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Original Article
Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease
  1. Christoph Grander1,
  2. Timon E Adolph1,
  3. Verena Wieser1,
  4. Patrick Lowe2,
  5. Laura Wrzosek3,
  6. Benedek Gyongyosi2,
  7. Doyle V Ward4,5,
  8. Felix Grabherr1,
  9. Romana R Gerner1,
  10. Alexandra Pfister1,
  11. Barbara Enrich1,
  12. Dragos Ciocan3,6,7,
  13. Sophie Macheiner1,
  14. Lisa Mayr1,
  15. Matthias Drach8,
  16. Patrizia Moser9,
  17. Alexander R Moschen1,
  18. Gabriel Perlemuter3,6,7,
  19. Gyongyi Szabo2,
  20. Anne Marie Cassard3,6,
  21. Herbert Tilg1
  1. 1Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
  2. 2Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  3. 3Department of Inflammation, Chemokines and Immunopathology, INSERM UMR996, Clamart, France
  4. 4Center for Microbiome Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  5. 5Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  6. 6Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, CHU Bicêtre, Kremlin-Bicêtre, France
  7. 7AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère, Clamart, France
  8. 8Department of Dermatology, University Hospital Zürich, Zürich, Switzerland
  9. 9Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria
  1. Correspondence to Prof. Herbert Tilg, Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria; herbert.tilg{at}i-med.ac.at

Abstract

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.

  • Akkermansia muciniphila
  • alcoholic steatohepatitis
  • alcoholic liver disease
  • intestinal microbiota
  • gut barrier

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Footnotes

  • Contributors CG designed, performed and analysed most experiments together with VW, FG, BE, LW, PL, DVW, BG, DC, SM, LM and AP. MD performed histology analysis, and AMC, PM, RRG, ARM, GP, GS and TEA provided expertise. CG and TEA prepared the manuscript. HT coordinated the project.

  • Funding This work was supported by Christian Doppler Research Society (to HT). HT is supported by the excellence initiative (Competence Centers for Excellent Technologies) of the Austrian Research Promotion Agency FFG: Research Center of Excellence in Vascular Ageing Tyrol, VASCage (K:Project Nr. 843536) funded by the Bundesministerium für Verkehr, Inovation und Technologie (BMVIT), Bundesministerium für Wissenschaft, Forschung und Wirtschaft (BMWFW), the Wirtschaftsagentur Wien and the Standortagentur Tirol. TEA is supported by the Austrian Science Fund (FWF) P 29379:B28 and the Tyrolian Science Fund (TWF) 0404/1812. GS and PL were supported by R01 AA017729 from the National Institute on Alcoholism and Alcohol Abuse, USA.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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