Scientists have now discovered how alcohol can switch off an immune "alarm system" in the gut, allowing bad bacteria to escape their natural habitat to flood into the liver, rapidly causing inflammation to the organ. This bacterial invasion is a key driver of the inflammation and injury seen in alcohol-associated liver disease (ALD).
Researchers from the University of California San Diego (UC San Diego) have newly identified this mechanism that explains why chronic alcohol use has such a damaging effect on the liver – and, importantly, they also demonstrate that this process can be reversed. This opens the door to targeted treatments to stop the damage caused by ALD, which claims around 28,000 lives each year in the US.
ALD is one of the most serious consequences of drinking, with the mortality rate worldwide nearly doubling over the past two decades. Despite this, there are no effective therapies beyond abstinence, and much about the disease’s underlying biology has remained poorly understood – until now.
When the researchers examined intestinal tissue from people with ALD, they found that activity of a key gut receptor, muscarinic acetylcholine receptor M4 (mAChR4), was significantly reduced compared to healthy controls. mAChR4 is like a surveillance system that, in normal circumstances, instructs goblet cells to build tiny cellular checkpoints, known as goblet-cell-associated antigen passages (GAPs). These GAPs allow small fragments of bacteria to pass through to immune cells in order for the system to keep an eye on microbes in the gut. When mAChR4 activity is suppressed, bacteria slip past the barrier and make their way into the liver, where they set off inflammation.
Essentially, alcohol switches off the mAChR4 receptor, dismantling the gut's border security that's in place to stop bad bacteria escaping, opening the floodgates direct to the liver.
In follow-up mice models that mimicked long-term alcohol use, the scientists showed that activity of the mAChR4 receptor dropped, the GAPs weren't able to form and bacteria escaped to build up in the liver. This invasion triggered inflammation and fat accumulation, recreating the hallmarks of ALD.
However, the researchers didn't just uncover this ALD pathway – they were able to block it. By stimulating another pathway – the IL-6 signaling pathway – they were able to switch mAChR4 back on inside goblet cells. With the receptor back in action, the gut once again formed GAPs, and the normal immune-cell sampling and monitoring of gut microbes was restored. This also prevented those bacteria from being able to escape to the liver.
In mice, this reset protected against the bacterial invasion and inflammation that drive ALD, suggesting a new therapeutic strategy for a condition that currently has no therapeutic intervention. What's more, with the liver no longer overrun with bacteria and the inflammatory responses they triggered, its natural repair capacity could also be restored, allowing it to heal from the damage it had incurred.
The study had its limitations – in particular, the findings came through mouse models and limited human samples – so long-term, large-scale human studies will be needed for the research to progress toward real-world ways to treat ALD.
"Despite these limitations, our study offers insights into the role of mAChR4-mediated GAP formation in promoting protective mucosal immunity to prevent ALD, thereby laying the foundation for future therapeutic innovations," the researchers wrote.
However, the findings also highlight the importance of the gut-immune connection in chronic illness. By showing that a single receptor on a specialized gut cell can result in organ damage elsewhere in the body, the study reveals how interconnected our systems are. It opens the door for therapies that target the gut’s communication with the immune system, rather than the liver itself, to treat alcohol-induced liver injury and disease.
"These findings establish GAPs as critical sentinel components of the gut–liver axis and underscore the importance of targeting mAChR4 as a potential interceptive strategy for ALD," the researchers noted.
Interestingly, the same receptor is also currently the target of neuroscience research. In the brain, it helps regulate communication between acetylcholine and dopamine – pathways that go awry in schizophrenia. Drug developers are testing compounds that boost mAChR4 activity as potential treatments for the cognitive symptoms of this disorder.
The research was published in the journal Nature.
