The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota

Jérôme Boursier*, Olaf Mueller, Matthieu Barret, Mariana Machado, Lionel Fizanne, Felix Araujo-Perez, Cynthia D. Guy, Patrick C. Seed, John F. Rawls, Lawrence A. David, Gilles Hunault, Frédéric Oberti, Paul Calès, Anna Mae Diehl

*Corresponding author for this work

Research output: Contribution to journalArticle

239 Citations (Scopus)

Abstract

Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion: NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.

Original languageEnglish (US)
Pages (from-to)764-775
Number of pages12
JournalHepatology
Volume63
Issue number3
DOIs
StatePublished - Mar 1 2016

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Dysbiosis
Fibrosis
Ruminococcus
Bacteroides
Non-alcoholic Fatty Liver Disease
Gastrointestinal Microbiome
Prevotella
Encyclopedias
16S Ribosomal RNA
RNA Sequence Analysis
Biopsy
Metagenomics

ASJC Scopus subject areas

  • Hepatology

Cite this

Boursier, J., Mueller, O., Barret, M., Machado, M., Fizanne, L., Araujo-Perez, F., ... Diehl, A. M. (2016). The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology, 63(3), 764-775. https://doi.org/10.1002/hep.28356
Boursier, Jérôme ; Mueller, Olaf ; Barret, Matthieu ; Machado, Mariana ; Fizanne, Lionel ; Araujo-Perez, Felix ; Guy, Cynthia D. ; Seed, Patrick C. ; Rawls, John F. ; David, Lawrence A. ; Hunault, Gilles ; Oberti, Frédéric ; Calès, Paul ; Diehl, Anna Mae. / The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. In: Hepatology. 2016 ; Vol. 63, No. 3. pp. 764-775.
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abstract = "Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion: NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.",
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Boursier, J, Mueller, O, Barret, M, Machado, M, Fizanne, L, Araujo-Perez, F, Guy, CD, Seed, PC, Rawls, JF, David, LA, Hunault, G, Oberti, F, Calès, P & Diehl, AM 2016, 'The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota', Hepatology, vol. 63, no. 3, pp. 764-775. https://doi.org/10.1002/hep.28356

The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. / Boursier, Jérôme; Mueller, Olaf; Barret, Matthieu; Machado, Mariana; Fizanne, Lionel; Araujo-Perez, Felix; Guy, Cynthia D.; Seed, Patrick C.; Rawls, John F.; David, Lawrence A.; Hunault, Gilles; Oberti, Frédéric; Calès, Paul; Diehl, Anna Mae.

In: Hepatology, Vol. 63, No. 3, 01.03.2016, p. 764-775.

Research output: Contribution to journalArticle

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T1 - The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota

AU - Boursier, Jérôme

AU - Mueller, Olaf

AU - Barret, Matthieu

AU - Machado, Mariana

AU - Fizanne, Lionel

AU - Araujo-Perez, Felix

AU - Guy, Cynthia D.

AU - Seed, Patrick C.

AU - Rawls, John F.

AU - David, Lawrence A.

AU - Hunault, Gilles

AU - Oberti, Frédéric

AU - Calès, Paul

AU - Diehl, Anna Mae

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion: NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.

AB - Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion: NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.

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