Liver Disease and the Gut Microbiome

Alcoholic Liver Disease

The reason why only some chronic alcoholics develop alcoholic hepatitis or cirrhosis remains unclear.^[23] Because only a small portion of alcoholics are at risk for advanced liver disease, other associations, such as an altered microbiome, are being evaluated as a potential association.^[24] Alterations of gastrointestinal bacterial populations develop with chronic ethanol ingestion.^[25,26] Intestinal Bacteroides populations are reduced and Proteobacteria populations are increased after chronic alcohol consumption. These changes may persist after subsequent sobriety.

Studies of alcohol-fed mice^[27] and rats^[28] identified dysbiosis of the microbiome of both species with small-intestinal bacterial overgrowth and increased mucosal permeability of the intestine. Changes in the microbiome in humans with alcoholic liver disease may also impair the intestinal mucosal barrier^[29] and result in elevated circulating endotoxin levels.^[26]

A fecal transfer study also indicates that the microbiome has a relationship to the severity of alcoholic liver disease.^[30] In this study, feces from human patients with alcoholic hepatitis were transferred to the intestines of gnotobiotic (germ-free) mice, which subsequently developed hepatic inflammation with accumulation of natural killer and T cells, hepatocellular necrosis coupled with increased intestinal permeability, and greater bacterial translocation compared with mice receiving fecal transfer from humans lacking alcoholic hepatitis.

Such data provide evidence that the microbiome may have a role in the severity of liver disease. Other studies have found that human mucosa-associated microbiota are altered by chronic alcohol ingestion^[26] and that small-intestinal bacterial overgrowth is associated with increased circulating endotoxin levels^[28] and greater severity of clinical liver disease.^[31]

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a frequent cause of abnormal liver tests in Western populations.^[32] In fact, the development of cirrhosis resulting from NAFLD is rapidly becoming the major indication for liver transplantation in the United States.^[33]

Defined by a lack of significant alcohol intake, manifestations of NAFLD include fatty metamorphosis of hepatocytes, hepatic inflammation, and risk of developing nonalcoholic steatohepatitis (NASH) and fibrosis/cirrhosis.^[34] Although NAFLD is associated with metabolic syndrome and obesity,^[35] the factors that result in progression of NAFLD remain unclear.^[36]

When obese patients with clinical NAFLD are compared with nonobese patients lacking liver disease, a variation of the microbiome in those with liver disease is observed, with a significant increase in fecal volatile organic compounds.^[37] Systemic obesity frequently accompanies NAFLD, and an alteration of the microbiome could play a role in the development of human obesity.^[38,39] Greater enzymatic activity for carbohydrate metabolism and increased availability of short-chain fatty acids as energy have been noted in obese patients, with a lower proportion of Bacteroidetes and a higher proportion of Firmicutes populations in their microbiome.^[5] Whether dysbiosis of the microbiome could also play a role in the progression of NAFLD is uncertain.

Much of the data regarding the role of the microbiome come from animal studies. Germ-free mice typically have a lower body mass than mice with a normal intestinal microbiome.^[40] With fecal transfer from normal mice to germ-free mice, body mass increases in the recipient mouse, associated with greater insulin resistance and risk for fatty change in the liver. Similar changes have also been described after fecal transfer from obese humans to germ-free mice.^[41] Another study found that mice eating a high-fat diet may develop obesity and fatty liver.^[42]

However, some mice are resistant to becoming obese while consuming high-fat diets and are noted to have a different microbiome from those that develop obesity. When germ-free mice were colonized with the microbiome of donor mice that either did or did not develop hyperglycemia and fatty liver after being fed a high-fat diet, the mice receiving the microbiome of those that initially developed hyperglycemia and fatty liver also developed these changes, whereas mice receiving the microbiome of those that did not develop hyperglycemia or fatty liver also failed to develop these changes.

These studies suggest that the microbiome puts the recipient mice at risk for changes of NAFLD. A reduction in Bacteroidetes populations with an increase in Firmicutes species may be the cause,^[43] although human studies are variable.^[44]

In studies of rats, dietary supplementation with a prebiotic (inulin-type fructan oligofructose) reduced hepatic steatosis and plasma triglyceride levels.^[45] Oligofructose is metabolized by intestinal bacteria to short-chain fatty acids and lactate and produces a proliferation of intestinal bacteria, with reduction of circulating triglyceride and cholesterol levels. This is also observed in humans after administration of a probiotic, with reduced fat production by the liver and a decrease in circulating triglyceride levels.^[46]

In a preliminary study, administration of the prebiotic oligofructose to seven patients with NASH reduced circulating aminotransferase levels, especially aspartate aminotransferase (AST), but did not reduce hepatomegaly on ultrasound after 4 or 8 weeks of treatment.^[47] Compared with patients treated with lifestyle modification alone, simultaneous administration of Bifidobacterium species and inulin-type fructans to humans resulted in a reduction of circulating inflammatory factors (C-reactive protein, tumor necrosis factor alpha, and serum endotoxin levels), AST levels, and low-density lipoprotein cholesterol levels associated with reduced hepatic fat and NASH activity index.^[48] Circulating endotoxin levels are also increased in patients with fatty liver, but their role in NAFLD is unclear.^[49]

When patients with NASH with or without hepatic fibrosis are evaluated,^[50] differences in bacterial quantities within the microbiome are observed. In multivariate analysis, Bacteroides species tend to be increased with NASH, whereas an increase in Ruminococcus is associated with both NASH and fibrosis.

At baseline, obese patients with NAFLD have lower quantities of Firmicutes species compared with controls with similar quantities of Bacteroidetes. After 8 weeks of probiotic supplementation with selected microorganisms, patients with NASH had improved liver tests and reduced radiologic evidence of fatty liver,^[6] associated with a microbiome containing increased Bacteroidetes and reduced quantities of Firmicutes.

Other investigations suggest that the microbiome plays a role in endogenous ethanol production and the development of fatty liver and obesity.^[12] In studies of obese children^[32] and adults^[51] with NAFLD, endogenous production of ethanol by the microbiome was noted. Could these studies mean that production of ethanol by the altered microbiome of patients with NAFLD is the cause of NAFLD and NASH?

These studies raise interesting questions and provide opportunities for the consideration of treatment with dietary changes; administration of prebiotics, probiotics, or antibiotics; and even studies of fecal transfer.

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