Genetic and Physiological Factors Affecting Human Milk Production and Composition.

Human milk is considered the optimal nutrition for infants as it provides additional attributes other than nutritional support for the infant and contributes to the mother's health as well. Although breastfeeding is the most natural modality to feed infants, nowadays, many mothers complain about breastfeeding difficulties. In addition to environmental factors that may influence lactation outcomes including maternal nutrition status, partner's support, stress, and latching ability of the infant, intrinsic factors such as maternal genetics may also affect the quantitative production and qualitative content of human milk. These genetic factors, which may largely affect the infant's growth and development, as well as the mother's breastfeeding experience, are the subject of the present review. We specifically describe genetic variations that were shown to affect quantitative human milk supply and/or its qualitative content. We further discuss possible implications and methods for diagnosis as well as treatment modalities. Although cases of nutrient-deficient human milk are considered rare, in some ethnic groups, genetic variations that affect human milk content are more abundant, and they should receive greater attention for diagnosis and treatment when necessary. From a future perspective, early genetic diagnosis should be directed to target and treat breastfeeding difficulties in real time.

A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother's own milk for preterm infants in the NICU.

BACKGROUND: Necrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at < 30 weeks' gestation. The incidence of NEC is reduced when infants are fed human milk. However, in many neonatal intensive care units (NICUs), it is standard practice to freeze and/or pasteurize human milk, which deactivates bioactive components that may offer additional protective benefits. Indeed, our pilot study showed that one feed of fresh mother's own milk per day was safe, feasible, and can reduce morbidity in preterm infants. To further evaluate the benefits of fresh human milk in the NICU, a randomized controlled trial is needed. METHODS: Our prospective multicenter, double-blinded, randomized, controlled trial will include infants born at < 30 weeks' gestation and admitted to one of 29 tertiary NICUs in China. Infants in the intervention (fresh human milk) group (n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks' corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks' corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors. DISCUSSION: Our double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants. TRIAL REGISTRATION: Chinese Clinical Trial Registry; #ChiCTR1900020577; registered January 1, 2019; http://www.chictr.org.cn/showprojen.aspx?proj=34276.

Diet and the Human Gut Microbiome: An International Review.

This review summarizes the key results of recently published studies on the effects of dietary change and nutritional intervention on the human microbiome from around the world, focusing on the USA, Canada, Europe, Asia, and Africa. It first explores mechanisms that might explain the ability of fiber-rich foods to suppress the incidence and mortality from westernized diseases, notably cancers of the colon, breast, liver, cardiovascular, infectious, and respiratory diseases, diabetes, and obesity (O'Keefe in Lancet Gastroenterol Hepatol 4(12):984-996, 2019; Am J Clin Nutr 110:265-266, 2019). It summarizes studies from Africa which suggest that disturbance of the colonic microbiome may exacerbate chronic malnutrition and growth failure in impoverished communities and highlights the importance of breast feeding. The American section discusses the role of the microbiome in the swelling population of patients with obesity and type 2 diabetes and examines the effects of race, ethnicity, geography, and climate on microbial diversity and metabolism. The studies from Europe and Asia extoll the benefits of whole foods and plant-based diets. The Asian studies examine the worrying changes from low-fat, high-carbohydrate diets to high-fat, low-carbohydrate ones and the increasing appearance of westernized diseases as in Africa and documents the ability of high-fiber traditional Chinese diets to reverse type 2 diabetes and control weight loss. In conclusion, most of the studies reviewed demonstrate clear changes in microbe abundances and in the production of fermentation products, such as short-chain fatty acids and phytochemicals following dietary change, but the significance of the microbiota changes to human health, with the possible exception of the stimulation of butyrogenic taxa by fiber-rich foods, is generally implied and not measured. Further studies are needed to determine how these changes in microbiota composition and metabolism can improve our health and be used to prevent and treat disease.

Postpartum human breast milk levels of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9)/NGAL complex in normal and pregnancies complicated with insulin-dependent gestational diabetes mellitus. A prospective pilot case-control study.

