For decades, we have heard that excessive drinking creates liver disease that is mostly irreversible. However, the exact mechanisms through which alcohol accelerates liver damage remained unclear to scientists, that is till now. However, a 2025 research study discovered a fresh gut–liver pathway, which explains how chronic alcohol consumption damages liver tissue.A new findThe research team of Nature (PMID: 40836099), discovered that long-term alcohol consumption decreases the presence of muscarinic acetylcholine receptor M4 (mAChR4) in the small intestine. The receptor mAChR4 plays a vital role in maintaining gut bacterial control through its function in goblet cells, which line the intestinal tract.
The gut lining contains goblet cells which produce GAPs (goblet cell-associated antigen passages). The immune system receives training through GAPs, to identify and regulate gut bacteria. The reduction of mAChR4 by alcohol consumption prevents goblet cells from creating proper GAPs. Because of this, the immune system becomes less capable of handling gut bacteria because of this condition.What happens as a resultThe absence of GAPs creates an environment where bacteria from the gut can escape through the gut barrier, to reach the liver. The liver becomes more susceptible to damage, when bacteria enters its tissue after reaching this organ. The research demonstrated this process occurred in both human liver biopsy samples and laboratory animal experiments. The research demonstrated that alcohol consumption resulted in decreased mAChR4 expression, which led to impaired defense mechanisms against harmful gut bacteria entering the liver.The research established a direct link between alcohol consumption and liver damage through the following sequence of events.The small intestine contains lower levels of mAChR4, when people consume alcohol.The decrease in mAChR4 expression results in reduced goblet cell GAP production.The immune system loses its ability to control gut bacteria when GAPs become scarce.Bacteria from the gut escape through the damaged gut wall to enter the liver.The bacteria entering the liver through this process intensify both alcohol-induced liver inflammation, and steatohepatitis.
Related diseasesThe condition known as alcohol-associated liver disease, (ALD) encompasses different liver conditions which develop from prolonged alcohol consumption. The first stage of fatty liver disease known as steatosis, develops when liver cells store fat, but usually produces no noticeable symptoms. The progression of alcohol consumption leads to alcoholic steatohepatitis, which causes liver inflammation together with tissue damage. The progression of liver damage through fibrosis (scarring) eventually results in cirrhosis, which severely impairs liver function. The progression of cirrhosis results in liver failure, which creates dangerous complications that may require patients to receive a liver transplant. The research reveals how bacterial gut invasion leads to worsened inflammation and tissue damage in steatohepatitis and ALD stages, which creates new therapeutic possibilities to stop this destructive process.Potential for new treatmentsThe research demonstrated that GAP signaling restoration enables the immune system to fight bacterial infections effectively. The direct activation of mAChR4 in goblet cells of mice, protected their livers from alcohol-related damage. The discovery indicates that future medical treatments for alcohol-associated liver disease could focus on mAChR4, and its associated signaling pathways.Requires further testingMost of the research data however, stems from animal experiments together with limited human biopsy tissue analysis. The medical field lacks evidence about using mAChR4 or gp130 immune pathway treatments for patients with alcohol-related liver damage. Additional clinical trials must be conducted to determine if these innovative methods will work safely and effectively for liver protection in patients.
