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1.
Serum cytokine patterns are modulated in infants fed formula with probiotics or milk fat globule membranes: A randomized controlled trial.
Li, X, Peng, Y, Li, Z, Christensen, B, Heckmann, AB, Lagerqvist, C, Stenlund, H, Lönnerdal, B, Hernell, O, West, CE
PloS one. 2021;(5):e0251293
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.
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A randomized controlled trial of different young child formulas on upper respiratory and gastrointestinal tract infections in Chinese toddlers.
Leung, TF, Ulfman, LH, Chong, MKC, Hon, KL, Khouw, IMSL, Chan, PKS, Delsing, DJ, Kortman, GAM, Bovee-Oudenhoven, IMJ
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2020;(7):745-754
Abstract
BACKGROUND Bioactive proteins and human milk oligosaccharides (HMOs), important ingredients in breast milk, that protect against infections are lacking in young child formula (YCF). This study investigated the effects of new YCFs on respiratory and gastrointestinal infections in toddlers. METHODS Four hundred and sixty one healthy Chinese children aged 1-2.5 years were recruited in this randomized, controlled, double-blind, parallel-group clinical trial of different YCFs. They were randomly assigned to either standard milk formula (YCF-Ref) or one of three new YCFs containing bioactive proteins and/or the HMO 2'-fucosyllactose (2'-FL) and/or milk fat for six months. Primary outcomes were incidence of upper respiratory tract infection (URTI) and duration of gastrointestinal tract infections (GITI). RESULTS There were no significant between-group differences in primary outcomes. For secondary outcomes, subjects receiving 2'-FL-supplemented YCF had longer URTI. Subjects receiving YCF supplemented with milk fat and intact bioactive proteins, and 2'-FL at levels found in breast milk, had more GITI episodes and shorter time to first GITI but similar effects on URTI duration than YCF-Ref recipients. No effects on URTI and GITI were observed in toddlers receiving YCF with bioactive proteins at lower levels than breast milk. Occurrence of adverse events and anthropometry were similar in all groups. CONCLUSIONS All three YCFs supplemented with different combinations of intact bioactive proteins, 2'-FL, and milk fat are safe in toddlers. No difference is detected among YCFs on URTI incidence and GITI duration. Further studies are needed to verify these findings especially in infants who may benefit most from the immune-boosting effects of bioactive proteins and HMOs.
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Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development.
Wopereis, H, Sim, K, Shaw, A, Warner, JO, Knol, J, Kroll, JS
The Journal of allergy and clinical immunology. 2018;(4):1334-1342.e5
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Abstract
BACKGROUND Development of the gut microbiota in infancy is important in maturation of the immune system. Deviations in colonization patterns have been associated with allergic manifestations such as eczema, but exact microbiome dysfunctions underlying allergies remain unclear. We studied the gut microbiota of 138 infants at increased risk of allergy, participating in a clinical trial investigating the effectiveness of a partially hydrolyzed protein formula supplemented with nondigestible oligosaccharides on the prevention of eczema. OBJECTIVE The effects of interventions and breast-feeding on fecal microbiota were investigated. Additionally, we aimed to identify microbial patterns associated with the onset of eczema. METHODS Bacterial taxonomic compositions in the first 26 weeks of life were analyzed by using 16S rRNA gene sequencing. Additionally, fecal pH and microbial metabolite levels were measured. RESULTS Fecal microbial composition, metabolites, and pH of infants receiving partially hydrolyzed protein formula supplemented with nondigestible oligosaccharides was closer to that of breast-fed infants than that of infants receiving standard cow's milk formula. Infants with eczema by 18 months showed discordant development of bacterial genera of Enterobacteriaceae and Parabacteroides species in the first 26 weeks, as well as decreased acquisition of lactate-utilizing bacteria producing butyrate, namely Eubacterium and Anaerostipes species, supported by increased lactate and decreased butyrate levels. CONCLUSIONS We showed that a partially hydrolyzed protein infant formula with specific prebiotics modulated the gut microbiota closer to that of breast-fed infants. Additionally, we identified a potential link between microbial activity and onset of eczema, which might reflect a suboptimal implementation of gut microbiota at specific developmental stages in infants at high risk for allergy.
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Effects of osteopontin-enriched formula on lymphocyte subsets in the first 6 months of life: a randomized controlled trial.
