Recovery of ethanol-induced <i>Akkermansia muciniphila</i> depletion ameliorates alcoholic liver disease.

Abstract

Alcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. <i>Akkermansia muciniphila</i>, a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of <i>A. muciniphila</i> administration on the course of ALD. The intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal <i>A. muciniphila</i> abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of <i>A. muciniphila</i> on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed. Patients with ASH exhibited a decreased abundance of faecal <i>A. muciniphila</i> when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in <i>A. muciniphila</i> abundance. Ethanol-induced intestinal <i>A. muciniphila</i> depletion could be restored by oral <i>A. muciniphila</i> supplementation. Furthermore, <i>A. muciniphila</i> administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. <i>A. muciniphila</i> also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, <i>A. muciniphila</i> used therapeutically ameliorated hepatic injury and neutrophil infiltration. Ethanol exposure diminishes intestinal <i>A. muciniphila</i> abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. <i>A. muciniphila</i> promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from <i>A. muciniphila</i> supplementation.