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.

Fig 1. Study flow chart.

The figure was previously published in “Feeding infants formula with probiotics or milk fat globule membrane: A double-blind randomized controlled trial”. Li, et al. Front Pediatr 2019; 7:347.

Fig 2. Cytokine responses.

At 4 months of age cytokine concentrations were analyzed in 98 infants in the breastfed (BF) group, 99 infants in the standard formula (SF) group, 99 infants in the milk fat globule membrane (MFGM) group and 100 infants in the Lactobacillus F19 (F19) group. The MFGM group had lower IL-2 (p = 0.028, effect size 0.34) and IL-17A concentrations (p = 0.014, effect size 0.31) compared with SF. IL-2 concentrations were greater in the F19 compared with the SF group (p = 0.024, effect size 0.14) whereas the IFN-γ concentrations were lower (p = 0.008, effect size 0.39). Scatterplots show median, 25^th and 75^th percentile. *p<0.05 **p<0.005.