Targeting the gut-liver axis and gut microbiome in pediatric metabolic dysfunction-associated steatotic liver disease: current evidence and future directions.

UNLABELLED: Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in children, closely linked to the rising prevalence of childhood obesity and metabolic syndrome. Increasing evidence highlights the central role of the gut-liver axis and the gut microbiome in disease pathogenesis, offering potential targets for therapeutic modulation. This review aims to summarize current evidence on interventions targeting the gut-liver axis and the gut microbiome in pediatric MASLD and explore emerging strategies in this field. This narrative review was undertaken after searching PubMed and Embase databases for available up-to-date literature on pediatric MASLD and therapeutic interventions targeting the gut microbiome and gut-liver axis, including dietary therapy, prebiotics, probiotics, synbiotics, fecal microbiota transplantation (FMT), and pharmacological therapies. Dietary interventions, including low-free-sugar and Mediterranean-style diets, improve hepatic and metabolic outcomes, although microbiome-mediated benefits remain unproven in children. Probiotics and synbiotics show modest and variable effects, with heterogeneity in strains, dosing, and outcomes limiting definitive conclusions. Evidence for FMT in pediatric MASLD is absent, with only indirect evidence from adolescent obesity and other pediatric diseases. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and farnesoid X receptor agonists, have demonstrated metabolic and hepatic benefits primarily in adult populations, while effects on microbial metabolism, intestinal barrier integrity, and bile acid signalling provide potential mechanisms linking these therapies to the gut-liver axis. Although microbiome-mediated mechanisms have been proposed, direct evidence linking these therapies to microbiome changes in pediatric MASLD is currently lacking. Emerging approaches such as precision nutrition, engineered probiotics, and bacteriophage therapy offer potential avenues for targeted modulation of disease-relevant pathways.

CONCLUSION: Therapeutic modulation of the gut-liver axis and the gut microbiome represents a biologically plausible and evolving strategy in pediatric MASLD. Current pediatric evidence remains limited, and robust, well-designed clinical trials incorporating microbiome profiling and clinically meaningful endpoints are needed to establish efficacy and enable personalized, therapeutic strategies.

WHAT IS KNOWN: • Pediatric MASLD is increasing in prevalence, and alterations in the gut-liver axis and the gut microbiome are known to contribute to the pathogenesis of the disease by influencing various disease-relevant pathways such as intestinal permeability, bile acid signaling, hepatic lipid metabolism, inflammation, and fibrogenesis.

WHAT IS NEW: • This review provides current evidence for interventions targeting the gut microbiome and gut-liver axis in pediatric MASLD including dietary modulation, probiotics, and pharmacological interventions and highlights new approaches such as precision nutrition, engineered probiotics, bacteriophage therapy, and personalized treatment strategies.