West, CE, Kvistgaard, AS, Peerson, JM, Donovan, SM, Peng, YM, Lönnerdal, B
Pediatric research. 2017;(1):63-71
Abstract
BackgroundHuman milk is rich in osteopontin (OPN), which has immunomodulatory functions.MethodsIn a randomized controlled trial, standard formula (SF) and the same formula with 65 mg of OPN/L (F65) or 130 mg of OPN/L (F130), representing ~50 and 100% of the OPN concentration in human milk, were compared. We examined frequencies and composition of peripheral blood immune cells by four-color immunoflow cytometry of formula-fed infants at ages 1, 4, and 6 months, and compared them with a breastfed (BF) reference group.ResultsThe F130 group had increased T-cell proportions compared with the SF (P=0.036, average effect size 0.51) and F65 groups (P=0.008, average effect size 0.65). Compared with the BF group, the monocyte proportions were increased in the F65 (P=0.001, average effect size 0.59) and F130 (P=0.006, average effect size 0.50) groups, but were comparable among the formula groups.ConclusionOPN in an infant formula at a concentration close to that of human milk increased the proportion of circulating T cells compared with both SF and formula with added OPN at ~50% of the concentration in human milk. This suggests that OPN may favorably influence immune ontogeny in infancy and that the effects appear to be dose-dependent.
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Reduction of Arachidonate Is Associated With Increase in B-Cell Activation Marker in Infants: A Randomized Trial.
Miklavcic, JJ, Larsen, BM, Mazurak, VC, Scalabrin, DM, MacDonald, IM, Shoemaker, GK, Casey, L, Van Aerde, JE, Clandinin, MT
Journal of pediatric gastroenterology and nutrition. 2017;(3):446-453
Abstract
BACKGROUND Infants who are not breast-fed benefit from formula with both docosahexaenoic acid (C22:6n3) and arachidonic acid (ARA; C20:4n6). The amount of ARA needed to support immune function is unknown. Infants who carry specific fatty acid desaturase (FADS) polymorphisms may require more dietary ARA to maintain adequate ARA status. OBJECTIVE The aim of the study was to determine whether ARA intake or FADS polymorphisms alter ARA levels of lymphocytes, plasma, and red blood cells in term infants fed infant formula. METHODS Infants (N = 89) were enrolled in this prospective, double-blind controlled study. Infants were randomized to consume formula containing 17 mg docosahexaenoic acid and 0, 25, or 34 mg ARA/100 kcal for 10 weeks. Fatty acid composition of plasma phosphatidylcholine and phosphatidylethanolamine, total fatty acids of lymphocytes and red blood cells, activation markers of lymphocytes, and polymorphisms in FADS1 and FADS2 were determined. RESULTS Lymphocyte ARA was higher in the 25-ARA formula group than in the 0- or 34-ARA groups. In plasma, 16:0/20:4 and 18:0/20:4 species of phosphatidylcholine and phosphatidylethanolamine were highest and 16:0/18:2 and 18:0/18:2 were lowest in the 34-ARA formula group. In minor allele carriers of FADS1 and FADS2, plasma ARA content was elevated only at the highest level of ARA consumed. B-cell activation marker CD54 was elevated in infants who consumed formula containing no ARA. CONCLUSIONS ARA level in plasma is reduced by low ARA consumption and by minor alleles in FADS. Dietary ARA may exert an immunoregulatory role on B-cell activation by decreasing 16:0/18:2 and 18:0/18:2 species of phospholipids. ARA intake from 25 to 34 mg/100 kcal is sufficient to maintain cell ARA level in infants across genotypes.
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Similar to Those Who Are Breastfed, Infants Fed a Formula Containing 2'-Fucosyllactose Have Lower Inflammatory Cytokines in a Randomized Controlled Trial.
