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Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial.

ABSTRACT: BACKGROUND:Post-natal gut maturation in infants interrelates maturation of the morphology, digestive, and immunological functions and gut microbiota development. Here, we explored both microbiota development and markers of gut barrier and maturation in healthy term infants during their early life to assess the interconnection of gut functions during different infant formulae regimes. METHODS:A total of 203 infants were enrolled in this randomized double-blind controlled trial including a breastfed reference group. Infants were fed starter formulae for the first four weeks of life, supplemented with different combination of nutrients (lactoferrin, probiotics (Bifidobacterium animal subsp. Lactis) and prebiotics (Bovine Milk-derived Oligosaccharides-BMOS)) and subsequently fed the control formula up to eight weeks of life. Stool microbiota profiles and biomarkers of early gut maturation, calprotectin (primary outcome), elastase, ?-1 antitrypsin (AAT) and neopterin were measured in feces at one, two, four, and eight weeks. RESULTS:Infants fed formula containing BMOS had lower mean calprotectin levels over the first two to four weeks compared to the other formula groups. Elastase and AAT levels were closer to levels observed in breastfed infants. No differences were observed for neopterin. Global differences between the bacterial communities of all groups were assessed by constrained multivariate analysis with hypothesis testing. The canonical correspondence analysis (CCA) at genus level showed overlap between microbiota profiles at one and four weeks of age in the BMOS supplemented formula group with the breastfed reference, dominated by bifidobacteria. Microbiota profiles of all groups at four weeks were significantly associated with the calprotectin levels at 4 (CCA, p = 0.018) and eight weeks of age (CCA, p = 0.026). CONCLUSION:A meaningful correlation was observed between changes in microbiota composition and gut maturation marker calprotectin. The supplementation with BMOS seems to favor gut maturation closer to that of breastfed infants.

SUBMITTER: Castanet M

PROVIDER: S-EPMC7284641 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial.

Castanet Mireille M Costalos Christos C Haiden Nadja N Hascoet Jean-Michel JM Berger Bernard B Sprenger Norbert N Grathwohl Dominik D Brüssow Harald H De Groot Nanda N Steenhout Philippe P Pecquet Sophie S Benyacoub Jalil J Picaud Jean-Charles JC

Nutrients 20200520 5

<h4>Background</h4>Post-natal gut maturation in infants interrelates maturation of the morphology, digestive, and immunological functions and gut microbiota development. Here, we explored both microbiota development and markers of gut barrier and maturation in healthy term infants during their early life to assess the interconnection of gut functions during different infant formulae regimes.<h4>Methods</h4>A total of 203 infants were enrolled in this randomized double-blind controlled trial incl ...[more]

PMID: 32443684

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Project description:Several lines of evidence suggest that the intestinal microbiota plays crucial roles in infant development, and that it is highly influenced by extrinsic and intrinsic factors. Prebiotic-containing infant formula may increase gastrointestinal tolerance and improve commensal microbiota composition. However, it remains unknown whether supplementation of milk-formulas with prebiotics and 1,3-olein-2-palmitin (OPO) can achieve feeding outcomes similar to those of breastfeeding. In the present study, we investigated the effects of two kinds of infant formula with different additives on the overall diversity and composition of the fecal microbiota, to determine which was closer to breastfeeding. A total of 108 infants were enrolled, including breastfeeding (n=59) and formula feeding group (n=49). The formula feeding infants were prospectively randomly divided into a standard formula group (n=18), and a supplemented formula group(n=31). The fecal samples were collected at 4 months after intervention. Fecal microbiota analysis targeting the V4 region of the 16S rRNA gene was performed using MiSeq sequencing. The overall bacterial diversity and composition, key functional bacteria, and predictive functional profiles in the two different formula groups were compared with breastfeeding group. We found that the alpha diversity of the gut microbiota was not significantly different between the OPO and breastfeeding groups with Chaos 1 index (p=0.346). The relative abundances of Enhydrobacter and Akkermansia in the OPO group were more similar to those of the breastfeeding group than to those of the standard formula group. The gut microbiota metabolism function prediction analysis showed that the supplemented formula group was similar to the breastfeeding group in terms of ureolysis (p=0.297). These findings suggest that, when formula supplemented with prebiotics and OPO was given, the overall bacterial diversity and parts of the composition of the fecal microbiota would be similar to that of breastfeeding infants.

