In the US, the most common reason why someone needs a liver transplant is alcohol-associated liver disease (ALD). In 2019, this illness was estimated to be responsible for the loss of 11 million life-years worldwide and the burden of ALD continues to grow. Scientists are trying to learn more about this disease, and are looking for new ways to treat it. Reporting in Nature, researchers have now gained new insights into the mechanisms underlying ALD.
In this study, the investigators determined that chronic alcohol intake disrupts the production of a protein that ensures gut microbes and the molecules they produce are sequestered in the gut. Problems in the gut lining have been linked to a variety of health problems. The levels of this protein, known as muscarinic acetylcholine receptor M4 (mAChR4), were reduced after chronic alcohol exposure; this finding was confirmed in a mouse model as well as human liver biopsies.
Lower levels of mAChR4 impaired the formation of structures called goblet cell-associated antigen passages (GAPs), which help the immune system ‘learn’ to fight microbial pathogens, and protect the liver from gut bacteria that could migrate there.
When mAChR4 function was boosted, the researchers found that GAPs could form normally, and ALD risk was reduced.
This study was analyzing mAChR4 in the gut. But this protein is also expressed in parts of the brain that are known to help control addiction, learning, and habit formation.
Previous work has shown that mAChR4 levels are reduced in alcohol use disorder (AUD) patients, so these findings could be relevant to disorders like alcoholism.
There are also mAChR4-targeting drugs that are now being tested in clinical trials; these trials are meant to assess how well these drugs schizophrenia. If they are found to be safe and effective, it may be possible to use them to treat ALD and AUD as well. More research will be needed to determine whether that could work.
Sources: University of California - San Diego, Nature