Goehring, KC, Marriage, BJ, Oliver, JS, Wilder, JA, Barrett, EG, Buck, RH
The Journal of nutrition. 2016;(12):2559-2566
Abstract
BACKGROUND Evidence suggests that human milk oligosaccharides (HMOs) provide multiple benefits to infants, including prebiotic effects, gut maturation, antimicrobial activities, and immune modulation. Clinical intervention studies with HMOs are required to confirm these benefits in infants. OBJECTIVE Our objective was to investigate the effects of feeding formulas supplemented with the HMO 2'-fucosyllactose (2'-FL) on biomarkers of immune function in healthy term infants. METHODS We performed a substudy nested within a randomized, double-blind, controlled growth and tolerance study in healthy singleton infants (birth weight ≥2490 g) who were enrolled by 5 d of life and exclusively formula-fed (n = 317) or breastfed (n = 107) from enrollment to 4 mo of age. Formula-fed infants were randomly assigned to receive 1 of 3 formulas, all containing 2.4 g total oligosaccharides/L [control: galacto-oligosaccharides (GOS) only; experimental formulas: GOS + 0.2 or 1.0 g 2'-FL/L], and compared with a breastfed reference group. For this substudy, blood samples were drawn from infants at 6 wk of age (n = 31-42/group). Peripheral blood mononuclear cells (PBMCs) were isolated for cellular phenotyping and stimulated ex vivo with phytohemagglutinin for proliferation and cell cycle progression or respiratory syncytial virus (RSV). Cytokine concentrations were measured in plasma and in ex vivo-stimulated culture supernatants. RESULTS Breastfed infants and infants fed either of the experimental formulas with 2'-FL were not different but had 29-83% lower concentrations of plasma inflammatory cytokines than did infants fed the control formula [interleukin (IL) receptor antagonist (IL-1ra), IL-1α, IL-1β, IL-6, and tumor necrosis factor α (TNF-α)] (P ≤ 0.05). In ex vivo RSV-stimulated PBMC cultures, breastfed infants were not different than either of the groups fed formula with 2'-FL, but they had lower concentrations of TNF-α (31%) and interferon γ (IFN-γ 54%) (P ≤ 0.05) and tended to have lower IL-1ra (25%) and IL-6 (38%) (unadjusted P ≤ 0.05) and IL-1β (30%) (unadjusted P = 0.06) than did infants fed the control formula. CONCLUSIONS Our data indicate that infants fed formula supplemented with 2'-FL exhibit lower plasma and ex vivo inflammatory cytokine profiles, similar to those of a breastfed reference group. This trial was registered at clinicaltrials.gov as NCT01808105.
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Effects of short-chain fructooligosaccharides on faecal bifidobacteria and specific immune response in formula-fed term infants: a randomized, double-blind, placebo-controlled trial.
Paineau, D, Respondek, F, Menet, V, Sauvage, R, Bornet, F, Wagner, A
Journal of nutritional science and vitaminology. 2014;(3):167-75
Abstract
The aim of this study was to evaluate the effect of an infant formula supplemented with short-chain fructooligosaccharides (scFOS) on faecal concentration of bifidobacteria. Sixty-one healthy formula-fed infants participated in this double-blind controlled trial and were randomized to receive either the scFOS-supplemented formula (4 g/L scFOS) or the placebo-supplemented formula (4 g/L maltodextrins) until the age of 4 mo. Stool samples were analyzed for bifidobacteria at enrolment and at the age of 2 and 3 mo and for antipoliovirus IgA at the age of 4 mo. Parents completed a questionnaire to assess digestive tolerance. Change in faecal bifidobacteria after 2 mo were higher with scFOS compared to the placebo. At 4 mo, specific IgA tended to be higher with the scFOS group than with the placebo. Somatic growth and digestive tolerance were similar between groups. This study confirms that scFOS-supplemented formula can increase the concentration of faecal bifidobacteria while being well tolerated.
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A fermented formula in pre-term infants: clinical tolerance, gut microbiota, down-regulation of faecal calprotectin and up-regulation of faecal secretory IgA.
Campeotto, F, Suau, A, Kapel, N, Magne, F, Viallon, V, Ferraris, L, Waligora-Dupriet, AJ, Soulaines, P, Leroux, B, Kalach, N, et al
The British journal of nutrition. 2011;(12):1843-51
Abstract
Intestinal bacterial colonisation in pre-term infants is delayed compared with full-term infants, leading to an increased risk of gastrointestinal disease. Modulation of colonisation through dietary supplementation with probiotics or prebiotics could decrease such a risk. The present study evaluated clinical tolerance, the effects on gut microbiota, and inflammatory and immunological mucosal responses to an infant formula adapted for pre-term infants that included in its manufacturing process a fermentation step with two probiotic strains, Bifidobacterium breve C50 and Streptococcus thermophilus 065, inactivated by heat at the end of the process. A total of fifty-eight infants (gestational age: 30-35 weeks), fed either the fermented pre-term formula or a standard pre-term formula, were followed up during their hospital stay. Clinical tolerance, faecal microbiota using a culture and a culture-independent method (temporal temperature gel electrophoresis), faecal calprotectin and secretory IgA were analysed weekly. No difference was observed regarding anthropometric data and digestive tolerance, except for abdominal distension, the incidence of which was lower in infants fed the fermented formula for 2 weeks. Bacterial colonisation was not modified by the type of feeding, particularly for bifidobacteria. Faecal calprotectin was significantly lower in infants fed the fermented formula for 2 weeks, and secretory IgA increased with both mother's milk and the fermented formula. The fermented formula was well tolerated and did not significantly modulate the bacterial colonisation but had benefits on inflammatory and immune markers, which might be related to some features of gastrointestinal tolerance.
