Linear programming–based structural lipid optimization of preterm infant formula enhances growth, lipid metabolism, and organ development in preterm rats

Preterm birth (<37 weeks) is a major global health challenge, and optimal nutrition is critical for reducing growth restriction, metabolic disorders, and impaired neurodevelopment. Human milk (HM) provides unique lipid structures, notably sn-2 palmitic acid-enriched triacylglycerols (TAGs), which promote efficient fat absorption and physiological development. However, most commercial preterm infant formulas (IFs) lack these structural features due to reliance on vegetable oils. This study compared lipidomic profiles of commercial IFs with preterm HM, focusing on fatty acid composition, sn-2 fatty acid distribution, TAG species, and phospholipids. A linear programming model was applied to coordinately optimize multiple lipid dimensions and design an optimized formula (DF), enriched in OPO and OPL, with higher sn-2 palmitic acid and lower OOO and OPP compared with IFs. Validation in a preterm rat model showed that DF improved body growth, intestinal villus development, and liver–kidney maturation relative to IF. DF also reduced visceral fat accumulation, improved lipid distribution, and alleviated hepatic burden. Serum analysis indicated lower triglycerides and low-density lipoprotein cholesterol (LDL-C), elevated insulin-like growth factor (IGF-1) and growth hormone, and preserved liver function. Digestive product analysis further revealed enhanced retention of polyunsaturated fatty acids at the sn-2 position as 2-monoacylglycerols, promoting absorption while reducing fecal saturated fatty acid–calcium soaps. These findings demonstrate that multidimensional structural lipid optimization, particularly enrichment of sn-2 palmitic acid and HM-like TAGs, represents a promising approach for next-generation preterm formulas to better align with HM and support metabolic health in preterm infants.