Project description:Infant microbiota is influenced by numerous factors, such as delivery mode, environment, prematurity and diet (breast milk or formula) and last but not least, the diet composition. In the diet composition, protein and carbohydrate are very important for the growth of microbiota, many infant fomulas (different ratio protein/carbohydrate) can regulate the development of gut microbiota by different metabolism. The effect of low-protein, high-carbohydrate infant formula on the establishment of microbiota remains unclear, and the effect of human breast milk on the gut microbiota of the rats has also not been reported.In a 7 d intervention, a total of 36 neonatal SD rats (14 d old) were randomly assigned to the following groups: (1) breast-fed group (A group); (2) low-protein, high-carbohydrate infant formula-fed group (B group); (3) human breast milk-fed group (C group). After 7 days, we selected 6 rats at random from each group to study. Microbial composition in the contents of the large intestines was analysed by Miseq Sequencing. Significantly different (p<0.05) microbial colonisation patterns were observed in the large intestines of breast-fed group from low-protein, high-carbohydrate infant formula-fed and human breast milk-fed rats, but the microbiota of low-protein, high-carbohydrate infant formula-fed group and human breast milk-fed group have high similarity. At the phylum level, the absolute quantity of Bacteroidetes, Firmicutes and Proteobacteria (p<0.001) significantly differentiated in breast-fed group from low- protein, high- carbohydrate infant formula-fed and human breast milk-fed groups. Lachnospiraceae, Bacteroidaceae, Porphyromonadaceae and Prevotellaceae were the 4 top families in breast-fed group, but the top 4 families in low-protein, high- carbohydrate infant formula-fed and human breast milk-fed groups were the same, which were Bacteroidaceae, Enterobacteriaceae, Porphyromonadaceae and Lachnospiraceae. At the genus level, Bacteroides was the most abundant division, their OTUS abundance in three groups was 14.91%, 35.94%, 43.24% respectively.This study showed that infant formula closer resembling human milk was more different than rats' breast milk and led to a microbiota profile similar to that for human breast milk-fed neonates. The finding could support a new thinking to develop infant formulas, and provide much more details than what is known previously.

Project description:BackgroundBovine milk-derived oligosaccharides (MOS) containing primarily galacto-oligosaccharides with inherent concentrations of sialylated oligosaccharides can be added to infant formula to enhance the oligosaccharide profile.ObjectiveTo investigate the effects of an MOS-supplemented infant formula on gut microbiota and intestinal immunity.MethodsIn a double-blind, randomized, controlled trial, healthy term formula-fed infants aged 21-26 d either received an intact protein cow milk-based formula (control group, CG, n = 112) or the same formula containing 7.2 g MOS/L (experimental group, EG, n = 114) until the age of 6 mo. Exclusively human milk-fed infants (HFI, n = 70) from an observational study served as the reference. Fecal samples collected at baseline, and the ages of 2.5 and 4 mo were assessed for microbiota (16S ribosomal RNA-based approaches), metabolites, and biomarkers of gut health and immune response.ResultsAged 2.5 and 4 mo, redundancy analysis (P = 0.002) and average phylogenetic distance (P < 0.05) showed that the overall microbiota composition in EG was different from CG and closer to that of HFI. Similarly, EG caesarean-born infants were different from CG caesarean- or vaginally born infants and approaching HFI vaginally born infants. Relative bifidobacteria abundance was higher in EG compared with CG (P < 0.05) approaching HFI. At the age of 4 mo, counts of Clostridioides difficile and Clostridium perfringens were ∼90% (P < 0.001) and ∼65% (P < 0.01) lower in EG compared with CG, respectively. Geometric LS mean (95% CI) fecal secretory IgA in EG was twice that of CG [70 (57, 85) compared with 34 (28, 42) mg/g, P < 0.001] and closer to HFI. Fecal oral polio vaccine-specific IgA was ∼50% higher in EG compared with CG (P = 0.065). Compared with CG, EG and HFI had lower fecal calcium excretion (by ∼30%, P < 0.005) and fecal pH (P < 0.001), and higher lactate concentration (P < 0.001).ConclusionsInfant formula with MOS shifts the gut microbiota and metabolic signature closer to that of HFI, has a strong bifidogenic effect, reduces fecal pathogens, and improves the intestinal immune response.