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Effect of providing a formula supplemented with long-chain polyunsaturated fatty acids on immunity in full-term neonates.
Field, CJ, Van Aerde, JE, Robinson, LE, Clandinin, MT
The British journal of nutrition. 2008;(1):91-9
Abstract
To determine the effect of feeding formula containing long-chain PUFA (LCP) on immune function, healthy term infants were randomised at age 2 weeks to either a standard term formula (Formula; n 14) or the same formula supplemented with the LCP 20 : 4n-6 and 22 : 6n-3 (Formula+LCP; n 16). Peripheral blood was collected at 2 and 6 weeks to measure immune cell response (the rate of [3H]thymidine uptake and cytokine production after stimulation with phytohaemagglutinin (PHA)). Compared with cells from infants receiving only human milk (HM), the rate of [3H]thymidine uptake in response to PHA, but not IL-2 production, was lower for Formula+LCP infants (P < 0.05). Compared with HM-fed infants, Formula-fed infants (but not Formula+LCP infants) produced more TNF-alpha (unstimulated) and had a fewer CD3+CD44+ cells before stimulation and fewer CD11c+ cells post-stimulation (P < 0.05). However, compared with Formula-fed infants, the Formula+LCP infants had an immune cell distribution (higher percentage CD3+CD44+ and CD4+CD28+ cells) and cytokine profile (lower production of TNF-alpha post-stimulation) that did not differ from HM infants. Additionally, it was found that feeding infants formula during the first 10 d of life influenced immune function. These infants had a higher percentage of CD3+, CD4+CD28+, and lower percentage of CD14+ cells and produced more TNF-alpha and interferon-gamma after PHA stimulation than HM-fed infants (P < 0.05). These results demonstrate that early diet influences both the presence of specific cell types and function of infant blood immune cells. Since many diseases have a strong immunological component, these immune changes may be of physiological importance to the developing infant.
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Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial.
Hawkes, JS, Gibson, RA, Roberton, D, Makrides, M
European journal of clinical nutrition. 2006;(2):254-64
Abstract
OBJECTIVE To examine the effect of nucleotide (NT)-supplemented cow's milk-based formula on growth and biochemical indices of immune function in healthy infants. DESIGN Randomized controlled trial (RCT) of formula-fed term infants allocated to control formula with an innate level of NT at 10 mg/l (n = 102), or formula fortified with NT at 33.5 mg/l (n = 98). A parallel group of 125 breastfed infants followed the same protocol as a reference. OUTCOME MEASURES Growth was assessed at enrolment, 7 weeks, 4 months and 7 months of age. Natural killer cell activity, cytokine production and lymphocyte subpopulations were assessed at 7 weeks of age. Antibody responses to diphtheria toxoid, tetanus toxoid and Haemophilus influenzae type b (Hib) immunizations were measured at 7 months of age. RESULTS NT supplementation did not influence the growth of formula fed infants or any markers of immunity measured at 7 weeks of age. Antibody responses to tetanus toxoid were higher in the NT-supplemented group (n = 68) compared with the control group (n = 70) at 7 months of age (median (5th, 95% percentile): 1.57(0.42, 3.43) vs 1.01(0.41, 4.66) IU/ml, P < 0.03). A difference between treatments was seen in response to diphtheria toxoid but this effect disappeared when adjusted for hepatitis B immunization at birth. There was no effect of treatment on antibody responses to Hib immunization. CONCLUSIONS Supplementation of formulas with NT at 33.5 mg/l resulted in a modest improvement in antibody response consistent with RCTs that used higher levels of NT supplementation. Whether this translates to clinical benefits in well-nourished infants requires further study. SPONSORSHIP Supported by a grant from Wyeth Nutrition. Dr Makrides was supported by an RD Wright Fellowship from the National Health and Medical Research Council of Australia and Dr Gibson was partially supported by the MS McLeod Research Trust and a Senior Research Fellowship from the National Health and Medical Research Council of Australia.