Milk phospholipid-coated lipid droplets modulate the infant gut microbiota and metabolome influencing weight gain

Background: The supramolecular structure and composition of milk fat globules in breast milk is complex. Lipid droplets in formula milk are typically smaller compared to human milk and differ in their lipid and protein composition. These droplets play an important role in gut and immune maturation, and their components possess antimicrobial and antiviral properties. Here, the influence of a concept infant formula (IF) containing large milk phospholipid-coated lipid droplets on the maturation of the infant microbiota, metabolome, and weight gain in the first year of life was investigated. Results: Formula-fed infants were randomized to receive either a standard IF (Control) or a Test formula containing large milk phospholipid-coated lipid droplets (Test) until 17 weeks of age. A breast-fed Reference group was also investigated. At 3 months of age, several taxa identified as opportunistic pathogens (e.g., Enterobacter, Klebsiella, Enterococcus, Streptococcus) were less abundant in the Test stools compared to Control, while an enrichment of the butyrate-producing Ruminococcaceae and Lachnospiraceae was observed. These findings indicate that the Test formula resulted in gut microbiota maturation trajectories more comparable to healthy breast-fed infants. This was accompanied by variation in several fecal and plasma metabolites at 3 months of age related to gut microbial metabolism including bile acids, hippurate, phenylacetylglycine, trimethylamine, and various lipids and fatty acids. At 12 months, measures of subcutaneous fat and body mass index (BMI) were significantly higher in infants receiving standard IF compared to those receiving breast milk. However, this weight gain and adiposity was attenuated in the Test group infants. Conclusions: The presence of large phospholipid-coated lipid droplets in formula milk positively influenced the development of the infants’ gut microbiota, their metabolomic profiles, and their body composition to more closely resemble breast-fed infants compared to standard IF. These droplets may further enhance the restriction of pathogenic bacteria seen with standard infant formula and suggest a potential impact on infant metabolic programming that may contribute to physiological development. ^{7v6PFTcmWWdyMsjsLchbsCVideo Abstract}.