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Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic
Jeffrey B Schwimmer1, Jethro S Johnson2, Jorge E Angeles3
1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California; Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California.
Insights
The intestinal microbiome in children with nonalcoholic fatty liver disease (NAFLD) shows reduced diversity and specific bacterial changes linked to disease severity. These gut microbiome alterations may indicate NAFLD progression and serve as diagnostic markers.
Area of Science:
- Pediatric Gastroenterology
- Microbiome Research
- Hepatology
Background:
- Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in children.
- The intestinal microbiome's role in NAFLD development and severity is under investigation.
Purpose of the Study:
- To analyze and compare the fecal microbiomes of children with and without NAFLD.
- To identify specific microbial and functional alterations associated with NAFLD and its severity in pediatric populations.
Main Methods:
- Prospective, observational, cross-sectional study of 87 children with NAFLD and 37 controls.
- 16S rRNA amplicon and metagenomic shotgun sequencing of fecal samples.
- Analysis of microbial taxa and bacterial pathways using statistical modeling and gene set enrichment analysis.
Main Results:
- Children with NAFLD exhibited lower fecal microbiome alpha-diversity compared to controls.
- Nonalcoholic steatohepatitis (NASH) was associated with the lowest alpha-diversity.
- Increased Prevotella copri abundance correlated with more severe fibrosis; lipopolysaccharide biosynthesis genes were enriched in NASH microbiomes.
- Models incorporating liver enzymes and specific microbial genes accurately identified NASH and fibrosis severity.
Conclusions:
- Pediatric NAFLD and NASH are associated with intestinal dysbiosis.
- Gut microbiome alterations, including increased inflammatory bacterial products, may contribute to NAFLD pathogenesis.
- Intestinal microbiome profiles could serve as potential biomarkers for NAFLD diagnosis and severity assessment.
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.
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