Characterization of Gut Microbiomes in Nonalcoholic Steatohepatitis (NASH) Patients: A Connection Between Endogenous Alcohol and NASH

Abstract

Nonalcoholic 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 ribosomal RNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of 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 levels between healthy subjects and obese patients (with or without NASH), and relatively fewer differences were observed between 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 types exhibiting significant difference between obese and NASH microbiomes. Similar blood-ethanol concentrations were observed between healthy subjects and obese non-NASH patients, but NASH patients exhibited significantly elevated blood ethanol levels. Conclusions: The increased abundance of alcohol-producing bacteria in NASH microbiomes, 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 postulate that the distinct composition of the gut microbiome among NASH, obese, and healthy controls could offer a target for intervention or a marker for disease. (HEPATOLOGY 2013;57:601-609) N onalcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is the most common cause of elevated liver enzymes in the United States.1 NAFLD with inflammation and fibrosis is known as nonalcoholic steatohepatitis (NASH) because it resembles alcoholic liver disease (ALD) without a history of alcohol ingestion. The incidence of NASH has been increasing over the past 20 years. 3 In the United States, the current prevalence of NAFLD and NASH could be as high as 46% and 12%, respectively. 4 Without an effective available treatment, the prognosis of NASH is not optimistic. NASH is responsible for approximately 10% of liver transplants in the United States and is projected to become the most common indication for liver transplantation in the near future.

Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

“…Major contributors of the Bacteroidetes phylum are Bacteroides, Parabacteroides, Porphyromonas, Prevotellaceae (Prevotella), and Rikenellaceae (Alistipes). The most prominent Actinobacteria are Bifidobacteriaceae (Bifidobacterium), and the most abundant Proteobacteria are the Enterobacteriaceae (Escherichia) (15,16). Although the functions of most Firmicutes are not yet clear, there is some evidence that indicates that some members of this phylum are among the butyrate-producing bacteria that increase energy extraction from the diet (17)(18)(19).…”

“…Understanding the functions associated with the microbial community is important, because alterations in the intestinal microbiota have been associated with host diseases, including obesity, type 2 diabetes, and NAFLD (8,21,22). In patients with NAFLD, the microbiome's abundance (23) and community structure is altered (also called dysbiosis) (15,24). The importance of the gut microbiome in the prevention and treatment of NAFLD is highlighted by the fact that fecal transplantation from mice with NAFLD into wild-type mice caused NAFLD in mice that received the microbiota (25).…”

“…The contribution of increased intestinal permeability (20), overgrowth of bacteria (15), and elevated serum LPS (31,32) has been shown in patients with NAFLD. Overgrowth of bacteria, in particular gram-negative bacteria, increases the production of hepatotoxic products such as LPS (23).…”

The management of childhood liver diseases in adulthood

“…Hepatocyte death subsequently results in fibrogenesis through hepatic stellate cell activation [121]. Other pathophysiological mechanisms implicated include single nucleotide polymorphisms in patatin-like phospholipase domain-containing protein (PNPLA3), increased consumption of trans fats and fructose, intestinal dysbiosis and bacterial translocation, and an increase in male sex hormones [122][123][124][125][126][127].…”

Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome

“…It is now well-recognized in humans that changes in microbiota composition, termed dysbiosis, are strongly associated with the development of both obesity and NAFLD [57,58]. Modifications in gut flora metabolism can be strongly influenced by diet.…”