Faculty Collaboration Database

Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019 Oct;157(4):1109-1122

Date

07/01/2019

Pubmed ID

31255652

Pubmed Central ID

PMC6756995

DOI

10.1053/j.gastro.2019.06.028

Scopus ID

2-s2.0-85072272749 (requires institutional sign-in at Scopus site)   265 Citations

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.

Author List

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

Authors

Amy Y. Pan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Nita H. Salzman MD, PhD Center Director in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Bacteria
Case-Control Studies
Child
Cross-Sectional Studies
DNA, Bacterial
Dysbiosis
Feces
Female
Gastrointestinal Microbiome
Host-Pathogen Interactions
Humans
Intestines
Liver Cirrhosis
Male
Metagenome
Non-alcoholic Fatty Liver Disease
Prospective Studies
RNA, Ribosomal, 16S
Ribotyping
Severity of Illness Index