Liver Disease and the Gut Microbiome

The Growing Importance of the Microbiome

The microbiome of the human gastrointestinal tract contains 10-100 trillion microbes composed of 500-1000 different species,^[1] with the majority contained in four phyla: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria.^[2] Bacteroidetes and Firmicutes account for a significant portion of the total microbiome,^[3] which also includes viruses, yeasts, protozoa, and archaea. Archaea are single-celled microorganisms that lack a nucleus or organelles and reproduce by binary fission.^[4]

Knowledge of the importance of the intestinal microbiome on health and disease continues to grow. Approximately 30% of the organisms contained in the microbiome have been cultured, but not all organisms can be grown in vitro with current techniques. As a consequence, culture-negative determinations, such as quantitative polymerase chain reaction, in situ hybridization, and 16S ribosomal RNA gene sequencing, are used to study the role of the microbiome.^[5]

The microbiome varies from person to person^[6] and is affected by diet, antibiotics, age, living conditions and activities, and host factors.^[7] Development of the microbiome begins shortly after birth with a baby's initial exposure to bacteria. Dietary changes, such as ingestion of a Mediterranean diet, also have a significant impact on the microbiome.^[8]

Benefits from our microbiome include the formation of nutrients and vitamins, energy from short-chain fatty acid production during the metabolism of foodstuffs, breakdown of indigestible dietary fibers, protection from infection through prevention of colonization by pathogenic bacteria, and development of mucosal immunity. However, the dynamics of a normal, "healthy" microbiome remain difficult to determine, because each human has a unique pattern of microbes. It seems clear, however, that the symbiotic relationship between a healthy microbiome and the host is crucial to overall health.^[9]

Disruption and alteration of microbiome homeostasis is referred to as "dysbiosis" and seems to be associated with systemic disease. For example, the development of human and animal obesity has been related to alterations of the microbiome,^[10] including a reduction of Bacteroidetes species and an increase in the number of Firmicutes and Actinobacteria.^[10,11] Methane-producing archaea have also been associated with obesity development.^[12]

The Microbiome and the Liver

Blood flow to the liver arrives from both the hepatic artery (25% of total flow) and the portal vein from the gastrointestinal tract (75%). This exposes the liver to a variety of gastrointestinal factors, including nutrients, volatile fatty acids, vitamins, bacteria, and bacterial factors. As a result, the liver provides a first-pass defense against antigens, bacteria, and bacterial products.

The microbiome is a factor in the maintenance of mucosal integrity and normal permeability of the intestinal mucosa. Changes to intestinal integrity may play a role in the development of systemic disorders, such as liver disease—and changes in liver integrity, such as hepatic fibrosis, can add to the dysbiosis of the intestinal microbiome by altering bile acid production. This causes increased resistance to portal blood flow, which raises venous pressure within the intestinal mucosa, altering mucosal permeability^[13] and allowing bacterial overgrowth in the small intestine, altering small-bowel motility.^[14]

Patients with nonalcoholic fatty liver disease may translocate bacterial factors and bacteria into the portal circulation, causing systemic circulation of bacterial DNA^[9] and bacterial endotoxin^[15] owing to altered intestinal permeability.^[14] Translocation of intact bacteria from the gastrointestinal tract to the portal circulation in patients with cirrhosis can result in bacteremia or spontaneous bacterial peritonitis. It seems that aerobic bacteria translocate from the gut more easily than anaerobes.

Although liver disease can promote dysbiosis, the microbiome of patients with clinically stable cirrhosis may remain intact.^[16] However, once clinical decompensation of the cirrhotic patient occurs, the microbiome changes as clinical disease worsens.^[17] More pathogenic organisms, such as Staphylococcus, Enterobacteriaceae, and Enterococcus, may be present in the microbiome, with decompensation associated with a reduction in such species as Veillonella.^[16]

In addition, end-stage liver patients with systemic bacteremia can have an altered microbiome compared with those without systemic infection.^[16] The occurrence of hepatic encephalopathy may be associated with dysbiosis. Even the salivary microbiome is different in patients with end-stage liver disease who have hepatic encephalopathy.^[18] Animal studies suggest that the microbiome also plays a role in the neuroinflammatory response associated with advanced liver disease.^[19]

Treatment with lactulose can alter the microbiome and increase quantities of Enterobacteriaceae.^[16] Probiotics may decrease the occurrence of hepatic encephalopathy in patients with cirrhosis.^[20]

Other suggested relationships to the dysbiosis of chronic liver disease include worsening of serum bilirubin levels, elevation of the international normalized ratio and creatinine level, and increased Model for End-Stage Liver Disease scores in patients awaiting liver transplantation.^[21] Chronic opioid use in patients with cirrhosis may also result in dysbiosis, with increased endotoxemia and more frequent hospitalizations.^[22]

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