Neutrophil gelatinase-associated lipocalin (NGAL) and its complex with matrix metalloproteinase-9 (MMP-9) are present in a variety of human tissues and extracellular fluids. The aim of this pilot prospective case-control study was to detect NGAL and MMP-9/NGAL complex in human breast milk postpartum in women with normal and pregnancies that developed insulin-depended gestational diabetes mellitus (iGDM). We detected both biomarkers in human breast milk and concentrations were determined at the first day of colostrum secretion and two days after, in 22 normal pregnancies and 13 pregnancies with iGDM. Mean NGAL concentration decreased significantly from the first to the second sample, in both groups. Mean MMP-9/NGAL complex concentration decreased also significantly from the first to the second sample in normal pregnancies. Mean complex concentration was significantly higher in diabetic pregnancies compared to normal ones in the second sample.IMPACT STATEMENTWhat is already known on this subject? There is limited information on the presence of Neutrophil gelatinase-associated lipocalin (NGAL) in human milk and its physiological role.What the results of this study add? It is the first time that MMP-9/NGAL complex is detected in human milk in both normal and pregnancies complicated with insulin-depended gestational diabetes mellitus (iGDM). We confirm the presence of NGAL in colostrum of normal pregnancies and for the first time we detected NGAL in milk of pregnancies with iGDM. Concentrations of NGAL and MMP-9/NGAL complex tend to lessen postpartum in both groups. Pregnancies with iGDM compared to normal ones showed significantly higher concentration of MMP-9/NGAL complex two days after the beginning of lactation.What the implications are of these findings for clinical practice and/or further research? Further studies are necessary to determine the levels of NGAL and MMP-9/NGAL complex in human milk postpartum in normal and pathological pregnancies. Taking into consideration the well-established NGAL's ability to act as a bacteriostatic agent and its mucosal healing activity in gastrointestinal track, early breastfeeding of neonates is a logical recommendation. Finally, new studies on the actual physiological role of milk NGAL in neonates are necessary.

A Comparison of Changes in the Fatty Acid Profile of Human Milk of Spanish Lactating Women during the First Month of Lactation Using Gas Chromatography-Mass Spectrometry. A Comparison with Infant Formulas.

Breastfeeding is the ideal way to provide infants with the nutrients they need for healthy growth and development. Milk composition changes throughout lactation, and fat is one of the most variable nutrients in human milk. The aim of this study was to determine the main differences between the fatty acid (FA) profile of human milk samples (colostrum, transitional, and mature milk group) and infant formulas. Human milk samples were provided by lactating women from Granada. Moreover, different commercial infant formulas were analyzed. FAs were determined using gas chromatography coupled with mass spectrometry. According to the results, oleic acid was the predominant monounsaturated fatty acid (41.93% in human milk and 43.53% in infant formulas), while palmitic acid was the most representative saturated fatty acid (20.88% in human milk and 23.09% in infant formulas). Significant differences were found between human milk groups and infant formulas, mainly in long-chain polyunsaturated FAs (LC-PUFAs). The content of araquidonic acid (AA) and docoxahexaenoic acid (DHA) was higher in human milk (0.51% and 0.39%, respectively) than in infant formulas (0.31% and 0.22%, respectively). Linoleic acid (LA) percentage (15.31%) in infant formulas was similar to that found in human milk (14.6%). However, α-linolenic acid (ALA) values were also much higher in infant formulas than in human milk (1.64% and 0.42%, respectively).

Breast Milk-Derived Extracellular Vesicles Enriched in Exosomes From Mothers With Type 1 Diabetes Contain Aberrant Levels of microRNAs.

The breast milk plays a crucial role in shaping the initial intestinal microbiota and mucosal immunity of the infant. Interestingly, breastfeeding has proven to be protective against the early onset of immune-mediated diseases including type 1 diabetes. Studies have shown that exosomes from human breast milk are enriched in immune-modulating miRNAs suggesting that exosomal miRNAs (exomiRs) transferred to the infant could play a critical role in the development of the infant's immune system. We extracted exomiRs from breast milk of 52 lactating mothers (26 mothers with type 1 diabetes and 26 healthy mothers), to identify any differences in the exomiR content between the two groups. Small RNA-sequencing was performed to identify known and novel miRNAs in both groups. A total of 631 exomiRs were detected by small RNA sequencing including immune-related miRNAs such as hsa-let-7c, hsa-miR-21, hsa-miR-34a, hsa-miR-146b, and hsa-miR-200b. In addition, ~200 novel miRNAs were identified in both type 1 diabetes and control samples. Among the known miRNAs, nine exomiR's were found differentially expressed in mothers with type 1 diabetes compared to healthy mothers. The highly up-regulated miRNAs, hsa-miR-4497, and hsa-miR-3178, increased lipopolysaccharide-induced expression and secretion of tumor necrosis factor α (TNFα) in human monocytes. The up-regulated miRNA target genes were significantly enriched for longevity-regulating pathways and FoxO signaling. Our findings suggest a role of breast milk-derived exomiRs in modulating the infant's immune system.

Aleitamento materno e seus benefícios para a saúde da mulher / Breastfeeding and the benefits of lactation for women's health

A oferta do seio materno às crianças é um direito inquestionável das mães e de seus filhos, e todos os esforços devem ser feitos no sentido de promover, acompanhar e manter o aleitamento materno exclusivo até os 6 meses e complementado até que a criança complete 2 anos de idade. A literatura apresenta incontáveis publicações acerca das qualidades do leite materno, seus benefícios e repercussões para a saúde, estimulando a prática do aleitamento materno e embasando campanhas. Porém, mesmo sendo de conhecimento geral que a amamentação é uma importante etapa no processo reprodutivo da mulher e que sua prática oferece benefícios para mãe e filho, a grande maioria das informações destaca os benefícios que o leite materno oferece às crianças, esquecendo-se de mencionar todas as repercussões que o aleitamento materno traz para a saúde da mãe. Assim, o objetivo deste artigo é destacar os inúmeros benefícios que o aleitamento materno proporciona à saúde física e emocional da lactante. Para tanto, os autores consultaram artigos publicados nas bases de dados PubMed, Biblioteca Virtual de Saúde e Web of Science utilizando as palavras-chave aleitamento materno, leite materno, lactação e saúde materna.(AU)

The offer of the maternal breast to the baby is an unquestionable right of mothers and their children, and all efforts should be made to promote, follow and maintain exclusive breastfeeding for up to 6months and supplement it until the child completes 2 years of age. Many publications are available in the literature about the qualities of breast milk, its benefits and health repercussions, stimulating the practice of breastfeeding and supporting campaigns for its implementation. However, although it is widely known that breastfeeding is an important step in the reproductive process of women and its practice offers benefits to both mother and child, most of the available information highlights the benefits of breast milk for children, while mention of the effects of breastfeeding on the health of the mother is usually neglected. Thus, the objective of the present study is to highlight the multiple benefits of breastfeeding for the physical and emotional health of the nursing mother. The authors consulted articles published in the databases PubMed, Virtual Health Library and Web of Science using the keywords breastfeeding, breast milk, lactation and maternal health.(AU)

Comportamiento de la lactancia materna. Consultorio Médico de Familia No. 16. Policlínico "Manuel Piti Fajardo" / Behavior of the breastfeeding. Family Doctor´s Office Nr. 16. Policlínic "Manuel Piti Fajardo"

RESUMEN Introducción: que un niño reciba y se alimente con lactancia materna en las sociedades actuales, cada día es una tarea más compleja. Objetivo: caracterizar el comportamiento de la lactancia materna en el Consultorio Médico de Familia No 16. Policlínico "Manuel Piti Fajardo", municipio Cárdenas. Materiales y métodos: se realizó un estudio observacional, descriptivo, transversal. El universo lo constituyeron 68 madres de nacidos vivos pertenecientes a esa área de salud, en el período de enero 2011 -diciembre 2015. Las variables estudiadas fueron: edad, nivel escolar, ocupación, tiempo de lactancia, factores que incidieron en la suspensión de la lactancia materna, planificación familiar, conocimientos sobre lactancia materna. Los datos se obtuvieron de las historias clínicas familiares e individuales, del registro de nacimientos del Departamento de Estadística del Policlínico, del Análisis Integral de la Situación de Salud del Consultorio, la encuesta y la observación. Resultados: predominó en las madres de nacidos vivos el grupo de edad de 25 a 29 años, con el 41,7 %. El 77,9 % tenían nivel preuniversitario y el 47,0 % eran trabajadoras. El 47,5 % lactan entre 1-3 meses. Incidió en el abandono de la lactancia materna el no tener suficiente leche con un 44,1 %, el 50,0 % no planificaron el embarazo, y el 58,8 % no poseían los conocimientos adecuados. Conclusiones: un elevado porcentaje de las madres lactan hasta los 3 primeros meses de vida, la causa de abandono más frecuente de lactancia materna fue el no tener suficiente leche. Prevaleceieron los conocimientos no adecuados sobre la lactancia materna.

ABSTRACT Introduction: breastfeeding in current societies is a very complex task. Objective: to characterize breastfeeding in the Family Doctor´s Office Nr. 16 of the Policlinic ¨Manuel Pity Fajardo¨, municipality of Cardenas. Materials and methods: a cross-sectional, descriptive, observational study was carried out. The universe was composed by 68 mothers of born-alive children belonging to that health area in the period January 2011-December 2015. The studied variables were age, scholarship, job, breastfeeding time, factors causing breastfeeding delay, family planning, and knowledge on breastfeeding. Data were gathered from the individual and family records, from the births´ register of the Policlinic Statistics Department, from the Comprehensive Analysis of Health Situation, enquire and observation. Results: the 25-29-years-old age group predominated among mothers of born-alive children (41.7 %). 77.9 % had senior high school scholarship, and 47.0 % were workers. 47.5 % of them breastfeed 1-3 months. Not having enough breast milk (44.1 %), a non-planed pregnancy (50.0 %), and not having the adequate knowledge (58.8 %) influenced in breastfeeding delay. Conclusions: a high percent of mothers breastfeed just during the first three months of life; the most common cause of breastfeeding delay was not having enough breast milk. There it was a prevalence of non-adequate knowledge on maternal breastfeeding.

Human Milk and Clinical Outcomes in Preterm Infants.

The LOVE MOM cohort (Longitudinal Outcomes of VLBW Infants Exposed to Mothers' Own Milk; NIH: R010009; Meier PI) enrolled 430 infants with very low birth weight (VLBW) between 2008 and 2012 to study the impact of the dose and exposure period of MOM during hospitalization in the neonatal intensive care unit (NICU) on potentially preventable complications of prematurity and their associated costs. In this prospective study, MOM and formula feedings were calculated daily (mL), medical diagnoses for NICU morbidities (necrotizing enterocolitis [NEC], late-onset sepsis [sepsis], and bronchopulmonary dysplasia [BPD]) were confirmed independently by 2 neonatologists, and propensity scoring was used to analyze covariates. Neurodevelopmental outcome was measured for a subset of 251 LOVE MOM infants at 20 months of age, corrected for prematurity (CA). Data revealed a dose-response relationship between higher amounts of MOM received during critical NICU exposure periods and a reduction in the risk of NEC, sepsis, BPD, and their costs, as well as higher cognitive index scores at 20 months CA. MOM appears to function via different mechanisms during NICU exposure periods to reduce the risk of potentially preventable complications and their costs in VLBW infants. Institutions should prioritize the economic investments needed to acquire, store, and feed high-dose MOM in this population.

Water-Soluble Vitamins in Human Milk Factors Affecting Their Concentration and Their Physiological Significance.

Most B vitamins and vitamin C are among the nutrients in milk most strongly affected by maternal status and/or dietary intake. Recent analytical methods are more efficient and valid, revealing major differences in water-soluble vitamins across population groups. An inadequate supply in milk can be detrimental to the breastfed infant's health and development although cutoff points below which risk is increased are often uncertain, and little attention has been paid to adverse effects of low milk water-soluble vitamins on infant health and function. Concentrations change during lactation: thiamine, niacin, and pantothenic acid increase; B6, B12, and ascorbic acid gradually decrease; while riboflavin concentrations are stable, as is choline after an initial increase. Folate fluctuates until stabilizing in late lactation. Water-soluble vitamin concentrations in milk are also influenced by maternal supplementation, and, for some, by parity, preterm delivery, smoking, and maternal illness. However, there is relatively little change in concentrations during a feed nor is diurnal variation a major influence. Reported concentrations are used to set adequate intakes for infants and incremental requirements for lactation. However, the status of available data is poor due to the small number of participants in most studies, uncertainties about maternal nutritional status, and variable times of milk collection postpartum.

Impact of Maternal Nutrition and Perinatal Factors on Breast Milk Composition after Premature Delivery.

(1) Background: Premature infants require mothers' milk fortification to meet nutrition needs, but breast milk composition may be variable, leading to the risk of inadequate nutrition. We aimed at determining the factors influencing mothers' milk macronutrients. (2) Methods: Milk samples were analyzed for the first five weeks after premature delivery by infrared spectroscopy. Mothers' nutritional intake data were obtained during standardized interviews with dieticians, and then analyzed with reference software. (3) Results: The composition of 367 milk samples from 81 mothers was (median (range) g/100 mL): carbohydrates 6.8 (4.4⁻7.3), lipids 3.4 (1.3⁻6.4), proteins 1.3 (0.1⁻3.1). There was a relationship between milk composition and mothers' carbohydrates intake only (r = 0.164; p < 0.01). Postnatal age was correlated with milk proteins (r = -0.505; p < 0.001) and carbohydrates (r = +0.202, p < 0.001). Multiple linear regression analyses showed (coefficient) a relationship between milk proteins r = 0.547 and postnatal age (-0.028), carbohydrate intake (+0.449), and the absence of maturation (-0.066); associations were also found among milk lipids r = 0.295, carbohydrate intake (+1.279), and smoking (-0.557). Finally, there was a relationship among the concentration of milk carbohydrates r = 0.266, postnatal age (+0.012), and smoking (-0.167). (4) Conclusions: The variability of mothers' milk composition is differentially associated for each macronutrient with maternal carbohydrate intake, antenatal steroids, smoking, and postnatal age. Improvement in milk composition could be achieved by the modification of these related factors.

Association between human breast milk and retinopathy of prematurity / Associação entre ingesta de leite materno e desenvolvimento de retinopatia da prematuridade

ABSTRACT Purpose: To evaluate the possible protective effect of breast milk against retinopathy of prematurity by comparing the amount of breast milk received by patients who developed retinopathy of prematurity and those who did not and to determine both the required minimum amount of breast milk and the time of life during which neonates need to receive breast milk for this effect to be significant. Methods: Cohort study of newborns with a birth weight of <1500 g or gestational age of <32 weeks, or both, born between January 2011 and October 2014 and hospitalized within the first 24 h of life in the Hospital Criança Conceição Neonatal Intensive Care Unit in Porto Alegre, RS, Brazil. Results: The prevalence of retinopathy of prematurity of any degree was 31% (100 of 323 patients) and that of severe retinopathy of prematurity was of 9% (29 of 323 patients). The median amounts of breast milk received daily by patients with and without retinopathy of prematurity were 4.9 mL/kg (interquartile range, 0.3-15.4) and 10.2 mL/kg (1.5-25.5), respectively. The amount of breast milk received in the first 6 weeks of life was inversely associated with the incidence of both retinopathy of prematurity of any degree and severe retinopathy of prematurity in the univariate analyses. However, the statistical significance was maintained only during the sixth week of life in a per-period multivariate analysis controlling for confounding factors. Conclusions: Small amounts of breast milk are inadequate to prevent retinopathy of prematurity in premature newborns at risk for the disease.

RESUMO Objetivos: Avaliar o possível efeito protetor do leite materno contra a retinopatia da prematuridade, através da comparação da quantidade de leite materno recebida entre os pacientes que desenvolveram retinopatia da prematuridade e aqueles livres da doença. Tentar determinar a quantidade mínima necessária e o momento em que o recém-nascido precisa receber o leite materno para que esse efeito seja significativo. Métodos: Estudo de coorte observacional incluindo recém-nascidos com peso de nascimento inferior a 1500 gramas e/ou com idade gestacional inferior a 32 semanas, nascidos no período de janeiro de 2011 a outubro de 2014 e internados nas primeiras 24 horas de vida na UTI Neonatal do Hospital da Criança Conceição em Porto Alegre. Resultados: A prevalência da retinopatia da prematuridade em qualquer grau foi de 31% (100 casos em 323 pacientes) e a de retinopatia da prematuridade grave foi de 9% (29 casos em 323 pacientes). A mediana da quantidade de leite materno recebida pelos pacientes foi de 10,2 mL/kg/dia entre os pacientes sem retinopatia da prematuridade (amplitude interquartil 1,5-25,5) e de 4,9 mL/kg/dia entre os pacientes com retinopatia da prematuridade (0,3-15,4). A quantidade de leite materno recebida nas primeiras seis semanas de vida foi inversamente associada à incidência de retinopatia da prematuridade em qualquer grau e de retinopatia da prematuridade grave nas análises univariadas, mas a significância estatística não se manteve após análise multivariada para controle de fatores confundidores na maioria dos períodos avaliados, exceto na sexta semana de vida. Conclusão: Pequenas quantidades de leite materno não são suficientes para prevenção de retinopatia da prematuridade em recém-nascidos com de risco para a doença.

A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula.

Purpose: Chemicals with hormonelike activity, such as estrogenic isoflavones, may perturb human development. Infants exclusively fed soy-based formula are highly exposed to isoflavones, but their physiologic responses remain uncharacterized. Estrogen-responsive postnatal development was compared in infants exclusively fed soy formula, cow-milk formula, and breast milk. Methods: We enrolled 410 infants born in Philadelphia-area hospitals between 2010 and 2014; 283 were exclusively fed soy formula (n = 102), cow-milk formula (n = 111), or breast milk (n = 70) throughout the study (birth to 28 or 36 weeks for boys and girls, respectively). We repeatedly measured maturation index (MI) in vaginal and urethral epithelial cells using standard cytological methods, uterine volume and breast-bud diameter using ultrasound, and serum estradiol and follicle-stimulating hormone levels. We estimated MI, organ-growth, and hormone trajectories by diet using mixed-effects regression splines. Results: Maternal demographics did not differ between cow-milk-fed and soy-fed infants but did differ between formula-fed and breastfed infants. Vaginal-cell MI trended higher (P = 0.01) and uterine volume decreased more slowly (P = 0.01) in soy-fed girls compared with cow-milk-fed girls; however, their trajectories of breast-bud diameter and hormone concentrations did not differ. We observed no significant differences between boys fed cow-milk vs soy formula; estradiol was not detectable. Breastfed infants differed from soy-formula-fed infants in vaginal-cell MI, uterine volume, and girls' estradiol and boys' breast-bud diameter trajectories. Conclusions: Relative to girls fed cow-milk formula, those fed soy formula demonstrated tissue- and organ-level developmental trajectories consistent with response to exogenous estrogen exposure. Studies are needed to further evaluate the effects of soy on child development.

A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects.

SLC30A2 encodes a zinc (Zn) transporter (ZnT2) that imports Zn into vesicles in highly-specialized secretory cells. Numerous mutations and non-synonymous variants in ZnT2 have been reported in humans and in breastfeeding women; ZnT2 variants are associated with abnormally low milk Zn levels and can lead to severe infantile Zn deficiency. However, ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and vesicle secretion, indicating that normal ZnT2 function is critical for MEC function. Here we report that women who harbor a common ZnT2 variant (T288S) present with elevated levels of several oxidative and endoplasmic reticulum (ER) stress markers in their breast milk. Functional studies in vitro suggest that substitution of threonine for serine at amino acid 288 leads to hyperphosphorylation retaining ZnT2 in the ER and lysosomes, increasing ER and lysosomal Zn accumulation, ER stress, the generation of reactive oxygen species, and STAT3 activation. These changes were associated with decreased abundance of zona occludens-1 and increased tight junction permeability. This study confirms that ZnT2 is important for normal breast function in women during lactation, and suggests that women who harbor defective variants in ZnT2 may be at-risk for poor lactation performance.

Breastfeeding effects on DNA methylation in the offspring: A systematic literature review.

BACKGROUND: Breastfeeding benefits both infants and mothers. Recent research shows long-term health and human capital benefits among individuals who were breastfed. Epigenetic mechanisms have been suggested as potential mediators of the effects of early-life exposures on later health outcomes. We reviewed the literature on the potential effects of breastfeeding on DNA methylation. METHODS: Studies reporting original results and evaluating DNA methylation differences according to breastfeeding/breast milk groups (e.g., ever vs. never comparisons, different categories of breastfeeding duration, etc) were eligible. Six databases were searched simultaneously using Ovid, and the resulting studies were evaluated independently by two reviewers. RESULTS: Seven eligible studies were identified. Five were conducted in humans. Studies were heterogeneous regarding sample selection, age, target methylation regions, methylation measurement and breastfeeding categorisation. Collectively, the studies suggest that breastfeeding might be negatively associated with promoter methylation of LEP (which encodes an anorexigenic hormone), CDKN2A (involved in tumour suppression) and Slc2a4 genes (which encodes an insulin-related glucose transporter) and positively with promoter methylation of the Nyp (which encodes an orexigenic neuropeptide) gene, as well as influence global methylation patterns and modulate epigenetic effects of some genetic variants. CONCLUSIONS: The findings from our systematic review are far from conclusive due to the small number of studies and their inherent limitations. Further studies are required to understand the actual potential role of epigenetics in the associations of breastfeeding with later health outcomes. Suggestions for future investigations, focusing on epigenome-wide association studies, are provided.

Cytokine modulation (IL-6, IL-8, IL-10) by human breast milk lipids on intestinal epithelial cells (Caco-2).

Human breast milk is the best form of nourishment for infants during the first year of life. It is composed by a complex mixture of carbohydrates, proteins and fats. Breast milk provides nutrients and bioactive factors that themselves modulate maturation and development of the gastrointestinal tract. Many studies have shown that it provides protection against gastrointestinal tract inflammation. In this sense, this study aimed to evaluate the effect of human breast milk lipids on epithelial intestinal cells (Caco-2) cytokine regulation and the fatty acid transporter protein (FATP) involved in this process. Caco-2 cells were cultivated and stimulated with different concentration of human milk lipids from healthy human mothers (18-30-year-olds) or single commercial lipids for 48 h. We measured the concentrations and mRNA levels of IL-6, IL-8 and IL-10 cytokines by immunoassay (ELISA) and quantitative-PCR (qRT-PCR) technique, respectively. We observed a two to three times decrease in pro-inflammatory cytokine levels (p < 0.01) as well as an increase in anti-inflammatory IL-10 levels in cells stimulated with increasing concentrations of breast milk lipids. These results suggest that human breast milk lipids could have an important role on the cytokine modulation in the newborn bowel.

Níveis séricos do Fator neurotrófico derivado do cérebro e citocinas e a duração da amamentação em crianças e adolescentes / Serum levels of brain-derived neurotrophic factor and cytokines and duration of breastfeeding in children adolescents

INTRODUÇÃO: O Fator Neurotrófico Derivado do Cérebro (BDNF) é uma importante neurotrofina que está presente no tecido cerebral e periférico. O leite materno é considerado o alimento “padrão ouro” para o desenvolvimento cerebral, tornando o desmame precoce um fator de risco no desenvolvimento infantil. OBJETIVO: Avaliar a concentração de BDNF, IL6, IL10, TNF-α em crianças e correlacionar com a duração da amamentação. MÉTODOS: Trinta e sete crianças foram recrutadas e classificadas de acordo com a duração do aleitamento materno: < 6 meses (desmame precoce) e ≥ 6 meses. Foram realizadas duas consultas: a consulta basal em 2007 (T0) e a consulta de seguimento em 2011 (T1). Os níveis séricos de BDNF foram avaliados por ELISA sanduíche e os de citocinas por citometria de fluxo. RESULTADOS: Níveis séricos de BDNF em T0 foram significativamente menores no grupo amamentado por ≥ 6 meses (p=0,025), sendo que este não teve diferença entre os grupos em T1 (p=0,863). Níveis de IL6 apresentaram-se aumentados significativamente em T0 no grupo de desmame precoce (p=0,016). O IMC em T1 foi maior no grupo de desmame precoce (p=0,007). E em relação aos níveis de IL10 e TNF-α não houve diferenças significativas entre os grupos. CONCLUSÃO: Os resultados deste estudo mostraram semelhanças entre os níveis séricos de BDNF medidos a longo prazo, entre crianças amamentadas por < 6 meses e ≥ 6 meses, sugerindo que futuros estudos são necessários, com dosagens durante o período de amamentação para investigar o papel de marcadores neuroquímicos na duração do aleitamento materno e suas implicações no estado nutricional e cognição das crianças amamentadas.

BACKGROUND: The Brain-Derived Neurotrophic Factor (BDNF) is an important neurotrophin found in the brain and peripheral tissues. Breast milk is considered to be the “gold standard” food for brain development, making early weaning a risk factor in child development. AIM: To evaluate the concentration of BDNF, IL6, IL10, TNF-α in children and its correlation with the duration of breastfeeding. METHODS: Thirty-seven children were recruited and classified according to the duration of breastfeeding: <6 months (early weaning) and ≥ 6 months. There were two visits: the baseline interview in 2007 (T0) and the follow-up visit in 2011 (T1). BDNF levels were assayed using a sandwich ELISA, and cytokines were assayed with flow cytometry. RESULTS: Serum BDNF levels at T0 were significantly lower in the group breastfed for ≥ 6 months (p = 0.025), and they did not differ between groups at T1 (p = 0.863). IL-6 levels were significantly increased in the early weaning group at T0 (p = 0.016). Body mass index at T1 was higher in the early weaning group (p = 0.007). There was no significant difference in IL10 and TNF-α levels between groups. CONCLUSION: The results of this study showed similarities in serum BDNF levels over time between children who had been breastfed <6months and ≥ 6 months. This suggests that further studies, with measurements taken during the breastfeeding period, are needed to investigate the role of neurochemical markers in the duration of breastfeeding and its implications on nutritional status and cognition of breastfed children.

Inactivation of hepatitis C virus infectivity by human breast milk.

BACKGROUND: Hepatitis C virus (HCV) is spread through direct contact with blood, although alternative routes of transmission may contribute to the global burden. Perinatal infection occurs in up to 5% of HCV-infected mothers, and presence of HCV RNA in breast milk has been reported. We investigated the influence of breast milk on HCV infectiousness. METHODS/RESULTS: Human breast milk reduced HCV infectivity in a dose-dependent manner. This effect was species-specific because milk from various animals did not inhibit HCV infection. Treatment of HCV with human breast milk did not compromise integrity of viral RNA or capsids but destroyed the lipid envelope. Fractionation of breast milk revealed that the antiviral activity is present in the cream fraction containing the fat. Proteolytic digestion of milk proteins had no influence on its antiviral activity, whereas prolonged storage at 4°C increased antiviral activity. Notably, pretreatment with a lipase inhibitor ablated the antiviral activity and specific free fatty acids of breast milk were antiviral. CONCLUSIONS: The antiviral activity of breast milk is linked to endogenous lipase-dependent generation of free fatty acids, which destroy the viral lipid envelope. Therefore, nursing by HCV-positive mothers is unlikely to play a major role in vertical transmission.