Impact of Extensively Hydrolyzed Infant Formula on Circulating Lipids During Early Life

Abstract

Background: Current evidence suggests that the composition of infant formula (IF) affects the gut microbiome, intestinal function, and immune responses during infancy. However, the impact of IF on circulating lipid profiles in infants is still poorly understood. The objectives of this study were to (1) investigate how extensively hydrolyzed IF impacts serum lipidome compared to conventional formula and (2) to associate changes in circulatory lipids with gastrointestinal biomarkers including intestinal permeability.

Methods: In a randomized, double-blind controlled nutritional intervention study (n = 73), we applied mass spectrometry-based lipidomics to analyze serum lipids in infants who were fed extensively hydrolyzed formula (HF) or conventional, regular formula (RF). Serum samples were collected at 3, 9, and 12 months of age. Child's growth (weight and length) and intestinal functional markers, including lactulose mannitol (LM) ratio, fecal calprotectin, and fecal beta-defensin, were also measured at given time points. At 3 months of age, stool samples were analyzed by shotgun metagenomics.

Results: Concentrations of sphingomyelins were higher in the HF group as compared to the RF group. Triacylglycerols (TGs) containing saturated and monounsaturated fatty acyl chains were found in higher levels in the HF group at 3 months, but downregulated at 9 and 12 months of age. LM ratio was lower in the HF group at 9 months of age. In the RF group, the LM ratio was positively associated with ether-linked lipids. Such an association was, however, not observed in the HF group.

Conclusion: Our study suggests that HF intervention changes the circulating lipidome, including those lipids previously found to be associated with progression to islet autoimmunity or overt T1D.

Clinical trial registration: [Clinicaltrials.gov], identifier [NCT01735123].

Keywords: early life; extensively hydrolyzed infant formula; intestinal permeability; lipidome; lipidomics; metabolomics.

FIGURE 1

An overview of the study setting. Serum samples for lipidomic analysis were obtained from the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity: Potential Mechanisms (EDIA) study which is a small-scale intervention trial comparing weaning infants onto an extensively hydrolyzed milk formula vs. a conventional cow’s milk-based formula. The study groups were matched by human leucocyte (HLA)-associated diabetes risk and period of birth. For each child, longitudinal samples were obtained corresponding to the ages of 3, 9, and 12 months. These age groups were selected with the objective of understanding the longitudinal lipid profiles in infants change after ingesting extensively hydrolyzed infant formula or conventional regular infant formula. Only, those children with information about amount of study formula per day were included in the data analysis.

FIGURE 2

Comparison of lipidome between the infants who consumed an extensively hydrolyzed milk formula vs. a conventional cow’s milk-based formula. (A) Total lipid concentration differences in each lipid class between the intervention groups. (B) Box plot showing selected lipid species representative of lipid classes that change at 3, 9, and 12 months of age when comparing the study groups. Here, HF stands for extensively hydrolyzed infant formula and RF for conventional regular infant formula.

FIGURE 3

Associations between serum lipids and gastrointestinal markers in the infants. (A) Comparison of lactulose mannitol ratio between HF vs. RF infants at 9 months of age. (B) Pairwise Spearman correlations as calculated between serum lipids and offspring gut inflammation marker and permeability. Here, FBD stands for fecal beta-defensin and FCP for fecal calprotectin. Correlations were calculated between simultaneous measurements at 9 months of age. Positive correlations marked in red, inverse correlations marked in blue. Dot size for each pairwise correlation corresponds to the strength of the calculated correlation.