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Introduction: Bifidobacterium longum subspecies infantis ( B. infantis ) may play a key role in infant gut development. This trial evaluated safety, tolerability, and efficacy of B. infantis LMG11588 supplementation., Methods: This randomized, placebo-controlled, double-blind study conducted in the Philippines included healthy breastfed and/or formula-fed infants (14-21 days old) randomized for 8 weeks to a control group (CG; n  = 77), or any of two B. infantis experimental groups (EGs): low (Lo-EG; 1*10 8 CFU/day; n  = 75) or high dose (Hi-EG; 1.8*10 10 CFU/day; n  = 76). Primary endpoint was weight gain; secondary endpoints included stooling patterns, gastrointestinal symptoms, adverse events, fecal microbiome, biomarkers, pH, and organic acids., Results: Non-inferiority in weight gain was demonstrated for Hi-EG and Lo-EG vs. CG. Overall, probiotic supplementation promoted mushy-soft stools, fewer regurgitation episodes, and increased fecal acetate production, which was more pronounced in the exclusively breastfed infants (EBF) and positively correlated with B. infantis abundance. In EBF, fecal pro-inflammatory cytokines (IL-1 beta, IL-8) were reduced. Strain-level metagenomic analysis allowed attributing the increased abundance of B. infantis in EGs versus CG, to LMG11588 probiotic colonization. Colonization by autochthonous B. infantis strains was similar between groups., Discussion: B. infantis LMG11588 supplementation was associated with normal infant growth, was safe and well-tolerated and promoted a Bifidobacterium -rich microbiota driven by B. infantis LMG11588 colonization without disturbing the natural dispersal of autochthonous B. infantis strains. In EBF, supplementation stimulated microbial metabolic activity and beneficially modulated enteric inflammation., Competing Interests: Authors employed by Nestlé Nutrition and Nestlé Research, Société des Produits Nestlé SA, Switzerland were involved in the study design (CIC), data analysis (CM, MN, KV, GLC, AF, BB, CB, CIC), as well as preparation and decision to submit the manuscript (TS, MN, KV, GLC, AF, BB, CIC). In addition, JMM, JKV, PM, and HBN, employees of Clinical Microbiomics, were involved in data analysis and preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Capeding, Phee, Ming, Noti, Vidal, Le Carrou, Frézal, Moll, Vogt, Myers, Nielsen, Boulangé, Samuel, Berger and Cercamondi.)

While ample research on independent associations between infant cognition and gut microbiota composition and human milk (HM) oligosaccharides (HMOs) has been reported, studies on how the interactions between gut microbiota and HMOs may yield associations with cognitive development in infancy are lacking. We aimed to determine how HMOs and species of Bacteroides and Bifidobacterium genera interact with each other and their associations with cognitive development in typically developing infants. A total of 105 mother-infant dyads were included in this study. The enrolled infants [2.9-12 months old (8.09 ± 2.48)] were at least predominantly breastfed at 4 months old. A total of 170 HM samples from the mothers and fecal samples of the children were collected longitudinally. Using the Mullen Scales of Early Learning to assess cognition and the scores as the outcomes, linear mixed effects models including both the levels of eight HMOs and relative abundance of Bacteroides and Bifidobacterium species as main associations and their interactions were employed with adjusting covariates; infant sex, delivery mode, maternal education, site, and batch effects of HMOs. Additionally, regression models stratifying infants based on the A-tetrasaccharide (A-tetra) status of the HM they received were also employed to determine if the associations depend on the A-tetra status. With Bacteroides species, we observed significant associations with motor functions, while Bif. catenulatum showed a negative association with visual reception in the detectable A-tetra group both as main effect (value of p  = 0.012) and in interaction with LNFP-I (value of p  = 0.007). Additionally, 3-FL showed a positive association with gross motor ( p  = 0.027) and visual reception ( p  = 0.041). Furthermore, significant associations were observed with the interaction terms mainly in the undetectable A-tetra group. Specifically, we observed negative associations for Bifidobacterium species and LNT [ breve ( p  = 0.011) and longum ( p  = 0.022)], and positive associations for expressive language with 3'-SL and Bif. bifidum ( p  = 0.01), 6'-SL and B. fragilis ( p  = 0.019), and LNFP-I and Bif. kashiwanohense ( p  = 0.048), respectively. Our findings suggest that gut microbiota and HMOs are both independently and interactively associated with early cognitive development. In particular, the diverse interactions between HMOs and Bacteroides and Bifidobacterium species reveal different candidate pathways through which HMOs, Bifidobacterium and Bacteroides species potentially interact to impact cognitive development in infancy., Competing Interests: TS, JH, and NS are employees of Société des Produits Nestlé, SA, Switzerland. This study was supported in part by a grant from Nestlé Product Technology Center-Nutrition, Société des Produits Nestlé S.A., Switzerland. WL was a consultant of and received travel support from Nestlé SA, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cho, Samuel, Li, Howell, Baluyot, Hazlett, Elison, Zhu, Hauser, Sprenger and Lin.)

