Abstract
BACKGROUND: Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. OBJECTIVE: We examined the regulation of intestinal and intrahepatic CD8(+) T lymphocytes and their contribution to ALD. DESIGN: ALD patients were recruited for evaluation of intestinal and liver T cells. Single-cell RNA sequencing (scRNA seq) was performed to analyse intrahepatic and peripheral T cells in ALD. Wildtype, CD8-specific Bcl2 transgenic (Cd8 (Bcl-2)), and Cd8 (-/-) mice were subjected to chronic-plus-binge ethanol feeding. RESULTS: In ALD patients, duodenal CD8(+) T cells were selectively reduced and negatively correlated with liver injury and bacterial translocation markers, while intrahepatic CD8(+) T cells were markedly increased. ScRNA seq analysis of ALD patient livers revealed several populations of CD8(+) T cells expressing activation and survival genes (eg, Bcl2). Transcriptomics and functional studies revealed a key role of prosurvival BCL2 in this opposite regulation of CD8(+) T cells. Mechanistically, chronic-plus-binge ethanol feeding reduced CD8(+) T cells specifically in the duodenum where ethanol levels are high. Inducing BCL2 in CD8(+) T cells reversed ethanol-induced loss of duodenal CD8(+) T cells, improved gut barrier function and ameliorated ALD, while CD8 deficiency was linked to enhanced neutrophil and macrophage infiltration in the liver, exacerbating ALD in mice. CONCLUSIONS: ALD is associated with loss of duodenal CD8(+) T cells but elevation of intrahepatic CD8(+) T cells, which aggravates and ameliorates ALD, respectively. Restoration of survival and functions of intestinal and intrahepatic CD8(+) T cells may represent a novel therapeutic strategy for ALD patients.