Researchers have discovered a new mechanism that could help the development of a new alcohol-related liver disease treatment.
Alcohol-related liver disease is one of the most common causes of death mortality worldwide. Due to a lack of understanding of the factors contributing to the development of the disease, transplantation is still the only available liver disease treatment in most cases.
Thanks to an improved understanding of the molecular background of liver disease, a team led by Tim Hendrikx from MedUni Vienna’s Department of Laboratory Medicine have begun developing new liver disease treatment methods.
The results of the study have been published in the journal Gut.
Identifying the pIgR receptor
During the study, the researchers collaborated with a team from the University of California, San Diego. Together they identified a previously unknown function of the polymeric immunoglobulin receptor (pIgR) in alcohol-related liver disease.
Preclinical studies have shown that pIgR-mediated secretion of certain antibodies (immunoglobulin A or IgA) in the intestines is vital in protecting the liver against alcohol-related damage.
The development of alcohol-related liver disease is characterised by increased intestinal permeability or ‘leaky gut’. This allows bacteria (and their by-products) from the intestine to access the liver, triggering an inflammatory reaction. Secretion of IgA in the gut is an is essential for protection against invasive pathogens. Immunoglobulin A levels in the gut are controlled by pIgR, which binds to IgA and transports it before it is deposited it into the inner layer of the intestine.
“Our study revealed a build-up of pIgR and IgA in the livers of patients with alcohol-related hepatitis, which is an indication of defects in IgA transport and secretion,” explained Hendrikx.
The researchers used several animal models to demonstrate that low levels of IgA in the intestines of mice aggravated alcohol-induced liver complications without pIgR. The blood of the mice without pIgR also exhibited evidence of increased bacterial translocation. The research team also found a molecular mechanism that can partially restore IgA levels in the intestine. This mechanism alleviated alcohol-induced liver disease in mice without pIgR.
Improvements in liver disease treatment are still needed
Alcohol-related liver diseases range from mild steatosis (accumulation of fat) to cirrhosis, which is one of the most common and deadly chronic liver diseases worldwide. Although significant progress has been made in liver disease treatment has been made, treatment of alcohol-related liver damage still needs much improvement. The researchers were keen to emphasise the need for a better understanding of the molecular mechanisms behind the development of liver disease.
“Our data show that dysfunction in pIgR in the liver exacerbates alcohol-related liver disease because the antimicrobial response through IgA in the gut is impaired. This means that enhancing pIgR in the liver or increasing the IgA levels in the intestine could be a promising starting point for novel treatment options for alcohol-related liver disease,” concluded Hendrikx.