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Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease
Open accessAbstract
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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“MASH fibrosis is linked to a unique gut microbiome (193-197), and specific microbiome signatures can distinguish human MASH from MASLD (4, 198, 199).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [195]
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Peter‐Marske, K. M., Zhang, X., Wang, T., Liu, X., Fernandes, G. F., Engel, S. S., & Shankar, R. R. (2025) · PLoS ONE · doi:10.1371/journal.pone.0334971
“Due to the need for a liver biopsy to definitively diagnose MASH [16,17], data on pediatric MASH patients are limited to single-center, tertiary care settings, or multi-center specialty networks [18–20].”
Liu, X., Liu, D., Tan, C., & Feng, W. (2023) · Figshare · doi:10.6084/m9.figshare.24873066
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Huang, Y., Ye, Z., Li, X., Xu, R., Yu, Y., Yu, R., Xu, F., Zhao, X., Chen, X., Liu, C., et al. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1752300
“MASLD-associated gut dysbiosis and increased intestinal permeability may facilitate the translocation of bacterial products (e.g., lipopolysaccharides) into the circulation, contributing to systemic inflammation that aects both hepatic and pulmonary compartments (33).”
Nair, B., Kamath, A. J., Devan, A. R., Gopalakrishna, R., Unni, A. R., & Nath, L. R. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1773294
“In children, these microbial alterations increase the person-to-person variability and promote inflammation that contributes to liver injury, even when the overall metagenomic gene abundance remains unchanged (36).”
When sweetness overflows: fructose influences microbial and metabolic dysregulation
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Muniraj, A., Elango, S. V., Iyer, M., Rani, M. R., Vinayagam, S., Gnanasekaran, L., Yadav, M. K., Rao, K. R. S. S., Vellingiri, B., Mukherjee, A. G., et al. (2026) · Comprehensive physiology · doi:10.1002/cph4.70220 · Cited by 1
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“…antibiotic-resistant organisms, or transferring metabolically active donors whose profiles may be incompatible with IMD metabolic constraints—necessitate rigorous screening and gnotobiotic validation in animal models prior to clinical application (Barati et al., 2024; Schwimmer et al., 2019).”
Gut Microbial Topology and Metabolic Signatures Associated With Colorectal Neoplasia
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Gut microbiota shaping fatty liver disease progression
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Gut microbiome profiles associated with simple liver steatosis in MASLD
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Metadata
- Authors
- Schwimmer, J. B., Johnson, J. S., Angeles, J. E., Behling, C., Belt, P. H., Borecki, I., Bross, C., Durelle, J., Goyal, N. P., Hamilton, G., Holtz, M. L., Lavine, J. E., Mitreva, M., Newton, K. P., Pan, A., Simpson, P. M., Sirlin, C. B., Sodergren, E., Tyagi, R., Yates, K. P., Weinstock, G. M., & Salzman, N. H.
- Affiliations
- University of California San Diego (US)
- The Jackson Laboratory for Genomic Medicine (US)
- Sharp Memorial Hospital (US)
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- Medical College of Wisconsin (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Salzman, Nita H.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 157
- Issue
- 4
- Pages
- 1109-1122
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6756995
- OpenAlex
- W2953761756
- Cited by
- 298
- References
- 58
- Citations by year
- 2026: 31 · 2025: 37 · 2024: 41 · 2023: 54 · 2022: 32 · 2021: 56 · 2020: 40 · 2019: 6
- FWCI
- 11.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- School of Medicine, University of California, San Diego
- Office of Extramural Research, National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, gut microbiota, fecal microbiota, Prevotella copri, lipopolysaccharide biosynthesis, flagellar assembly, dysbiosis, alpha diversity, alanine aminotransferase, children, obesity, disease severity markers, 16S rRNA
- MeSH terms
- Gastrointestinal Microbiome, Adolescent, Bacteria, Child, Cross-Sectional Studies, DNA, Bacterial, Feces, Female, Humans, Intestines, Liver Cirrhosis, Male, Prospective Studies, RNA, Ribosomal, 16S, Severity of Illness Index, Case-Control Studies, Ribotyping, Host-Pathogen Interactions, Metagenome, Dysbiosis, Non-alcoholic Fatty Liver Disease
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