Critical advancement is needed in the study of human milk as a biological system that intersects and interacts with myriad internal (maternal biology) and external (diet, environment, infections) ...factors and its plethora of influences on the developing infant. Human-milk composition and its resulting biological function is more than the sum of its parts. Our failure to fully understand this biology in a large part contributes to why the duration of exclusive breastfeeding remains an unsettled science (if not policy). Our current understanding of human-milk composition and its individual components and their functions fails to fully recognize the importance of the chronobiology and systems biology of human milk in the context of milk synthesis, optimal timing and duration of feeding, and period of lactation. The overly simplistic, but common, approach to analyzing single, mostly nutritive components of human milk is insufficient to understand the contribution of either individual components or the matrix within which they exist to both maternal and child health. There is a need for a shift in the conceptual approach to studying human milk to improve strategies and interventions to support better lactation, breastfeeding, and the full range of infant feeding practices, particularly for women and infants living in undernourished and infectious environments. Recent technological advances have led to a rising movement towards advancing the science of human-milk biology. Herein, we describe the rationale and critical need for unveiling the multifunctionality of the various nutritional, nonnutritional, immune, and biological signaling pathways of the components in human milk that drive system development and maturation, growth, and development in the very early postnatal period of life. We provide a vision and conceptual framework for a research strategy and agenda to change the field of human-milk biology with implications for global policy, innovation, and interventions.
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Breast milk is the primary source of nutrition for newborns, and is rich in immunological components. MicroRNAs (miRNAs) are present in various body fluids and are selectively packaged inside the ...exosomes, a type of membrane vesicles, secreted by most cell types. These exosomal miRNAs could be actively delivered into recipient cells, and could regulate target gene expression and recipient cell function. Here, we analyzed the lactation-related miRNA expression profiles in porcine milk exosomes across the entire lactation period (newborn to 28 days after birth) by a deep sequencing. We found that immune-related miRNAs are present and enriched in breast milk exosomes (p<10(-16), χ(2) test) and are generally resistant to relatively harsh conditions. Notably, these exosomal miRNAs are present in higher numbers in the colostrums than in mature milk. It was higher in the serum of colostrum-only fed piglets compared with the mature milk-only fed piglets. These immune-related miRNA-loaded exosomes in breast milk may be transferred into the infant body via the digestive tract. These observations are a prelude to in-depth investigations of the essential roles of breast milk in the development of the infant's immune system.
Human milk is a complex fluid comprised of myriad substances, with one of the most abundant substances being a group of complex carbohydrates referred to as human milk oligosaccharides (HMOs). There ...has been some evidence that HMO profiles differ in populations, but few studies have rigorously explored this variability.
We tested the hypothesis that HMO profiles differ in diverse populations of healthy women. Next, we examined relations between HMO and maternal anthropometric and reproductive indexes and indirectly examined whether differences were likely related to genetic or environmental variations.
In this cross-sectional, observational study, milk was collected from a total of 410 healthy, breastfeeding women in 11 international cohorts and analyzed for HMOs by using high-performance liquid chromatography.
There was an effect of the cohort (
< 0.05) on concentrations of almost all HMOs. For instance, the mean 3-fucosyllactose concentration was >4 times higher in milk collected in Sweden than in milk collected in rural Gambia (mean ± SEM: 473 ± 55 compared with 103 ± 16 nmol/mL, respectively;
< 0.05), and disialyllacto-
-tetraose (DSLNT) concentrations ranged from 216 ± 14 nmol/mL (in Sweden) to 870 ± 68 nmol/mL (in rural Gambia) (
< 0.05). Maternal age, time postpartum, weight, and body mass index were all correlated with several HMOs, and multiple differences in HMOs e.g., lacto-
-neotetrose and DSLNT were shown between ethnically similar (and likely genetically similar) populations who were living in different locations, which suggests that the environment may play a role in regulating the synthesis of HMOs.
The results of this study support our hypothesis that normal HMO concentrations and profiles vary geographically, even in healthy women. Targeted genomic analyses are required to determine whether these differences are due at least in part to genetic variation. A careful examination of sociocultural, behavioral, and environmental factors is needed to determine their roles in this regard. This study was registered at clinicaltrials.gov as NCT02670278.