Project description:BackgroundA limited number of nondigestible oligosaccharides are available for use in infant formula. This study evaluated growth and safety in infants fed formula supplemented with a mixture of bovine milk-derived oligosaccharides (BMOS). This mixture, which was generated from whey permeate, contains galactooligosaccharides and other oligosaccharides from bovine milk, such as 3'- and 6'-sialyllactose. We hypothesized that growth in infants fed BMOS-supplemented formula would be noninferior to that in infants fed standard formula.MethodsHealthy term infants ≤14 days old were randomly assigned to standard formula (control; n = 84); standard formula with BMOS (IF-BMOS; n = 99); or standard formula with BMOS and probiotics (Bifidobacterium longum, Lactobacillus rhamnosus) (IF-BMOS + Pro; n = 98). A breastfed reference group was also enrolled (n = 30). The primary outcome was mean weight gain/day from enrollment to age 4 months (noninferiority margin: -3.0 g/day).Results189 (67.3%) formula-fed infants were included in the primary analysis. Mean differences in weight gain between the control and IF-BMOS and IF-BMOS + Pro groups were <1 g/day, with 97.5% confidence intervals above -3.0 g/day, indicating noninferior weight gain in the BMOS formula groups. Compared with control, infants in the BMOS groups had more frequent (p < 0.0001) and less hard (p = 0.0003) stools. No significant differences were observed between the control and BMOS groups in caregivers' reports of flatulence, vomiting, spitting up, crying, fussing, and colic. When based on clinical evaluation by the investigator, the incidence of colic was higher (p = 0.01) in IF-BMOS than in control; the incidence of investigator-diagnosed colic was not significantly different in control and IF-BMOS + Pro (p = 0.15). Stool bifidobacteria and lactobacilli counts were higher with IF-BMOS + Pro compared with control (p < 0.05), whereas Clostridia counts were lower (p < 0.05) in both BMOS groups compared with control.ConclusionsInfant formula containing BMOS either with or without probiotics provides adequate nutrition for normal growth in healthy term infants. Further studies are needed to fully explore the digestive tolerance of BMOS formula.Trial registrationClinicalTrials.gov NCT01886898 . Registered 24 June 2013.

Project description:IMPORTANCE:The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of ?-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. OBJECTIVE:To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS:A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013. INTERVENTIONS:The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate. MAIN OUTCOMES:AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS:The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. CONCLUSIONS AND RELEVANCE:Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

Project description:Infant formulae have been used since decades as an alternative to or a complement to human milk. Human milk, the "gold standard" of infant nutrition, has been studied for its properties in order to create infant formulae that bring similar benefits to the infant. One of the characteristics of milk is the size of the lipid droplets which is known to affect the digestion, gastric emptying and triglyceride metabolism. In the current study a concept infant milk formula with large, phospholipid coating of lipid droplets (mode diameter 3-5 ?m; NUTURIS, further described as "active"), was compared to a commercially available formula milk characterised by smaller lipid droplets, further described as "control" (both products derived from Nutricia). We investigated whether we could find an effect of lipid droplet size on volatile compounds in exhaled air upon ingestion of either product. For that purpose, exhaled breath was collected from a group of 29 healthy, non-smoking adult males before ingestion of a study product (baseline measurements, T0) and at the following time points after the test meal: 30, 60, 120, 180 and 240?min. Volatile organic compounds (VOCs) in breath were detected by gas chromatography-time-of-flight-mass spectrometry. Any differences in the time course of VOCs patterns upon intake of active and control products were investigated by regularised multivariate analysis of variance (rMANOVA). The rMANOVA analysis revealed statistically significant differences in the exhaled breath composition 240?min after ingestion of the active formula compared to control product (p-value?<?0.0001), but did not show significant changes between active and control product at any earlier time points. A set of eight VOCs in exhaled breath had the highest contribution to the difference found at 240?minutes between the two formulas. A set of ten VOCs was different between baseline and the two formulae at T240 with p-value?<?0.0001. To our knowledge this is the first study that shows the ability of VOCs in exhaled breath to monitor metabolic effects after ingestion of infant formulae with different lipid structure. The statistically significant differences in compound abundance found between active and control formula milk may be related to: (i) specific differences in the digestion, (ii) absorption of lipids and proteins and (iii) assimilation of the products in the gut.

Dataset Information

Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial.

Publications

Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial.

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