (iNOS), myeloid differentiation factor 88 (MyD88) and number of F4/80 positive cells in the liver were assessed. Occludin protein, DNA of microbiota in the small and large intestine and retinol binding protein 4 (RBP4) in plasma were analysed using Western blot, DNA fingerprinting and ELISA, respectively. F4/80 positive cells were determined by immunohistochemistry. The accumulation of TAG found in the livers of fructose-fed mice was associated with a significant induction of TLR 1-4 and 6-8. Plasma RBP4 concentration and hepatic mRNA expression levels of TNF-α, iNOS, MyD88 and number of F4/80 positive cells of fructose-fed animals were significantly higher than those of controls; however, these effects of fructose were attenuated in antibiotic-treated mice. Whereas protein concentration of occludin was lower in the duodenum of fructose-treated mice, no systematic alterations of microbiota were found in this part of the intestine. Taken together, these data support the hypothesis that (1) an increased intestinal translocation of microbial components and (2) an increased number of F4/80 positive cells and induction of several TLR and dependent pathways (e.g. MyD88 and iNOS) may be involved in the onset of fructose-induced NAFLD.

Gut microbiota transplantation may prevent development of diabetes and fatty liver disease

Exciting new data presented April 18 at the International Liver Congress^TM 2012 shows the gut microbiota's causal role in the development of diabetes and non-alcoholic fatty liver disease (NAFLD), independent of obesity. Though an early stage animal model, the French study highlights the possibility of preventing diabetes and NAFLD with gut microbiota transplantation -- the engrafting of new microbiota, usually through administering fecal material from a healthy donor into the colon of a diseased recipient.