Early life nutritional imbalance impairs colonic epithelial regeneration through gut microbiota dysbiosis and metabolic suppression

Childhood malnutrition represents a major global health burden that extends beyond caloric deficiency to include dietary imbalance. The early-life gut microbiome functions as a dynamic ecosystem whose structure and metabolic output are intimately linked to host development, yet how nutritional imbalance disrupts this ecosystem and its integration with the host remains poorly understood. Using an isocaloric but nutrient-imbalanced diet in a mouse model, we recapitulated chronic growth stunting and identified a systemic syndrome comprising growth retardation, oxidative stress, and immunosuppression. Gut microbiota dysbiosis was established as the central mediator of these pathological manifestations. Integrated multi-omics analyses revealed that nutritional imbalance compromised microbial community structure and function, reducing diversity and ecological stability whereas disrupting metabolic activity—particularly short-chain fatty acid (SCFA) production. Through single-cell RNA sequencing of colonic epithelium, we demonstrated that these microbial perturbations suppressed host energy metabolism and inhibited the Wnt/β-catenin signaling pathway in regenerative epithelial cells. This resulted in the downregulation of key stem cell regulators LGR5 and ASCL2, ultimately impairing epithelial renewal and manifesting as reduced crypt depth. Our findings reveal a microbiota-dependent mechanism linking dietary imbalance to impaired host development, demonstrating how nutritional stress disrupts gut microbial structure and metabolic output, ultimately compromising epithelial regeneration. This work highlights the importance of considering the gut microbiome as an ecosystem whose homeostasis is fundamental to early-life health.