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, The Jackson Laboratory
Rahul Tyagi
Katherine P Yates
George M. Weinstock, The Jackson Laboratory
Nita H Salzman


BACKGROUND & AIMS: The intestinal microbiome might affect 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 (8-17 years old) 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 rRNA 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 controls (3.32 vs 3.52; P=.016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had lowest α-diversity (controls, 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 NASH (P

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 pathogenesis of NAFLD and be used as markers of disease or severity.