Targeting gut signaling protein may protect against alcohol-related liver damage

Alcohol-associated liver disease (ALD) is a major cause of liver transplantation and death worldwide, and its impact is only growing. In 2022, the annual cost of ALD in the United States was $31 billion. By 2040, this number could be as high as $66 billion. ALD has limited therapeutic options, so scientists are looking for new ways to target the molecular biology of ALD to help prevent its occurrence or reduce its severity.

Now, scientists at University of California San Diego School of Medicine have found that chronic alcohol use impairs the production of a key cellular signaling protein that helps keep gut bacteria within the gut. Without this guardrail in place, bacteria from the gut can more easily migrate to the liver, exacerbating liver damage caused by alcohol. Targeting this mechanism with existing drugs could provide one approach to minimizing the liver damage from alcohol use and reducing the burden of ALD.

Studying a combination of human liver biopsies and mouse models of ALD, the researchers found:

• Chronic alcohol use reduced the expression of muscarinic acetylcholine receptor M4 (mAChR4), a key cellular communication protein in the gut.
• Reduced mAChR4 expression hindered the formation of goblet cell-associated antigen passages (GAPs), specialized structures that teach the immune system to promote antimicrobial immunity, thereby preventing harmful bacteria from migrating to the liver.
• Restoring mAChR4 function, either by chemically activating mAChR4 or by targeting related signaling pathways allowed GAPs to form and conferred resistance to ALD.

While the researchers focused on the role of mAChR4 in the gut, this cellular signaling protein is also known to play a critical role in sections of the brain that regulate habits, learning and addiction. This treatment approach may also have wider implications for alcohol-related disorders, because the expression of mAChR4 is known to be lower in the brains of patients with alcohol use disorder (AUD). Drugs that target mAChR4 are currently in clinical trials for schizophrenia, and the researchers suggest that these drugs could be readily repurposed for ALD and AUD. However, further research is required to demonstrate this potential.

The study, published in the journal Nature, was led by Cristina Llorente, Ph.D., Michael Karin, Ph.D., and Bernd Schnabl, M.D., at UC San Diego School of Medicine. The study was funded, in part, by the National Institutes of Health (grants R01 AA029106, R21 AA030654, P30 AR073761, D34 HP31027, P50 AA011999) and the American Association for the Study of Liver Diseases (award 8998GA). Bernd Schnabl has consulted for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen, and Takeda. He is also the founder of Nterica Bio.