IgE: novel target to treat alcohol-associated liver disease

Unhealthy nutrition and excessive alcohol consumption results in the accumulation of fat in the liver (steatosis), which may further progress to more severe liver damage and dysfunction in fibrosis and end-stage liver disease (cirrhosis), the 12th leading cause of death worldwide. In fact, approximately half of all deaths of patients with cirrhosis are due to alcohol abuse. Currently, the underlying mechanisms by which alcohol contributes to liver injury are largely unknown. Hence, therapeutic options for alcohol-associated liver disease are poor. An important role in developing alcohol-related liver disease has been proposed for bacteria in the gut. Trillions of microbes colonize the human gut and a noble interaction between our body and these bacteria is necessary to stay healthy. A disruption of this balance in the gut has been associated with alcoholic liver disease. Moreover, alcohol might destroy the intestinal barrier, leading to the invasion of harmful bacteria into the bloodstream by which they reach the liver and cause damage. Importantly, in order to protect against invading bacteria, our body produces antibodies, called immunoglobulins, which exist in different types that can recognize and bind bacteria to remove them. Interestingly, studies in humans and mouse models of alcohol-associated liver disease indicate that alcohol intake greatly affects antibody levels in the blood. Particularly, it has been reported that patients with alcohol- related liver disease have increased immunoglobulin type E (IgE) titers in the blood. Furthermore, IgE levels were shown to decrease when patients stopped drinking alcohol, suggesting a strong correlation between alcohol consumption and IgE antibody production. Yet, a profound characterization and functional studies that describe the contribution of IgE antibodies to the development and progression of alcohol-associated liver disease are lacking. In this project, using state-of-the-art methods and appropriate feeding models to genetically altered mice, the researchers will investigate how alcohol intake causes high amounts of IgE, and whether this is good (protective) or bad (harmful) for the onset of alcohol-induced fatty liver disease. This highly innovative research will provide insights and generate new ideas related to the underlying pathology of alcohol-associated liver disease. Ultimately, this will lead to the identification of promising key factors involved in the disease, and the generation of translatable evidence for targeting these factors as therapy options to prevent or treat the progression of alcohol-associated liver disease.

Excessive alcohol consumption can cause progressive liver damage, from fat accumulation and inflammation in the liver to irreversible scarring (cirrhosis). Treatment options remain limited, particularly in advanced disease, highlighting the need for new therapeutic approaches. People with alcohol-related liver disease often have elevated blood levels of immunoglobulin E (IgE), the antibody best known for its role in allergic reactions, where it can cause life-threatening effects. This project investigated whether IgE is more than a bystander and actively contributes to liver injury. The team found that alcohol-induced disruption of the gut barrier and microbiome triggers an allergy-like immune response in the intestine, leading to increased IgE production. Experiments in mice showed that IgE worsens alcohol-related liver injury by activating immune cells and promoting inflammation, with basophils emerging as important contributors. Patient data support the relevance of these findings: IgE levels were elevated in alcohol-related liver disease, correlated with disease severity and began to decline within two weeks of alcohol cessation. Intestinal samples also showed immune signals consistent with the mechanism identified in mice. Importantly, blocking and reducing IgE protected mice against alcohol-induced liver injury, suggesting a potential new treatment strategy. As medicines targeting IgE are already approved for certain allergic diseases, this pathway could offer an opportunity to repurpose existing therapies. Yet, further investigation of treatments targeting the cells responsible for releasing inflammatory mediators are still required. Together, these findings reveal an unexpected connection between gut damage, allergic inflammation and alcohol-related liver injury. The work identifies IgE as a potential therapeutic target, although further studies in patients are needed to establish its clinical significance and determine whether IgE-targeted treatments can prevent or reduce liver injury. Reducing or stopping alcohol consumption remains essential to limiting further damage. The team is completing its final experiments and preparing the findings for publication. Future studies will evaluate potential treatments and investigate the role of IgE in larger patient cohorts, and aim to identify the mechanisms by which IgE secretion is promoted in liver disease, and what molecules they recognize, thereby enhancing inflammation.