Early dietary exposure via human milk nutrients offers a window of opportunity to support cognitive and temperament development. While several studies have focused on associations of few pre-selected human milk nutrients with cognition and temperament, it is highly plausible that human milk nutrients synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of three major classes of human milk nutrients with cognition and temperament during the first 6 months of life when human milk is the primary source of an infant's nutrition and explore whether there were persistent effects up to 18 months old. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of 54 exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12, and 12-18 months old. Human milk samples were obtained from the mothers of the participants at less than 6 months of age and analyzed for fatty acids [total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)], phospholipids [phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin], and choline [free choline, phosphocholine (PCho), glycerophosphocholine]. Feature selection was performed to select nutrients associated with cognition and temperament. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed ( p = 0.024). A significant effect of DHA, n-6/n-3, PE, and TSFA concentrations on receptive language ( R 2 = 0.39, p = 0.025) and the elevated ARA, PCho, and PI with increased surgency ( R 2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of human milk nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months ( p = 0.002). Our study highlighted that various human milk nutrients work together to support the development of cognition and temperament traits during early infancy., Competing Interests: TS, JH, and NS were the employees of Société des Produits Nestlé SA, Switzerland. WL was a consultant of and received travel support from Nestlé SA, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Samuel, Zhu, Howell, Cho, Baluyot, Hazlett, Elison, Wu, Hauser, Sprenger, Zhu and Lin.)

Background: The effect of the mode of neonatal delivery (cesarean or vaginal) on the nutrient composition of human milk (HM) has rarely been studied. Given the increasing prevalence of cesarean section (C-section) globally, understanding the impact of C-section vs. vaginal delivery on the nutrient composition of HM is fundamental when HM is the preferred source of infant food during the first 4 postnatal months., Objective: This study aimed to evaluate the association between mode of delivery and nutrient composition of HM in the first 4 months of life., Design: Milk samples were obtained from 317 healthy lactating mothers as part of an exploratory analyses within a multicenter European longitudinal cohort (ATLAS cohort) to study the HM composition, and its potential association with the mode of delivery. We employed traditional mixed models to study individual nutrient associations adjusted for mother's country, infant birth weight, parity, and gestational age, and complemented it, for the first time, with a multidimensional data analyses approach (non-negative tensor factorization, NTF) to examine holistically how patterns of multiple nutrients and changes over time are associated with the delivery mode., Results: Over the first 4 months, nutrient profiles in the milk of mothers who delivered vaginally ( n = 237) showed significantly higher levels of palmitoleic acid (16:1n-7), stearic acid (18:0), oleic acid (18:1n-9), arachidic acid (20:0), alpha-linolenic acid (18:3n-3), eicosapentaenoic acid (20:5n-3), docosahexenoic acid (22:6n-3), erucic acid (22:1n-9), monounsaturated fatty acids (MUFA)%, calcium, and phosphorus, whereas the ratios of arachidonic acid/docosahexaenoic acid (ARA/DHA) and n-6/n-3, as well as polyunsaturated fatty acids (PUFA)% were higher in milk from women who had C-sections, in the unadjusted analyses ( p < 0.05 for all), but did not retain significance when adjusted for confounders in the mixed models. Using a complementary multidimension data analyses approach (NTF), we show few similar patterns wherein a group of mothers with a high density of C-sections showed increased values for PUFA%, n-6/n-3, and ARA/DHA ratios, but decreased values of MUFA%, 20:1n-9, iodine, and fucosyl-sialyl-lacto-N-tetraose 2 during the first 4 months of lactation., Conclusion: Our data provide preliminary insights on differences in concentrations of several HM nutrients (predominantly fatty acids) among women who delivered via C-section. Although these effects tend to disappear after adjustment for confounders, given the similar patterns observed using two different data analytical approaches, these preliminary findings warrant further confirmation and additional insight on the biological and clinical effects related to such differences early in life., Competing Interests: ’This study received funding from Société des Produits Nestlé S.A. The funder had the following involvement with the study: study design, data analysis, interpretation of the results, and reporting in scientific journal. TS, LL, CC, FG, SD, and ST are currently employees of Société des Produits Nestlé S.A. PF and FT are consultants to Société des Produits Nestlé S.A. CM-C, KH, GM, MA, TR, MC, J-CP, and CB received funding from Société des Produits Nestlé S.A. to conduct the study. FT received funding for the research and drafting the manuscript., (Copyright © 2022 Samuel, Thielecke, Lavalle, Chen, Fogel, Giuffrida, Dubascoux, Martínez-Costa, Haaland, Marchini, Agosti, Rakza, Costeira, Picaud, Billeaud and Thakkar.)

Human milk (HM) is dynamic and shows a high inter- and intra-individual variability. To characterize HM with precision, it is necessary to understand the factors that modulate its composition. The objective of this narrative review is to summarize the maternal, infant and methodological factors that affect HM composition. We searched SCOPUS and PubMed databases for articles related to factors that are known to or could potentially influence HM composition and volume across lactation periods. Our comprehensive review encompasses various maternal-, infant-related, and methodological factors that modulate aspects of HM composition including macro- and micronutrients, vitamins and minerals, as well as volume. The most profound changes were observed in HM lipids and lipophiles. Evidence exists for many of the infant-related factors known to affect the nutritive and non-nutritive components of HM (e.g., birth weight, gestational age, infant age/stage of lactation). In contrast, less is known with respect to maternal factors; where there is either limited research or conflicting evidence (e.g., maternal lifestyle, obstetric history, medical conditions), except for the mother's diet, for which there is a relatively well-established understanding. Equally, although many of the methodological factors (e.g., HM sampling, handling and analytics) are known to impact HM composition, few studies have investigated this as a primary outcome, making it an important area of future research in HM. Here we propose a systematic capture of numerous maternal- and infant-related characteristics to facilitate associative comparisons of HM data within and across studies. Additionally, it would be prudent to standardize the methodological aspects known to affect HM composition in analytics, not only for HM lipids and lipophiles, but also for those nutrients whose variability is yet less well-understood. Defining the factors determining HM composition with accuracy will open perspectives for maternal intervention to optimize milk composition for specific needs of infants., (Copyright © 2020 Samuel, Zhou, Giuffrida, Munblit, Verhasselt and Thakkar.)