Multistage Metabolomic Analyses Reveal the Differential Effects of Infant Formula and Breast Milk on the Growth and Development of Human Small Intestinal Organoids

ABSTRACT The first 6 months of life are crucial for an infant's growth and gastrointestinal development. Proper nutrition is vital to support this maturation, especially considering the limited digestive capacity of infants at this stage. While breast milk is considered the optimal source, infant formula serves as an important alternative for mothers who cannot breastfeed. This study employed human embryonic stem cell‐derived small intestinal organoids (SIOs) to simulate neonatal intestinal digestion and nutrient absorption. Breast milk and different brands of infant formulas were subjected to in vitro digestion and subsequent SIO absorption. Metabolomics analysis was conducted at three stages: predigestion, postdigestion, and postabsorption. Significant differences were found in the metabolic profiles between breast milk and infant formulas at each developmental stage, indicating distinct nutrient processing and absorption patterns. The study highlights the metabolic and absorption variations between breast milk and formula during early infancy. These findings provide important insights into how different nutritional sources influence gastrointestinal development, offering valuable guidance for optimizing infant formula composition to better replicate the benefits of breast milk.