Pediatric MASH Linked to Distinct Changes in the Gut Microbiome

Long before liver enzymes rise or fibrosis becomes visible on imaging, subtle changes in the gut may already be signaling disease progression in children living with obesity.¹ New evidence suggests that shifts in the intestinal microbiome track closely with worsening liver pathology, offering potential clues for earlier identification of metabolic dysfunction–associated steatohepatitis (MASH) in pediatric populations.²

In a meta-analysis published in Gut Microbes, investigators pooled shotgun metagenomic sequencing data to examine how gut microbial composition differed among children with obesity alone, metabolic dysfunction–associated steatotic liver disease (MASLD), and MASH, compared with healthy peers.

The work addressed a key gap in pediatric hepatology: Although MASLD is now the most common chronic liver disease in children, factors that drive progression to MASH remain poorly defined, and most microbiome data have come from adults.

The researchers systematically identified 9 prior studies and combined them with a newly recruited cohort from Austria, yielding a pediatric sample of 413 individuals. Of these, 281 were children with obesity, including 153 with MASLD and 70 with MASH, and 132 were healthy controls. Median ages ranged from 9 years in the control group to 13 years among those with obesity or MASLD, and median body mass index values exceeded 30 in all disease groups. Liver enzyme levels rose stepwise with disease severity, with median alanine aminotransferase values increasing from 21 U/L in children with obesity to 48.6 U/L in MASLD and 63.1 U/L in MASH.

Using standardized bioinformatic pipelines, the investigators found that overall microbial richness was significantly reduced in children with MASH compared with healthy controls, children with obesity, and those with MASLD (Bonferroni-corrected P < .001 for all comparisons). Differences in community composition were also pronounced: beta diversity analyses showed that gut microbial profiles differed across all groups, suggesting progressive dysbiosis as liver disease advanced.

At the taxonomic level, children with MASLD and MASH showed consistent alterations in key bacterial groups. The relative abundance of Faecalibacterium prausnitzii, a species often linked to gut barrier integrity and anti-inflammatory effects, was lower in children with MASLD and MASH than in those with obesity alone. In contrast, Prevotella copri increased with disease severity and was more abundant in children with MASH and in those with more advanced fibrosis. The authors also observed that microbial composition varied with fibrosis stage, with distinct patterns emerging even among children with the same diagnosis.

To assess whether these microbial differences could distinguish disease states, the team applied machine learning approaches. Models based on microbial species abundance accurately discriminated MASLD from obesity, achieving an area under the receiver operating characteristic curve (AUROC) of 87%, and MASH from MASLD, with an AUROC of 89%. Pathway-based models using microbial metabolic functions performed similarly. According to the investigators, “The gut microbial composition is increasingly altered with the progression of MASLD toward MASH,” underscoring the potential of microbiome-derived markers to reflect disease severity.

Functional analyses supported these findings. Pathways involved in short-chain fatty acid production, including butyrate and propionate synthesis, were reduced in children with MASLD and MASH compared with those with obesity. Conversely, pathways related to secondary bile acid synthesis were more abundant in MASH, aligning with prior evidence that bile acid metabolism plays a role in liver inflammation and fibrosis. These functional shifts suggested that microbiome changes were not merely compositional but may have metabolic consequences relevant to disease progression.

The study also compared pediatric and adult MASH cohorts and found marked differences between age groups, even at similar fibrosis stages. Machine learning models distinguished pediatric from adult MASH with an AUROC of 97%, indicating that microbial signatures of liver disease may be age-specific. This finding highlights the importance of pediatric-focused research rather than extrapolating from adult data.

Several limitations tempered the conclusions. The analysis relied on retrospective data drawn from heterogeneous international cohorts, with overrepresentation of certain ethnic groups, particularly Chinese and Hispanic populations. Dietary information was limited, and causal inferences could not be made. In addition, the lack of an external validation cohort constrained assessment of the predictive models’ generalizability.

Despite these constraints, the authors emphasized the clinical relevance of their findings. By integrating high-resolution sequencing with advanced analytics, the study suggested that gut microbiome features could serve as noninvasive biomarkers of MASLD progression in children. The results also reinforce the potential role of diet-based or microbiome-targeted interventions early in life, when the gut ecosystem may be more adaptable.

As therapies for MASH continue to emerge, understanding which children are most likely to experience progression—and why—may be essential for targeting prevention strategies and optimizing long-term outcomes.

References

1. Ting Y-W, Wong S-W, Zaini AA, Mohamed R, Jalaludin MY. Metabolic syndrome is associated with advanced liver fibrosis among pediatric patients with non-alcoholic fatty liver disease. Front Pediatr. 2019;7:491. doi:10.3389/fped.2019.00491

2. Zöggeler T, Kavallar AM, Pollio AR, et al. Meta-analysis of shotgun sequencing of gut microbiota in obese children with MASLD or MASH. Gut Microbes. 2025;17(1):2508951. doi:10.1080/19490976.2025.2508951