New Research Explains How Alcohol Inhibits Gut Health

Alcohol-associated liver disease (ALD) is a leading cause of liver transplantation and mortality globally, and its effect is only increasing. In 2022, the yearly cost of ALD in the United States was $31 billion. By 2040, the figure may be as high as $66 billion. ALD has limited therapeutic options; thus, scientists are exploring novel strategies to address its molecular biology to either prevent or minimize its severity.

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Researchers at the University of California, San Diego School of Medicine have discovered that prolonged alcohol consumption inhibits the development of a crucial cellular signaling protein that helps retain gut bacteria in the gut.

Without this barrier, bacteria from the gut can more easily travel to the liver, worsening the damage caused by alcohol. Targeting this pathway with current medications could represent one method to limit liver damage from alcohol use and lower the burden of ALD.

Using a combination of human liver biopsies and mouse models of ALD, the researchers discovered:

• Chronic alcohol use lowered the expression of the muscarinic acetylcholine receptor M4 (mAChR4), an important cellular communication protein in the gut
• Reduced mAChR4 expression inhibited the creation of goblet cell-associated antigen passages (GAPs), which are specialized structures that train the immune system to increase antimicrobial immunity, preventing harmful bacteria from moving to the liver
• Restoring mAChR4 function, by either chemically stimulating mAChR4 or targeting associated signaling pathways, enabled GAP formation and provided resistance to ALD

While the researchers concentrated on the significance of mAChR4 in the gut, this cellular signaling protein is also known to play an important role in brain regions that control habits, learning, and addiction. This therapeutic strategy could potentially have broader implications for alcohol-related diseases, as mAChR4 expression is known to be reduced in the brains of people with alcohol use disorder (AUD).

According to the researchers, drugs that target mAChR4 are presently undergoing clinical trials for schizophrenia and can be easily adapted for ALD and AUD. To prove this possibility, more investigation is necessary.