Cirrhosis, or end-stage liver disease, is one of the most common causes of morbidity and mortality in the world.
The disease has an estimated 26.4% mortality per 2-year interval in the United States alone and is the 12th leading cause of death.
Cirrhosis is the result of several years to decades of inflammation and fibrosis. Several etiologies, the most prevalent being viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD/NASH), can cause cirrhosis. NAFLD is a spectrum of liver disease associated with metabolic syndrome and obesity.
There is a strong link between the gut microbiota and cirrhosis. Similar to the effect of the gut microbiota, emerging evidence also suggests there is a possible link between oral health and liver disease.
Gut microbiota and dysbiosis
The human gut microbiota contains over 10 billion microbes and is broadly classified by 5 major phyla – Firmmicutes, Bacteroidetes, Actinobacteria, Proteobactereia, and Verrucomicrobia.
“Dysbiosis” is a term for an imbalance or maladaptation inside the body. Healthy individuals tend to have a larger amount of Firmicutes and thus can serve as a potential biomarker of a healthy microbiota. Firmicutes members help digest complex carbohydrates, ferment simple sugars, and produce short-chain fatty acids – including butyrate, propionate, and acetate which serve as a source of fuel for colonocytes (cells within the colon).
Alterations in these members are associated with mucosal immunological impairment which can encourage the progression of disease, such as cirrhosis.
Cirrhosis pathophysiology, including gut microbial dysbiosis
Certain common underlying pathways drive the progression of inflammation in the liver. Upregulation of inflammation and inflammatory mediator-related changes in the liver is postulated to be the primary driver of liver disease. In addition to liver inflammation and injury, cirrhosis progression is also associated with an impaired intestinal barrier, systemic inflammation, altered bile acid profile, and gut dysbiosis.
The intestinal barrier has several layers of defense – mucus layer, tight-junction proteins, physical integrity, and immune surveillance. Colonic inflammation has shown to contribute to increased intestinal permeability in NASH cirrhosis. In alcoholic cirrhosis, injury to the small intestine has been documented along with increased intercellular space in tight junctions. Reduced secretory IgA and generalized reductions in immunity could further weaken the intestinal barrier and result in translocation of bacteria and their products – such as endotoxins – and trigger an inflammatory response.
Multiple animal model studies of NAFLD and alcoholic liver disease have shown a clear association between disease and dysbiosis. There is also evidence that the microbiome influences progression of NAFLD, alcoholic liver disease, and viral hepatitis to end-stage liver disease in humans.
One study demonstrated that fecal microbiota from cirrhosis patients exhibit a relative reduction in Bacteroidetes, an increase in Proteobacteria and Fusobacteria, and a change in Firmicutes compared with healthy individuals.
Another group demonstrated differences in microbiota composition of cirrhosis patients that showed these alterations correlated with cognitive dysfunction and outcome. Hepatic encephalopathy (HE) is a widespread complication or cirrhosis that represents an altered gut-liver-brain axis. The microbiome in patients with HE has been noted to be altered and it is hypothesized that gut bacterial production of ammonia and inflammatory cytokines affect different parts of the brain.
An interesting aspect of liver disease-associated microbiota changes is the effect of organ (liver) transplant on the recipient’s microbiota. Transplantation showed a significant improvement in gut microbial diversity over time, although never reaching the levels observed in healthy controls. A greater microbial diversity has been associated with better overall health.
The emerging oral-gut-liver axis
The oral mucosa serves as a gateway between the environment and the body and is the body’s first line of defense against microbes and their products. Similar to the gut, oral microbes can be either beneficial or potentially pathogenic and is kept in balance by natural defense mechanisms of the oral cavity. Despite the continuous presence of a heavy microbial load, the oral mucosa maintains a balanced tissue homeostasis and displays minimal inflammation in healthy individuals.
Periodontal disease is one of the most prevalent oral diseases, affecting almost half the population. It can be categorized as gingivitis or periodontitis. Development of periodontitis is driven primarily by the dysbiotic microbiota and the inability of the host to restrain inflammation due to environmental, genetic, and/or epigenetic factors which in turn also promote dysbiosis. Periodontitis is also associated with increased risk of several systemic conditions such as diabetes, cardiovascular and respiratory diseases, pregnancy complications, cancer, and possibly liver diseases.
It is routine clinical practice to treat periodontitis prior to liver transplant in order to eliminate potential infection and reduce the risk of post-transplant complications. While not as well established as associations between periodontitis and other systemic conditions, it is likely that similar factors related to the oral microbiota and inflammation connect oral and liver disease as well. It is also possible that the link between the liver and the oral cavity could be connected via the gut through increased intestinal permeability. A higher incidence of periodontitis has been reported in cirrhotic patients compared with healthy controls (25-68%). Periodontitis prevalence tends to be concentrated in patients with alcoholic cirrhosis, which is frequently accompanied by poor oral hygiene.
Therapeutic strategies targeting the microbiota in cirrhosis
Studies have been done in cirrhotic patients to evaluate the effects of altering the microbiome with probiotics and antibiotics. There is good evidence that probiotics influence the native microbiome in non-cirrhotic patients, but more evidence is needed to determine the effects in cirrhosis.
Manipulation of the gut microbiota has been shown to change oral microbial composition. Several studies have found that administration of probiotics significantly reduced gingivitis, however most changes were reversed after probiotic use was discontinued.
There is growing evidence that gut dysbiosis aids in the pathogenesis of liver cirrhosis and contributes to overall systemic inflammation. Similar to the gut microbiome, emerging evidence suggests that the oral microbiome influences changes in the liver. The oral cavity has potential to be considered an additional factor in future discussion on the impact of microbiota on cirrhosis-associated complications.