Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease

被引：538

作者：

Grander, Christoph ^{[1
]}

Adolph, Timon E. ^{[1
]}

Wieser, Verena ^{[1
]}

Lowe, Patrick ^{[2
]}

Wrzosek, Laura ^{[3
]}

Gyongyosi, Benedek ^{[2
]}

Ward, Doyle V. ^{[4
,5
]}

Grabherr, Felix ^{[1
]}

Gerner, Romana R. ^{[1
]}

Pfister, Alexandra ^{[1
]}

Enrich, Barbara ^{[1
]}

Ciocan, Dragos ^{[3
,6
,7
]}

Macheiner, Sophie ^{[1
]}

Mayr, Lisa ^{[1
]}

Drach, Matthias ^{[8
]}

Moser, Patrizia ^{[9
]}

Moschen, Alexander R. ^{[1
]}

Perlemuter, Gabriel ^{[3
,6
,7
]}

Szabo, Gyongyi ^{[2
]}

Cassard, Anne Marie ^{[3
,6
]}

Tilg, Herbert ^{[1
]}

机构：

[1] Med Univ Innsbruck, Dept Internal Med Gastroenterol Endocrinol & Meta, A-6020 Innsbruck, Austria

[2] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA

[3] INSERM, UMR996, Dept Inflammat Chemokines & Immunopathol, Clamart, France

[4] Univ Massachusetts, Sch Med, Ctr Microbiome Res, Worcester, MA USA

[5] Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA USA

[6] Univ Paris Saclay, Univ Paris Sud, DHU Hepatinov, Labex Lermit,CHU Bicetre, Le Kremlin Bicetre, France

[7] Hop Antoine Beclere, AP HP, Hepatogastroenterol & Nutr, Clamart, France

[8] Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland

[9] Med Univ Innsbruck, Inst Pathol, Innsbruck, Austria

来源：

GUT | 2018年 / 67卷 / 05期

基金：

奥地利科学基金会;

关键词：

HEPATIC NEUTROPHIL INFILTRATION; INTESTINAL BARRIER; POSSIBLE MECHANISM; MOUSE MODEL; GUT; MICROBIOME; INJURY; STEATOHEPATITIS; PERMEABILITY; INFLAMMATION;

D O I：

10.1136/gutjnl-2016-313432

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Objective A lcoholic 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.

引用

页码：892 / +

页数：11

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