Serum cytokine patterns are modulated in infants fed formula with probiotics or milk fat globule membranes: A randomized controlled trial

Abstract

Background Proteins and lipids of milk fat globule membrane (MFGM) and probiotics are immunomodulatory. We hypothesized that Lactobacillus paracasei ssp. paracasei strain F19 (F19) would augment vaccine antibody and T helper 1 type immune responses whereas MFGM would produce an immune response closer to that of breastfed (BF) infants. Objective To compare the effects of supplementing formula with F19 or bovine MFGM on serum cytokine and vaccine responses of formula-fed (FF) and BF infants. Design FF infants were randomized to formula with F19 (n = 195) or MFGM (n = 192), or standard formula (SF) (n = 194) from age 21±7 days until 4 months. A BF group served as reference (n = 208). We analyzed seven cytokines (n = 398) in serum at age 4 months using magnetic bead-based multiplex technology. Using ELISA, we analyzed anti-diphtheria IgG (n = 258) and anti-poliovirus IgG (n = 309) concentrations in serum before and after the second and third immunization, respectively. Results Compared with SF, the F19 group had greater IL-2 and lower IFN-γ concentrations (p<0.05, average effect size 0.14 and 0.39). Compared with BF, the F19 group had greater IL-2, IL-4 and IL-17A concentrations (p<0.05, average effect size 0.42, 0.34 and 0.26, respectively). The MFGM group had lower IL-2 and IL-17A concentrations compared with SF (p<0.05, average effect size 0.34 and 0.31). Cytokine concentrations were comparable among the MFGM and BF groups. Vaccine responses were comparable among the formula groups. Conclusions Contrary to previous studies F19 increased IL-2 and lowered IFN-γ production, suggesting that the response to probiotics differs across populations. The cytokine profile of the MFGM group approached that of BF infants, and may be associated with the previous finding that infectious outcomes for the MFGM group in this cohort were closer to those of BF infants, as opposed to the SF group. These immunomodulatory effects support future clinical evaluation of infant formula with F19 or MFGM.

Metabolic Phenotype and Microbiome of Infants Fed Formula Containing Lactobacillus paracasei Strain F-19

“…For these subsets of infants, we did not find any difference in the frequency of antibiotic use or diarrheal episodes among groups. We observed significantly higher serum IFN-γ in the SF group compared to the BF and F19 groups, which is what was published previously for this cohort ( 30 ). For the subset of infants used for metabolomics, we also observed higher serum IL-2 (general T cell stimulation) in the F19 group compared to the BF group, but this was not significant for the subset of infants used for microbiota analysis (data not shown).…”

“…In the current study, we assessed the impact of supplementation with L. paracasei strain F19 in human infants on the microbiome and the metabolome. As reported previously for this cohort ( 29 , 30 ), no adverse effects of the F19 probiotic were observed in infants when the probiotic was consumed with a standard infant formula; however, a significant cytokine response at 4 months of age [higher IL-2 in the F19 group relative to BF, and lower IFN-γ in the F19 group relative to the SF group (with no difference to BF)] was observed ( 30 ). The reason for this difference could be due to the probiotic itself, the probiotic-modulated gut microbiota, and/or the probiotic and microbiota-associated metabolites that interact with immune cells and epithelial cells.…”

“…To understand if F19 has an ecological relationship with species of Bifidobacterium in the gut of formula-fed infants, future analyses of bacterial species and strains or metagenomics should be performed. Nonetheless, this is an important observation as bifidobacterial species in general have been shown to have many health benefits, including immunomodulatory effects ( 41 – 43 ), which could together with L. paracasei F19 drive some of the changes in the levels of IL-2 and/or IFN-γ reported previously in this cohort ( 30 ). It is interesting to note that similar observations were not observed in an infant cohort provided L. paracasei F19 as part of weaning foods ( 28 , 51 ), thus the changes observed here may be specific to early supplementation.…”

Brain–immune–gut benefits with early life supplementation of milk fat globule membrane

“…Multiple reports have associated the positive effects of different MFGM bioactive components (in human and bovine milk) with cognitive and immunity development of infants, without impairing their growth. [35][36][37][38][39][40][41] A randomized controlled trial (RCT) involving 160 healthy term infants <2 months old compared standard formula (SF) to a formula containing bovine MFGM (Lactoprodan MFGM-10, Arla Foods Ingredients) (experimental formula, EF). The infants were fed formula exclusively up to age 6 months, and followed up until 12 months.…”

Infant Formula Based on Milk Fat Affects Immune Development in Both Normal Birthweight and Fetal Growth Restricted Neonatal Piglets

“…In vitro, the constituents of the MFGM have been shown to inhibit leucocyte proliferation and production of several cytokines [ 14 , 15 , 16 ]. In infants, supplementing formula with MGFM has been shown to reduce production of interleukins 2 and 17 [ 17 ] and reduce the incidence of acute otitis media [ 18 ]. Also, the phospholipid fraction of the MFGM has been shown to act as immune signaling molecules, capable of inhibiting pro-inflammatory responses in vitro [ 19 ] as well as protect the gut from lipopolysaccharide-induced inflammation in vivo and modulate systemic immune system development [ 20 , 21 ].…”