• ALCOHOL-INDUCED INJURY
• INTESTINAL PERMEABILITY
• LIVER
• INFLAMMATION

Alcohol-associated liver disease (ALD) is a leading cause of chronic liver disease and liver-related mortality worldwide. The progression of ALD can range from simple fatty liver (steatosis) to severe liver damage, including alcohol-associated hepatitis (AH), liver fibrosis or cirrhosis, and hepatocellular carcinoma.1 Research over the past few decades has shown that the mechanisms behind the development of ALD are complex, involving multiple cellular factors and interactions between different organs. At the cellular level, alcohol and its metabolites, such as acetaldehyde, can lead to the production of reactive oxygen species, increase in endoplasmic reticulum stress, mitochondrial damage and megamitochondria formation, impaired autophagy-lysosomal functions, and the accumulation of Mallory-Denk bodies resulting in hepatocyte death and degeneration, as well as increased infiltration of immune cells, particularly neutrophils with high IL-8 expression.1 2 Consequently, these changes also contribute to an increased ductular reaction (DR) and cholestasis, fibrosis, along with the accumulation of hepatic progenitor and ductular cells in severe AH (SAH) patients.1 3 Furthermore, two distinct populations of SAH have been identified based on their unique histopathological characteristics. Patients with high levels of hepatic neutrophils but low levels of CD8⁺ T cells exhibited higher MELD scores and serum alanine aminotransferase levels, yet they had less fibrosis compared with those with low hepatic neutrophils but high CD8⁺ T cells.4 However, the specific role and mechanisms of intrahepatic CD8⁺ T cells in ALD remain unclear.

Besides cellular interactions in the liver, the communication between the gut and liver has been well documented at the organ-organ crosstalk level and is thought to play a significant role in the pathogenesis of ALD.5 The intestinal epithelium acts as an impermeable barrier, …