Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease

Jeffrey B. Schwimmer, Jethro S. Johnson, Jorge E. Angeles, Cynthia Behling, Patricia H. Belt, Ingrid Borecki, Craig Bross, Janis Durelle, Nidhi P. Goyal, Gavin Hamilton, Mary L. Holtz, Joel E. Lavine, Makedonka Mitreva, Kimberly P. Newton, Amy Pan, Pippa M. Simpson, Claude B. Sirlin, Erica Sodergren, Rahul Tyagi, Katherine P. YatesGeorge M. Weinstock, Nita H. Salzman

Research output: Contribution to journalArticle

Abstract

Background & Aims: The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. Methods: We performed a prospective, observational, cross-sectional study of 87 children (age range, 8–17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. Results: Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-D-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). Conclusions: In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.

Original languageEnglish (US)
Pages (from-to)1109-1122
Number of pages14
JournalGastroenterology
Volume157
Issue number4
DOIs
StatePublished - Oct 2019

Fingerprint

Microbiota
Fatty Liver
Fibrosis
Genes
Non-alcoholic Fatty Liver Disease
Alanine Transaminase
ROC Curve
Lipopolysaccharides
Dysbiosis
Prevotella
16S Ribosomal RNA
RNA Sequence Analysis
Metagenomics
Pediatric Obesity
Firearms
Protein Biosynthesis

Keywords

  • Flagellin
  • Intestinal Microbiota
  • Lipopolysaccharide
  • Pediatric

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Schwimmer, J. B., Johnson, J. S., Angeles, J. E., Behling, C., Belt, P. H., Borecki, I., ... Salzman, N. H. (2019). Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology, 157(4), 1109-1122. https://doi.org/10.1053/j.gastro.2019.06.028

Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. / Schwimmer, Jeffrey B.; Johnson, Jethro S.; Angeles, Jorge E.; Behling, Cynthia; Belt, Patricia H.; Borecki, Ingrid; Bross, Craig; Durelle, Janis; Goyal, Nidhi P.; Hamilton, Gavin; Holtz, Mary L.; Lavine, Joel E.; Mitreva, Makedonka; Newton, Kimberly P.; Pan, Amy; Simpson, Pippa M.; Sirlin, Claude B.; Sodergren, Erica; Tyagi, Rahul; Yates, Katherine P.; Weinstock, George M.; Salzman, Nita H.

In: Gastroenterology, Vol. 157, No. 4, 10.2019, p. 1109-1122.

Research output: Contribution to journalArticle

Schwimmer, JB, Johnson, JS, Angeles, JE, Behling, C, Belt, PH, Borecki, I, Bross, C, Durelle, J, Goyal, NP, Hamilton, G, Holtz, ML, Lavine, JE, Mitreva, M, Newton, KP, Pan, A, Simpson, PM, Sirlin, CB, Sodergren, E, Tyagi, R, Yates, KP, Weinstock, GM & Salzman, NH 2019, 'Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease', Gastroenterology, vol. 157, no. 4, pp. 1109-1122. https://doi.org/10.1053/j.gastro.2019.06.028
Schwimmer, Jeffrey B. ; Johnson, Jethro S. ; Angeles, Jorge E. ; Behling, Cynthia ; Belt, Patricia H. ; Borecki, Ingrid ; Bross, Craig ; Durelle, Janis ; Goyal, Nidhi P. ; Hamilton, Gavin ; Holtz, Mary L. ; Lavine, Joel E. ; Mitreva, Makedonka ; Newton, Kimberly P. ; Pan, Amy ; Simpson, Pippa M. ; Sirlin, Claude B. ; Sodergren, Erica ; Tyagi, Rahul ; Yates, Katherine P. ; Weinstock, George M. ; Salzman, Nita H. / Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. In: Gastroenterology. 2019 ; Vol. 157, No. 4. pp. 1109-1122.
@article{4886ac900be341318638925f7ab50de5,
title = "Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease",
abstract = "Background & Aims: The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. Methods: We performed a prospective, observational, cross-sectional study of 87 children (age range, 8–17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. Results: Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-D-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). Conclusions: In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.",
keywords = "Flagellin, Intestinal Microbiota, Lipopolysaccharide, Pediatric",
author = "Schwimmer, {Jeffrey B.} and Johnson, {Jethro S.} and Angeles, {Jorge E.} and Cynthia Behling and Belt, {Patricia H.} and Ingrid Borecki and Craig Bross and Janis Durelle and Goyal, {Nidhi P.} and Gavin Hamilton and Holtz, {Mary L.} and Lavine, {Joel E.} and Makedonka Mitreva and Newton, {Kimberly P.} and Amy Pan and Simpson, {Pippa M.} and Sirlin, {Claude B.} and Erica Sodergren and Rahul Tyagi and Yates, {Katherine P.} and Weinstock, {George M.} and Salzman, {Nita H.}",
year = "2019",
month = "10",
doi = "10.1053/j.gastro.2019.06.028",
language = "English (US)",
volume = "157",
pages = "1109--1122",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease

AU - Schwimmer, Jeffrey B.

AU - Johnson, Jethro S.

AU - Angeles, Jorge E.

AU - Behling, Cynthia

AU - Belt, Patricia H.

AU - Borecki, Ingrid

AU - Bross, Craig

AU - Durelle, Janis

AU - Goyal, Nidhi P.

AU - Hamilton, Gavin

AU - Holtz, Mary L.

AU - Lavine, Joel E.

AU - Mitreva, Makedonka

AU - Newton, Kimberly P.

AU - Pan, Amy

AU - Simpson, Pippa M.

AU - Sirlin, Claude B.

AU - Sodergren, Erica

AU - Tyagi, Rahul

AU - Yates, Katherine P.

AU - Weinstock, George M.

AU - Salzman, Nita H.

PY - 2019/10

Y1 - 2019/10

N2 - Background & Aims: The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. Methods: We performed a prospective, observational, cross-sectional study of 87 children (age range, 8–17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. Results: Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-D-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). Conclusions: In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.

AB - Background & Aims: The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. Methods: We performed a prospective, observational, cross-sectional study of 87 children (age range, 8–17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. Results: Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-D-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). Conclusions: In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.

KW - Flagellin

KW - Intestinal Microbiota

KW - Lipopolysaccharide

KW - Pediatric

UR - http://www.scopus.com/inward/record.url?scp=85072272749&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072272749&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2019.06.028

DO - 10.1053/j.gastro.2019.06.028

M3 - Article

C2 - 31255652

AN - SCOPUS:85072272749

VL - 157

SP - 1109

EP - 1122

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -