Reversible aberrancies in gut microbiome of moderate and late preterm infants: results from a randomized, controlled trial.

The aim of this study was to obtain insight into the composition and function of the deviant gut microbiome throughout infancy in children born moderately and late preterm and their response to microbiome modulation. We characterized the longitudinal development of the gut microbiome from birth to the age of 12 months by metagenomic sequencing in 43 moderate and late preterm children participating in a randomized, controlled trial (ClinicalTrials.gov/no.NCT00167700) assessing the impact of a probiotic (Lactobacillus rhamnosus GG, ATCC 53,103, currently Lacticaseibacillus rhamnosus GG) and a prebiotic (galacto-oligosaccharide and polydextrose mixture, 1:1) intervention as compared to a placebo administered from 3 to 60 days of life. In addition, 9 full-term, vaginally delivered, breast-fed infants, who remained healthy long-term were included as references. Significant differences in taxonomy, but not in functional potential, were found when comparing the gut microbiome composition of preterm and full-term infants during the first month of life. However, the gut microbiome of preterm infants resembled that of full-term infants by 6 months age. Probiotic and prebiotic treatments were found to mitigate the shift in the microbiome of preterm infants by accelerating Bifidobacteria-dominated gut microbiome in beta diversity analysis. This study provides intriguing information regarding the establishment of the gut microbiome in children born moderately and late preterm, representing the majority of children born preterm. Specific pro- and prebiotics may reverse the proinflammatory gut microbiome composition during the vulnerable period, when the microbiome is low in resilience and susceptible to environmental exposure and simultaneously promotes immunological and metabolic maturation.

Shifting pattern of gut microbiota in pregnant women two decades apart - an observational study.

BACKGROUND: Past decades have witnessed a decrease in environmental biodiversity. We hypothesized a similar decrease in indigenous gut microbiota diversity, which may have contributed to the obesity epidemic. OBJECTIVE: To investigate the changes in the composition and function of the gut microbiota in pregnant women over a period of 20 years. STUDY DESIGN: Altogether 124 pregnant women (41 overweight and matched 83 normal weight) pregnant in 1997, 2007 or 2017 were included in the study. The gut microbiota composition was assessed from fecal samples obtained at 32 weeks of gestation by 16S rRNA gene sequencing. Fecal short chain fatty acid (SCFA) profiles were measured by gas chromatography mass spectrometry (GC-MS). RESULTS: Distinct gut microbiota profiles were detected in pregnant women from 1997, 2007 and 2017 (PERMANOVA Bray-Curtis R2 = 0.029, p = 0.001). The women pregnant in 1997 exhibited significantly higher microbiota richness and diversity as compared to those pregnant in 2007 and 2017. The total concentration of fecal SCFAs was significantly higher in the pregnant women in 1997 compared to those in 2007 and 2017. Significant differences in gut microbiota composition between normal weight and overweight women were manifest in 1997 but not in 2007 or 2017. CONCLUSIONS: The decrease in intestinal microbiota richness and diversity over two decades occurred in parallel with the decline in biodiversity in our natural surroundings. It appears that the gut microbiota of pregnant women has changed over time to a composition typical for overweight individuals.

The composition of the indigenous gut microbiota was investigated in pregnant women from three different time periods (1997, 2007 and 2017) in the same geographical and cultural area in Southwest Finland. Distinct gut microbiota profiles were evident in the women from the different time periods. The women pregnant in 1997 exhibited significantly higher microbiota richness and diversity as compared to the pregnant women from 2007 to 2017. The cause of the loss of gut microbiota richness and diversity over time remains obscure, since no major changes in the population, dietary practices or antibiotic use occurred in the area during the course of the study periods. Gut microbiota composition has been suggested to play a causal role in the development of overweight and obesity. In line with this notion, significant differences in the gut microbiota composition between normal weight and overweight were detectable in women pregnant in 1997. However, no such differences were manifest in women pregnant in 2007 or 2017 and the gut microbiota of these individuals resembled that of overweight pregnant women from 1997. The results of the study provide direct evidence for a decline in gut microbiota diversity over time in the same geographical area and the same population. It furthermore appears that the gut microbiota of pregnant women has changed over time to a composition typical for overweight individuals. The gut microbiota profiles may thus provide insight into the development and intergenerational transfer of overweight.

The preterm gut microbiota and administration routes of different probiotics: a randomized controlled trial.

BACKGROUND: Preterm children with their aberrant gut microbiota and susceptibility to infections and inflammation constitute a considerable target group for probiotic therapy to generate the age-appropriate healthy microbiota. METHODS: 68 preterm neonates were randomized into five intervention groups: Beginning from the median age of 3 days, 13 children received Lactobacillus rhamnosus GG (LGG) directly orally, and 17 via the lactating mother. 14 children received LGG with Bifidobacterium lactis Bb-12 (Bb12) orally, and 10 via the lactating mother. 14 children received placebo. The children's faecal microbiota was assessed at the age of 7 days by 16S rRNA gene sequencing. RESULTS: The gut microbiota compositions of the children directly receiving the probiotic combination (LGG + Bb12) were significantly different from those of the children receiving the other intervention modes or placebo (p = 0.0012; PERMANOVA), the distinction being due to an increase in the relative abundance of Bifidobacterium animalis (P < 0.00010; ANCOM-BC), and the order Lactobacillales (P = 0.020; ANCOM-BC). CONCLUSION: The connection between aberrant primary gut microbiota and a heightened risk of infectious and non-communicable diseases invites effective microbiota modulation. We show that the direct, early, and brief probiotic intervention of LGG + Bb12 109 CFU each, is sufficient to modulate the gut microbiota of the preterm neonate. IMPACT: Preterm children have a higher risk of several health problems partly due to their aberrant gut microbiota. More research is needed to find a safe probiotic intervention to modify the gut microbiota of preterm children. The maternal administration route via breast milk might be safer for the newborn. In our study, the early and direct administration of the probiotic combination Lactobacillus rhamnosus GG with Bifidobacterium lactis Bb-12 increased the proportion of bifidobacteria in the preterm children's gut at the age of 7 days, but the maternal administration route was not as effective.

Gestational diabetes is driven by microbiota-induced inflammation months before diagnosis.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities. DESIGN: We comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts. RESULTS: We found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy. CONCLUSION: GDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.

Residential green environments are associated with human milk oligosaccharide diversity and composition.

Increased exposure to greener environments has been suggested to lead to health benefits in children, but the associated mechanisms in early life, particularly via biological mediators such as altered maternal milk composition, remain largely unexplored. We investigated the associations between properties of the mother's residential green environment, measured as (1) greenness (Normalized Difference Vegetation index, NDVI), (2) Vegetation Cover Diversity (VCDI) and (3) Naturalness Index (NI), and human milk oligosaccharides (HMOs), known for their immune- and microbiota-related health effects on the infant (N = 795 mothers). We show that HMO diversity increases and concentrations of several individual HMOs and HMO groups change with increased VCDI and NI in residential green environments. This suggests that variation in residential green environments may influence the infant via maternal milk through modified HMO composition. The results emphasize the mediating role of breastfeeding between the residential green environments and health in early life.

Early life exposures and development of allergic disease in infants with familial risk: Results from ongoing probiotic intervention trials.

AIM: We search revision of risk determinants of the ongoing allergy epidemic. METHODS: Children numbering 433 born to mothers with allergic disease or sensitisation were selected from the three ongoing probiotic intervention trials for this case-control study. Children who developed atopic eczema or food allergy, had positive skinprick test results or had been prescribed inhaled corticosteroids by the age of 2 years were identified as cases (n = 231), while children without allergic manifestations were the healthy controls (n = 202). The data on early environmental exposures were collected from prospectively documented study records. The statistical analyses were adjusted for potential confounders. RESULTS: Determinants associated with the increased risk of atopic eczema were lower maternal prepregnancy BMI (aOR 0.15, 95% CI: 0.037-0.54) and maternal intrapartum antibiotic treatment (aOR 2.21, 95% CI 1.20-4.10), the latter also linked to obstructive respiratory symptoms (aOR 3.87, 95% CI 1.07-14.06). The risk of allergic sensitisation was associated with lower maternal prepegnancy BMI (aOR 0.18, 95% CI 0.43-0.79) and intrapartum antibiotic treatment (aOR 2.13, 95% CI 1.07-4.22). CONCLUSION: Based on our demonstrations, interventions such as personalised diets, can be optimised for specific subgroups and definite risk periods.

Feeding the preterm infant gut microbiota.

How nutritional management of very preterm neonates impacts microbiota development and clinical outcomes remains incompletely understood. In this issue of Cell Host & Microbe, Asbury et al. present a randomized controlled trial assessing the microbiota of very preterm infants fed human milk supplemented with human milk or cow's milk-based fortification.

Neighborhood Disadvantage, Greenness, and Population Density as Predictors of Breastfeeding Practices: A Population Cohort Study from Finland.

BACKGROUND: Many environmental factors are known to hinder breastfeeding, yet the role of the family living environment in this regard is still poorly understood. OBJECTIVES: We used data from a large cohort to identify associations between neighborhood characteristics and breastfeeding behavior. METHODS: Our observational study included 11,038 children (0-2 years) from the Southwest Finland Birth Cohort. Participant information was obtained from the Medical Birth Register and municipal follow-up clinics. Neighborhood socioeconomic disadvantage, greenness, and population density were measured for a period of 5 years prior to childbirth within the residential neighborhood on a 250 × 250-m grid. Any breastfeeding and breastfeeding at 6 months were the primary outcomes. Binary logistic regression models were adjusted for maternal health and socioeconomic factors. RESULTS: Adjusted analyses suggest that mothers living in less populated areas were less likely to display any breastfeeding (OR: 0.46; 95% CI: 0.36, 0.59) and breastfeeding at 6 months (OR: 0.37; 95% CI: 0.34, 0.40). Mothers living in highly disadvantaged neighborhoods were less likely to display any breastfeeding if the neighborhood was less populated (OR: 0.54; 95% CI: 0.30, 0.95) but more likely to breastfeed at 6 months if the neighborhood was highly populated (OR: 3.74; 95% CI: 1.92, 7.29). Low greenness was associated with higher likelihood of any breastfeeding (OR: 3.82; 95% CI: 1.53, 9.55) and breastfeeding at 6 months (OR: 4.41; 95% CI: 3.44, 5). CONCLUSIONS: Our results suggest that neighborhood characteristics are associated with breastfeeding behavior in Finland. Unravelling breastfeeding decisions linked to the living environment could help identify interventions that will allow the appropriate support for all mothers and infants across different environmental challenges.

Early-life formula feeding is associated with infant gut microbiota alterations and an increased antibiotic resistance load.

BACKGROUND: Infants are at a high risk of acquiring fatal infections, and their treatment relies on functioning antibiotics. Antibiotic resistance genes (ARGs) are present in high numbers in antibiotic-naive infants' gut microbiomes, and infant mortality caused by resistant infections is high. The role of antibiotics in shaping the infant resistome has been studied, but there is limited knowledge on other factors that affect the antibiotic resistance burden of the infant gut. OBJECTIVES: Our objectives were to determine the impact of early exposure to formula on the ARG load in neonates and infants born either preterm or full term. Our hypotheses were that diet causes a selective pressure that influences the microbial community of the infant gut, and formula exposure would increase the abundance of taxa that carry ARGs. METHODS: Cross-sectionally sampled gut metagenomes of 46 neonates were used to build a generalized linear model to determine the impact of diet on ARG loads in neonates. The model was cross-validated using neonate metagenomes gathered from public databases using our custom statistical pipeline for cross-validation. RESULTS: Formula-fed neonates had higher relative abundances of opportunistic pathogens such as Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Klebsiella oxytoca, and Clostridioides difficile. The relative abundance of ARGs carried by gut bacteria was 69% higher in the formula-receiving group (fold change, 1.69; 95% CI: 1.12-2.55; P = 0.013; n = 180) compared to exclusively human milk-fed infants. The formula-fed infants also had significantly less typical infant bacteria, such as Bifidobacteria, that have potential health benefits. CONCLUSIONS: The novel finding that formula exposure is correlated with a higher neonatal ARG burden lays the foundation that clinicians should consider feeding mode in addition to antibiotic use during the first months of life to minimize the proliferation of antibiotic-resistant gut bacteria in infants.

Neighborhood Socioeconomic Disadvantage and Childhood Body Mass Index Trajectories From Birth to 7 Years of Age.

BACKGROUND: The epidemic of increasing childhood overweight and obesity is a major global health concern, with local contextual factors identified as possible contributors. Robust research is needed to establish an evidence base supporting health policy decisions to reverse the trend. We aimed to examine the association between neighborhood socioeconomic disadvantage and trajectories of body mass index (BMI) from birth to age 7. METHODS: The present study included 11,023 children born within the Southwest Finland Birth Cohort who were free of severe conditions affecting growth with adequate exposure and growth data. We obtained child growth data until school age from municipal follow-up clinics. We based cumulative childhood neighborhood socioeconomic disadvantage on the average annual income, unemployment, and level of education in a residential area defined using a geographic grid at a spatial resolution of 250 m by 250 m. RESULTS: Cumulative neighborhood socioeconomic disadvantage was associated with distinct childhood BMI z score trajectories from birth to age 7. Despite being born in the lowest BMI z scores, children growing up in disadvantaged neighborhoods subsequently exhibited a trajectory of increasing BMI z scores starting at 4 years of age, ending up with a higher risk of overweight at the end of the follow-up (30%) as compared with children living in more affluent neighborhoods (22%). The corresponding risk of obesity was 5 % for those in affluent neighborhoods and 9 % and those in disadvantaged neighborhoods. CONCLUSION: Cumulative exposure to neighborhood socioeconomic disadvantage is independently associated with unfavorable BMI development and obesity in childhood.

Spontaneous preterm delivery is reflected in both early neonatal and maternal gut microbiota.

BACKGROUND: Aberrant gut microbiota composition in preterm neonates is linked to adverse health consequences. Little is known about the impact of perinatal factors or maternal gut microbiota on initial preterm gut colonization. METHODS: Fecal samples were collected from 55 preterm neonates (<35 gestational weeks), 51 mothers, and 25 full-term neonates during the first 3-4 postpartum days. Gut microbiota composition was assessed using 16S ribosomal RNA gene sequencing. RESULTS: Preterm neonates exhibited significantly lower gut microbiota alpha diversity and distinct beta diversity clustering compared to term neonates. Spontaneous preterm birth was associated with distinct initial gut microbiota beta diversity as compared to iatrogenic delivery. Gestational age or delivery mode had no impact on the preterm gut microbiota composition. The cause of preterm delivery was also reflected in the maternal gut microbiota composition. The contribution of maternal gut microbiota to initial preterm gut colonization was more pronounced after spontaneous delivery than iatrogenic delivery and not dependent on delivery mode. CONCLUSIONS: The initial preterm gut microbiota is distinct from term microbiota. Spontaneous preterm birth is reflected in the early neonatal and maternal gut microbiota. Transmission of gut microbes from mother to neonate is determined by spontaneous preterm delivery, but not by mode of birth. IMPACT: The initial gut microbiota in preterm neonates is distinct from those born full term. Spontaneous preterm birth is associated with changes in the gut microbiota composition of both preterm neonates and their mothers. The contribution of the maternal gut microbiota to initial neonatal gut colonization was more pronounced after spontaneous preterm delivery as compared to iatrogenic preterm delivery and not dependent on delivery mode. Our study provides new evidence regarding the early gut colonization patterns in preterm infants. Altered preterm gut microbiota has been linked to adverse health consequences and may provide a target for early intervention.

Maternal Intrapartum Antibiotic Treatment and Gut Microbiota Development in Healthy Term Infants.

OBJECTIVE: The aim of the study was to investigate the impact of intrapartum antibiotic treatment (IAT) on the compositional development of gut microbiota in healthy term infants. STUDY DESIGN: A case-control study of 24 infants exposed to and 24 matched infants not exposed to IAT was conducted. All subjects were born by vaginal delivery at term and breastfed. None of the infants received antibiotics during the immediate neonatal period. Fecal samples were obtained at the ages of 1 and 6 months. The composition of the intestinal microbiota was assessed by 16S rRNA gene sequencing. RESULTS: IAT was associated with reduced microbial richness but not diversity at 1 month of age. Furthermore, the relative abundances of Clostridiaceae and Erysipelotrichaceae were significantly altered in infants exposed to IAT as compared to nonexposed infants at 1 month of age. The observed deviations in gut microbiota composition between infants exposed and not exposed to IAT diminished by the age of 6 months. CONCLUSIONS: IAT is associated with short-term perturbations in the gut microbiota development in healthy term, vaginally delivered, breastfed infants. The composition of the gut microbiota is mostly restored by the age of 6 months.

Factors influencing the microbial composition of human milk.

Aside from nutritional components, human milk is rich in microorganisms. Through breastfeeding these microorganisms are introduced to the infant gut where they may transiently or persistently colonize it. Therefore, the human milk microbiota may be an important factor which shapes the infant gut microbiota further influencing infant health and disease. In the current review we aim to give a brief updated insight into the putative origin of the human milk microbiota, its constituents and the possible factors that shape it. Understanding the factors that determine the human milk microbiota composition and function will aid developing optimal postnatal feeding and intervention strategies to reduce the risk of communicable and noncommunicable diseases.

Preterm infant meconium microbiota transplant induces growth failure, inflammatory activation, and metabolic disturbances in germ-free mice.

Preterm birth may result in adverse health outcomes. Very preterm infants typically exhibit postnatal growth restriction, metabolic disturbances, and exaggerated inflammatory responses. We investigated the differences in the meconium microbiota composition between very preterm (<32 weeks), moderately preterm (32-37 weeks), and term (>37 weeks) human neonates by 16S rRNA gene sequencing. Human meconium microbiota transplants to germ-free mice were conducted to investigate whether the meconium microbiota is causally related to the preterm infant phenotype in an experimental model. Our results indicate that very preterm birth is associated with a distinct meconium microbiota composition. Fecal microbiota transplant of very preterm infant meconium results in impaired growth, altered intestinal immune function, and metabolic parameters as compared to term infant meconium transplants in germ-free mice. This finding suggests that measures aiming to minimize the long-term adverse consequences of very preterm birth should be commenced during pregnancy or directly after birth.

HPV infection and bacterial microbiota in the semen from healthy men.

BACKGROUND: Aberrant microbiota composition has been linked to disease development at numerous anatomical sites. Microbiota changes in reaction to viral infections, such as human papillomavirus (HPV), have been investigated almost exclusively in the female reproductive tract. However, HPV infection may also affect male health by reducing semen quality and fertility. The aim of this study was to investigate whether present HPV DNA is associated with detectable changes in semen bacterial microbiota composition and diversity. METHODS: This study relied on stored semen samples from 31 fertile healthy men who participated in the Finnish family HPV Study during the years 1998-2001. DNA was extracted from semen with PCR template preparation kit. HPV was genotyped using Luminex-based Multimetrix® assay. Microbiota was analyzed from the V3-V4 region of 16S rDNA gene following sequencing on an Illumina MiSeq platform. All statistical analyses were performed with Calypso software version 8.84. RESULTS: HPV DNA was detected in 19.4% (6/31) of the semen samples. HPV status in the semen did not impact the α-diversity estimations, as measured by Chao1 and Shannon indices, nor ß-diversity. Nevertheless, HPV-positive semen samples exhibited differences in the taxonomic composition of the bacterial microbiota including higher abundances of Moraxellaceae (p = 0.028), Streptococcus (p = 0.0058) and Peptostreptococcus (p = 0.012) compared to HPV-negative semen samples. CONCLUSION: HPV infection is associated with altered bacterial microbiota composition in semen, and this might have in impact to male health in general. As of present, it is unclear whether these changes result from HPV infection or whether altered bacterial microbiota increases susceptibility to HPV infection. More research is needed on viral-bacterial interactions in the male reproductive system.

Neonatal antibiotic exposure impairs child growth during the first six years of life by perturbing intestinal microbial colonization.

Exposure to antibiotics in the first days of life is thought to affect various physiological aspects of neonatal development. Here, we investigate the long-term impact of antibiotic treatment in the neonatal period and early childhood on child growth in an unselected birth cohort of 12,422 children born at full term. We find significant attenuation of weight and height gain during the first 6 years of life after neonatal antibiotic exposure in boys, but not in girls, after adjusting for potential confounders. In contrast, antibiotic use after the neonatal period but during the first 6 years of life is associated with significantly higher body mass index throughout the study period in both boys and girls. Neonatal antibiotic exposure is associated with significant differences in the gut microbiome, particularly in decreased abundance and diversity of fecal Bifidobacteria until 2 years of age. Finally, we demonstrate that fecal microbiota transplant from antibiotic-exposed children to germ-free male, but not female, mice results in significant growth impairment. Thus, we conclude that neonatal antibiotic exposure is associated with a long-term gut microbiome perturbation and may result in reduced growth in boys during the first six years of life while antibiotic use later in childhood is associated with increased body mass index.

The Microbiota of the Human Mammary Ecosystem.

Human milk contains a dynamic and complex site-specific microbiome, which is not assembled in an aleatory way, formed by organized microbial consortia and networks. Presence of some genera, such as Staphylococcus, Streptococcus, Corynebacterium, Cutibacterium (formerly known as Propionibacterium), Lactobacillus, Lactococcus and Bifidobacterium, has been detected by both culture-dependent and culture-independent approaches. DNA from some gut-associated strict anaerobes has also been repeatedly found and some studies have revealed the presence of cells and/or nucleic acids from viruses, archaea, fungi and protozoa in human milk. Colostrum and milk microbes are transmitted to the infant and, therefore, they are among the first colonizers of the human gut. Still, the significance of human milk microbes in infant gut colonization remains an open question. Clinical studies trying to elucidate the question are confounded by the profound impact of non-microbial human milk components to intestinal microecology. Modifications in the microbiota of human milk may have biological consequences for infant colonization, metabolism, immune and neuroendocrine development, and for mammary health. However, the factors driving differences in the composition of the human milk microbiome remain poorly known. In addition to colostrum and milk, breast tissue in lactating and non-lactating women may also contain a microbiota, with implications in the pathogenesis of breast cancer and in some of the adverse outcomes associated with breast implants. This and other open issues, such as the origin of the human milk microbiome, and the current limitations and future prospects are addressed in this review.

Growth Factor Concentrations in Human Milk Are Associated With Infant Weight and BMI From Birth to 5 Years.

