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

中文翻译：

---

乙醇诱导的 Akkermansia muciniphila 耗竭的恢复可改善酒精性肝病

目的 酒精性肝病 (ALD) 是一个全球性的健康问题，治疗选择有限。肠道屏障完整性和微生物群调节对 ALD 的易感性。Akkermansia muciniphila 是一种革兰氏阴性肠道共生菌，部分通过增强粘液产生来促进屏障功能。本研究的目的是研究 ALD 中的微生物改变，并确定 A. muciniphila 给药对 ALD 病程的影响。设计 在 Lieber-DeCarli ALD 小鼠模型中通过 16S 核糖体 DNA (rDNA) 测序以无偏倚的方法分析肠道微生物群，并在一组酒精性脂肪性肝炎 (ASH) 患者中测定粪便 A. muciniphila 丰度。在预防和治疗环境中确定了 A. muciniphila 对实验性急性和慢性 ALD 发展的影响，并对肠道屏障完整性进行了分析。结果 与与肝病严重程度间接相关的健康对照相比，ASH 患者粪便中嗜粘液杆菌的丰度降低。野生型小鼠的乙醇喂养导致 A. muciniphila 丰度显着下降。乙醇诱导的肠道 A. muciniphila 消耗可以通过口服 A. muciniphila 补充剂来恢复。此外，在预防性环境中进行 A. muciniphila 给药可减少肝损伤、脂肪变性和中性粒细胞浸润。A. muciniphila 还可以防止乙醇引起的肠道渗漏、粘液厚度增加和紧密连接表达。在已经建立的 ALD 中，A. muciniphila 使用治疗性改善的肝损伤和嗜中性粒细胞浸润。结论 乙醇暴露减少了小鼠和人类肠道 A. muciniphila 丰度，并且可以通过口服补充在实验性 ALD 中恢复。A. muciniphila 促进肠道屏障完整性并改善实验性 ALD。我们的数据表明，ALD 患者可能受益于 A. muciniphila 补充剂。