Lower-cholesterol formula feeding alters the early-life cholesterol-bile acid axis in neonatal piglets

Abstract Infancy is a period of rapid growth with high cholesterol demand, yet vegetable oil-based infant formulas provide substantially less cholesterol than mammalian milk. To characterize metabolic adaptations associated with lower cholesterol formula feeding, we performed a pathway-focused transcriptomic analysis, supported by targeted metabolomics, in neonatal piglets comparing formula-fed and sow-fed groups. Formula feeding consistently induced upregulation of SREBF2 -associated cholesterol biosynthetic genes in liver and ileum, along with altered expression of genes involved in cholesterol transport and lipoprotein assembly. Bile acid biosynthesis and transport pathways were also upregulated, reflecting a compensatory response favoring bile acid production and conservation. Despite this, luminal bile acid concentrations were reduced, accompanied by lower intestinal FGF19 signaling and reduced jejunal expression of genes involved in fatty-acid uptake and lipid processing. Together, these findings indicate that lower-cholesterol formula feeding triggers an early-life adaptive response along the cholesterol-bile acid axis, suggesting that dietary cholesterol warrants attention as a component of infant formula.