Background: Human milk bioactives may play a role in infant health and development. Although the variability in their concentrations in milk is well-established, the impact of differential milk profiles on infant growth outcomes remains unclear. Thus, the aim of the present study was to investigate whether different concentrations of metabolic hormones are associated with different weight and BMI in infants beyond the first year of life. Methods: Milk samples at 2.6 (±0.4) months after birth and anthropometric measures at 13 months, 2, 3, and 5 years were collected as part of the Finnish STEPS cohort study from 501 mothers and the respective 507 infants. Leptin, adiponectin, insulin-like growth factor (IGF)-1 and cyclic glycine-proline (cGP) in milk were analyzed. Multiple regression models and a repeated measures mixed model were used to examine associations between milk hormone concentrations and weight and BMI z-scores across time, at each time-point, and weight gain from birth to each follow-up visit. All models were corrected for birth weight, infant sex, duration of exclusive and total breastfeeding, time of introduction of solid foods and maternal pre-pregnancy BMI. Results: Higher milk IGF-1 was associated with higher weight at 13 months (p = 0.004) but lower weight at 3 (p = 0.011) and 5 years of age (p = 0.049). Higher cGP was associated with lower weight across the 5 years (p = 0.019) but with higher BMI at 5 years (p = 0.021). Leptin and adiponectin did not display associations with infant growth at this time. Sex interactions were also absent. Conclusions: Our results suggest that the interplay between human milk-borne IGF-1 and cGP is similar to that reported in other mammals and may have an important role in defining infant growth trajectories beyond the first year of life. Further research should explore the determinants and origins of these milk-borne compounds and evaluate their effect on infant growth and metabolism.

Milk Microbiome and Neonatal Colonization: Overview.

Breastfeeding confers the infant short- and long-term health benefits and significantly modulates the developing infant gut microbiome. A specific human milk microbiome has relatively recently been discovered, but its origin remains poorly understood. Data from experimental and clinical studies suggest that the bacteria in milk may originate in the maternal gut and be transported via a specific enteromammary pathway, the details of which have not been elucidated yet. The milk microbiome is affected by the maternal metabolic state, antibiotic use, as well as the mode of delivery. We are only in the initial stages of understanding the biological function of the milk microbiome and its potential contribution to infant gut colonization. Several clinical studies indicate, however, that despite considerable differences in the overall composition of the milk and infant gut microbiomes, specific bacteria are detectable both in human milk and infant feces, and that the bacteria in milk are a source of microbes colonizing the neonatal gut. If the microbes in human milk are discovered to contribute to the beneficial effects of breastfeeding, modulating or mimicking the milk microbiome may provide a novel means of improving child health.

Associations between human milk oligosaccharides and growth in infancy and early childhood.

BACKGROUND: Breastfeeding modulates infant growth and protects against the development of obesity. However, whether or not maternal variation in human milk components, such as human milk oligosaccharides (HMOs), is associated with programming of child growth remains unknown. OBJECTIVE: Our objective was to determine the association between maternal HMO composition and child growth during the first 5 y of life. In addition, the association between maternal prepregnancy BMI and HMO composition was assessed. METHODS: Human milk samples from 802 mothers were obtained from a prospective population-based birth cohort study, Steps to healthy development of Children (STEPS), conducted in Turku, Finland. HMO composition in these milk samples was analyzed by HPLC. Child growth data from 3 mo to 5 y were collected from municipal well-baby clinics and linked to maternal HMO composition data to test for associations. RESULTS: Maternal HMO composition 3 mo after delivery was associated with height and weight during the first 5 y of life in children of secretor mothers. Specifically, HMO diversity and the concentration of lacto-N-neo-tetraose (LNnT) were inversely associated and that of 2'-fucosyllactose (2'FL) was directly associated with child height and weight z scores in a model adjusted for maternal prepregnancy BMI, mode of delivery, birthweight z score, sex, and time. Maternal prepregnancy BMI was associated with HMO composition. CONCLUSIONS: The association between maternal HMO composition and childhood growth may imply a causal relation, which warrants additional testing in preclinical and clinical studies, especially since 2'FL and LNnT are among the HMOs now being added to infant formula. Furthermore, altered HMO composition may mediate the impact of maternal prepregnancy BMI on childhood obesity, which warrants further investigation to establish the cause-and-effect relation.