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

Christoph Grander, Timon E. Adolph, Verena Wieser, Patrick Lowe, Laura Wrzosek, Benedek Gyongyosi, Doyle V. Ward, Felix Grabherr, Romana R. Gerner, Alexandra Pfister, Barbara Enrich, Dragos Ciocan, Sophie Macheiner, Lisa Mayr, Matthias Drach, Patrizia Moser, Alexander R. Moschen, Gabriel Perlemuter, G. Szabó, Anne Marie CassardHerbert Tilg

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish
JournalGut
DOIs
Publication statusAccepted/In press - May 26 2017

Fingerprint

Alcoholic Liver Diseases
Ethanol
Alcoholic Fatty Liver
Neutrophil Infiltration
Mucus
Liver
Tight Junctions
Microbiota
Wounds and Injuries
Ribosomal DNA
DNA Sequence Analysis

Keywords

  • Akkermansia muciniphila
  • Alcoholic liver disease
  • Alcoholic steatohepatitis
  • Gut barrier
  • Intestinal microbiota

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Grander, C., Adolph, T. E., Wieser, V., Lowe, P., Wrzosek, L., Gyongyosi, B., ... Tilg, H. (Accepted/In press). Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut. https://doi.org/10.1136/gutjnl-2016-313432

Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. / Grander, Christoph; Adolph, Timon E.; Wieser, Verena; Lowe, Patrick; Wrzosek, Laura; Gyongyosi, Benedek; Ward, Doyle V.; Grabherr, Felix; Gerner, Romana R.; Pfister, Alexandra; Enrich, Barbara; Ciocan, Dragos; Macheiner, Sophie; Mayr, Lisa; Drach, Matthias; Moser, Patrizia; Moschen, Alexander R.; Perlemuter, Gabriel; Szabó, G.; Cassard, Anne Marie; Tilg, Herbert.

In: Gut, 26.05.2017.

Research output: Contribution to journalArticle

Grander, C, Adolph, TE, Wieser, V, Lowe, P, Wrzosek, L, Gyongyosi, B, Ward, DV, Grabherr, F, Gerner, RR, Pfister, A, Enrich, B, Ciocan, D, Macheiner, S, Mayr, L, Drach, M, Moser, P, Moschen, AR, Perlemuter, G, Szabó, G, Cassard, AM & Tilg, H 2017, 'Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease', Gut. https://doi.org/10.1136/gutjnl-2016-313432
Grander, Christoph ; Adolph, Timon E. ; Wieser, Verena ; Lowe, Patrick ; Wrzosek, Laura ; Gyongyosi, Benedek ; Ward, Doyle V. ; Grabherr, Felix ; Gerner, Romana R. ; Pfister, Alexandra ; Enrich, Barbara ; Ciocan, Dragos ; Macheiner, Sophie ; Mayr, Lisa ; Drach, Matthias ; Moser, Patrizia ; Moschen, Alexander R. ; Perlemuter, Gabriel ; Szabó, G. ; Cassard, Anne Marie ; Tilg, Herbert. / Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. In: Gut. 2017.
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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.",
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AU - Grander, Christoph

AU - Adolph, Timon E.

AU - Wieser, Verena

AU - Lowe, Patrick

AU - Wrzosek, Laura

AU - Gyongyosi, Benedek

AU - Ward, Doyle V.

AU - Grabherr, Felix

AU - Gerner, Romana R.

AU - Pfister, Alexandra

AU - Enrich, Barbara

AU - Ciocan, Dragos

AU - Macheiner, Sophie

AU - Mayr, Lisa

AU - Drach, Matthias

AU - Moser, Patrizia

AU - Moschen, Alexander R.

AU - Perlemuter, Gabriel

AU - Szabó, G.

AU - Cassard, Anne Marie

AU - Tilg, Herbert

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N2 - 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.

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KW - Alcoholic steatohepatitis

KW - Gut barrier

KW - Intestinal microbiota

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