Heavy alcohol consumption is a leading cause of gastrointestinal diseases, with binge drinking linked to increased intestinal permeability—a condition commonly known as "leaky gut." Despite the significant health impact of alcohol-associated gastrointestinal disorders, effective pharmacological treatments remain limited. A new study published in eGastroenterology explores the role of gut cannabinoid receptor 1 (CB1R) in alcohol binge-induced intestinal permeability and reveals how its inhibition can help protect the gut barrier.
The research, conducted by scientists from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) at the National Institutes of Health (NIH), demonstrates that alcohol bingeing increases endocannabinoid levels in the proximal small intestine, triggering CB1R activation in intestinal epithelial cells. This activation disrupts tight junction proteins, which generally maintain the integrity of the gut lining, leading to increased intestinal permeability. This process can allow harmful substances, such as bacteria and toxins, to enter the bloodstream, contributing to inflammation and other health complications.
To investigate the role of CB1R, the researchers developed genetically modified mice with intestinal epithelial-specific CB1R deletion (CB1IEC−/− mice). They found that alcohol bingeing significantly increased gut permeability in normal mice, but this effect was absent in CB1IEC−/− mice, indicating that CB1R is a key mediator of alcohol-induced leaky gut.
Additionally, the study examined the effects of pharmacological CB1R inhibition using a peripherally restricted CB1R antagonist (S)-MRI-1891. When administered to normal mice before alcohol bingeing, this compound successfully prevented the increase in intestinal permeability. However, the drug had no effect in CB1IEC−/− mice, further confirming that CB1R in the intestinal epithelium is responsible for alcohol-induced gut barrier disruption.
Mechanistic studies revealed that CB1R activation in the gut epithelium triggers the ERK1/2 signalling pathway, which leads to the downregulation of tight junction proteins and a reduction in villus length—key factors contributing to a leaky gut. By inhibiting CB1R, researchers could reverse these changes, restoring gut barrier function and improving overall gut health.
These findings hold significant implications for the treatment of alcohol-related digestive disorders. Currently, there are no FDA-approved drugs specifically designed to treat alcohol-induced intestinal permeability. The study suggests that targeting CB1R with peripherally restricted antagonists could provide a novel therapeutic approach, potentially preventing systemic inflammation and other complications associated with alcohol-induced gut barrier dysfunction.
These insights could have broader applications in gastrointestinal health beyond alcohol-related gut disorders. The endocannabinoid system is known to influence gut motility, immune function, and microbiota composition, and its role in intestinal permeability suggests that CB1R inhibition may be beneficial in other conditions characterized by increased gut permeability, such as inflammatory bowel disease and metabolic disorders.
However, the study also highlights some limitations. While CB1R inhibition effectively prevented alcohol-induced leaky gut, it did not significantly impact metabolic parameters or liver disease progression. This suggests that although a leaky gut contributes to alcohol-related health issues, other mechanisms are also at play in the development of liver disease and metabolic dysfunction.
Future research will explore whether combining CB1R inhibitors with other therapeutic strategies could offer more comprehensive protection against alcohol-induced organ damage. Additionally, further studies are needed to assess the long-term safety and efficacy of CB1R antagonists in clinical settings.
This groundbreaking study advances our understanding of the gut's response to alcohol and opens new avenues for targeted therapies. By identifying CB1R as a crucial mediator of alcohol-induced intestinal permeability, researchers have paved the way for potential pharmacological interventions that could help mitigate the harmful effects of binge drinking on gut health.
See the article:
Luca Maccioni, Szabolcs Dvorácskó, Grzegorz Godlewski, Resat Cinar, Malliga R Iyer, Bin Gao, George Kunos - Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability: eGastroenterology 2025;3:e100173.
https://doi.org/10.1136/egastro-2024-100173
About eGastroenterology
eGastroenterology is a new, open-access, and open peer-reviewed BMJ Journal, which focuses on basic, clinical, translational, and evidence-based medicine research in all areas of gastroenterology (including hepatology, pancreatology, esophagology, and gastrointestinal surgery). eGastroenterology is now indexed by PubMed, Scopus, CAS, DOAJ, Dimensions, OpenAlex, ROAD, and COPE, with more to come!
