Autonomous Ketone Body Synthesis Shapes the Morphogenic Profile of Neonatal Intestinal Epithelium

The intestinal epithelium undergoes significant maturation postnatally, yet its early-life characteristics remain poorly understood. Using single-cell RNA sequencing, we analyzed intestinal epithelial cells from neonatal (10-day-old) and juvenile (21-day-old) mice under both specific pathogen-free and germ-free conditions. Among the various cell types comprising the intestinal epithelium, we found that enterocytes in particular exhibit markedly different features between these stages. Enterocytes of neonatal mice have reduced expression of secretory intestinal defense-related genes independently of microbial conditions. These genes are upregulated in juvenile enterocytes in a microbiota-dependent manner. Conversely, neonatal enterocytes display significant upregulation of ketogenesis-related genes, with the produced ketone bodies contributing to cell morphogenesis rather than serving primarily as an energy source. These findings provide novel insights into early-life intestinal maturation and may have implications for understanding and preventing neonatal intestinal pathologies like necrotizing enterocolitis.