Background Despite global progress, infectious diarrhea remains a leading cause of under‐five mortality, with burdens unevenly distributed across ages and regions. Moving beyond traditional epidemiology, there is an urgent need to translate population‐level trends into actionable, biologically informed strategies. This study analyzes the global burden to identify high‐risk populations and define age‐specific etiological profiles, thereby creating a foundational map for targeted multiomics research and biomarker‐driven interventions. Methods Utilizing Global Burden of Disease (GBD) 2021 data from 204 countries and territories, we assessed the incidence, mortality, and death probability of infectious diarrhea in children under five, stratified by age, region, and sociodemographic index (SDI). Temporal trends from 1990 to 2021 were analyzed using estimated annual percentage change (EAPC) and joinpoint regression. A detailed pathogen‐attributable burden analysis was performed, elucidating age‐varying etiologies. These epidemiological patterns were framed to highlight critical gaps where multiomics approaches (e.g., gut microbiome, host immune response profiling) and subsequent biomarker discovery could elucidate underlying biological mechanisms of age‐specific susceptibility and pathogen dominance. Results In 2021, neonates (< 28 days) bore the highest burden. Mortality declined slowest among children aged 6–11 months (EAPC = −4.2%). Rotavirus persisted as the primary lethal pathogen. A critical transition was observed: The second‐leading cause of death shifted from adenovirus in infants (before 6–11 months) to Shigella in older children (after 12–23 months), with the proportional mortality attributable to Shigella, norovirus, and cholera increasing markedly after 12 months of age. This precise etiological mapping identifies distinct biological and immunological epochs in early childhood, each presenting unique targets for biomarker identification and mechanism‐based intervention. Conclusion This analysis clarifies the global and age‐stratified burden of pediatric infectious diarrhea, moving from descriptive statistics toward a framework for precision public health. The defined age–etiology transitions provide a direct rationale for applying multiomics technologies to discover the host and microbial biomarkers underlying these patterns. Integrating such biomarkers with demographic data can transform current “age‐tailored” guidelines into truly individualized risk prediction, vaccine strategy optimization, and targeted antimicrobial stewardship. Concurrently, our age‐specific characterization of pathogen transitions provides epidemiological evidence to optimize age‐specific management of childhood infectious diarrhea and to identify priority populations for intervention in resource‐limited settings, ultimately advancing more effective and personalized clinical and preventive care for vulnerable children.
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