GUT MICROBIOME DYSBIOSIS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE: FROM FOUNDATIONAL 16S EVIDENCE TO SHOTGUN METAGENOMICS AND A DEVELOPMENTAL INSTABILITY FRAMEWORK

Abstract

Pediatric inflammatory bowel disease (IBD) frequently emerges during periods of active immune maturation and microbiome assembly, suggesting that age at disease onset fundamentally shapes host–microbe interactions and disease architecture. Here, we synthesize evidence from foundational 16S rRNA and pediatric shotgun metagenomic studies, integrating taxonomic, functional, and host genetic findings into a developmental instability framework for interpreting dysbiosis in early-onset disease. Across independent pediatric cohorts, particularly in Crohn’s disease, a reproducible dysbiosis signature has emerged, characterized by reduced alpha diversity, depletion of major short-chain fatty acid (SCFA)-producing obligate anaerobes, including Faecalibacterium, Roseburia, and Blautia, and expansion of facultative anaerobes, especially members of the Enterobacteriaceae. Building on these compositional observations, shotgun metagenomic studies provide species- and strain-level resolution together with direct functional characterization, revealing pathway-level remodelling that includes reduced butyrate biosynthetic potential, disrupted bile acid and tryptophan metabolism, and altered nitrogen and amino acid metabolism. Longitudinal investigations further demonstrate coordinated ecological restructuring during exclusive enteral nutrition and biologic therapy, while mucosal datasets consistently reveal stronger host–microbe coupling than stool profiles alone. Host genetic variants in NOD2, ATG16L1, IL23R, CARD9, and FUT2 further shape microbial ecosystem development through distinct biological mechanisms whose frequencies and effects vary across ancestries, providing a biological rationale for population-specific pediatric cohorts, including those from Saudi Arabia and the broader Middle East. Collectively, these findings support a developmental instability framework in which inflammation arises within an incompletely stabilized immune microbiome ecosystem shaped in parallel by host genotype. Future longitudinal, compartment-resolved, age-stratified, and genotype-informed multi-omics studies will be essential to clarify causal relationships and identify therapeutic windows for precision microbiome-based interventions.