Gut microbiota and health-related quality of life in paediatric inherited metabolic disorders: a narrative review and conceptual framework.

Inherited metabolic disorders (IMDs) comprise more than 1,400 rare genetic conditions affecting paediatric patients worldwide. Despite advances in newborn screening and dietary management, many children experience chronic complications, gastrointestinal symptoms, and reduced health-related quality of life (HRQoL). Emerging evidence-predominantly from phenylketonuria (PKU)-suggests that gut microbiota may influence metabolic homeostasis and patient-centred outcomes in affected children. Because of substantial methodological heterogeneity and the rarity of individual disorders, we elected a narrative review format to synthesise current evidence rather than a formal quantitative synthesis. Electronic searches were performed in PubMed, Embase, and Web of Science from inception to February 2026. We synthesise current evidence regarding gut microbiota composition in major paediatric IMDs, including PKU, organic acidemias, glycogen storage diseases, lysosomal storage disorders, and mitochondrial diseases. For PKU, controlled studies report reduced microbial diversity and depletion of butyrate-producing taxa associated with long-term dietary treatment. For the remaining disorders, direct paediatric microbiome data are sparse or absent, and proposed links rely on mechanistic extrapolation from non-IMD populations. We present the gut microbiota-metabolism-quality of life axis as a conceptual framework that integrates microbial metabolites, intestinal barrier function, immune signalling, and patient-reported outcomes, while emphasising that direct causal evidence linking microbiota alterations to HRQoL in paediatric IMDs is currently lacking. Microbiota-directed interventions remain preliminary. Future multicentre longitudinal studies integrating microbiome profiling, multi-omics technologies, and validated patient-reported outcomes are needed to clarify causal mechanisms and therapeutic potential. Importantly, the available evidence is heterogeneous: direct paediatric microbiome evidence is strongest for PKU, whereas evidence for other IMDs is sparse and often observational, preclinical, or extrapolated from non-IMD populations. The proposed microbiota-metabolism-HRQoL axis is therefore presented as a hypothesis-generating framework rather than an established causal pathway.