Life history theory assumes there are trade-offs between competing functions such as reproduction and immunity. Although well studied in birds, studies of the trade-offs between reproduction and ...immunity in small mammals are scarce. Here we examined whether reduced immunity is a consequence of reproductive effort in lactating Brandt's voles (Lasiopodomys brandtii). Specifically, we tested the effects of lactation on immune function (Experiment I). The results showed that food intake and resting metabolic rate (RMR) were higher in lactating voles (6≤ litter size ≤8) than that in non-reproductive voles. Contrary to our expectation, lactating voles also had higher levels of serum total Immunoglobulin G (IgG) and anti-keyhole limpet hemocyanin (KLH) IgG and no change in phytohemagglutinin (PHA) response and anti-KLH Immunoglobulin M (IgM) compared with non-reproductive voles, suggesting improved rather than reduced immune function. To further test the effect of differences in reproductive investment on immunity, we compared the responses between natural large (n≥8) and small litter size (n≤6) (Experiment II) and manipulated large (11-13) and small litter size (2-3) (Experiment III). During peak lactation, acquired immunity (PHA response, anti-KLH IgG and anti-KLH IgM) was not significantly different between voles raising large or small litters in both experiments, despite the measured difference in reproductive investment (greater litter size, litter mass, RMR and food intake in the voles raising larger litters). Total IgG was higher in voles with natural large litter size than those with natural small litter size, but decreased in the enlarged litter size group compared with control and reduced group. Our results showed that immune function is not suppressed to compensate the high energy demands during lactation in Brandt's voles and contrasting the situation in birds, is unlikely to be an important aspect mediating the trade-off between reproduction and survival.
Macrophages are diverse immune cells that reside in all tissues. Although macrophages have been implicated in mammary-gland function, their diversity has not been fully addressed. By exploiting ...high-resolution three-dimensional imaging and flow cytometry, we identified a unique population of tissue-resident ductal macrophages that form a contiguous network between the luminal and basal layers of the epithelial tree throughout postnatal development. Ductal macrophages are long lived and constantly survey the epithelium through dendrite movement, revealed via advanced intravital imaging. Although initially originating from embryonic precursors, ductal macrophages derive from circulating monocytes as they expand during puberty. Moreover, they undergo proliferation in pregnancy to maintain complete coverage of the epithelium in lactation, when they are poised to phagocytose milk-producing cells post-lactation and facilitate remodelling. Interestingly, ductal macrophages strongly resemble mammary tumour macrophages and form a network that pervades the tumour. Thus, the mammary epithelium programs specialized resident macrophages in both physiological and tumorigenic contexts.
High ambient temperature has multiple potential effects on the organism such as hyperthermia, endotoxemia, and/or systemic inflammation. However, it is often difficult to discriminate between cause ...and consequence of phenotypic effects, such as the indirect influence of heat stress via reduced food intake. Lactating dairy cows are a particularly sensitive model to examine the effects of heat stress due to their intensive metabolic heat production and small surface:volume ratio. Results from this model show heat stress directly induced a so-far unknown infiltration of yet uncategorized cells into the mucosa and submucosa of the jejunum. Due to a pair-feeding design, we can exclude this effect being a consequence of the concurrent heat-induced reduction in feed intake. Isolation and characterization of the infiltrating cells using laser capture microdissection and RNA sequencing indicated a myeloic origin and macrophage-like phenotype. Furthermore, targeted transcriptome analyses provided evidence of activated immune- and phagocytosis-related pathways with LPS and cytokines as upstream regulators directly associated with heat stress. Finally, we obtained indication that heat stress may directly alter jejunal tight junction proteins suggesting an impaired intestinal barrier. The penetration of toxic and bacterial compounds during heat stress may have triggered a modulated immune repertoire and induced an antioxidative defense mechanism to maintain homeostasis between commensal bacteria and the jejunal immune system. Our bovine model indicates direct effects of heat stress on the jejunum of mammals already at moderately elevated ambient temperature. These results need to be considered when developing concepts to combat the negative consequences of heat stress.
Natural processes do not always function perfectly. In breastfeeding, problems are encountered in up to 80% of mother-infant dyads. Altogether, in Western societies, the difficulties reduce the ...breastfeeding rate within the first months drastically. To deal with the problems of breastfeeding efficiently requires a profound understanding of its physiology, as well as of its psychological and social determinants. This review focuses on the current knowledge of breastfeeding physiology, only touching the psychosocial factors, which are included in the promotion strategies. Subsequently, it scrutinizes definitions, incidences, prevention, and treatment of breastfeeding problems faced most frequently by nursing mothers and their consultants. Not all measures used in counseling mothers and not all treatments for the most common medical problems withstand a careful evaluation on the basis of current scientific data. However, applying proven prevention strategies will significantly improve the well being of mothers and their infants, and may contribute to an affective attitude that increases the success, frequency, and duration of breastfeeding.
Pregnancy-induced hypoaminoacidemia, ʟ-methionine (Met) included, disturbs embryogenesis and may also affect breast function. Supplementation with the dipeptideʟ-methionyl-Met (Met-Met) may improve ...lactation performance.
We compared the effects of supplemental Met or Met-Met during pregnancy on mammogenesis and lactogenesis and investigated underlying mechanisms.
In experiment 1, 9-wk-old ICR mice (n = 72, ~30 g) were divided into 3 groups. During the first 17 days of pregnancy (DP), the Control group was fed a diet with Met (8.2 g/kg) and saline was intraperitoneally injected, the Met group was fed a Met-devoid diet and 35% of the Met (92-mmoʟMet) as contained in the Control diet was intraperitoneally injected, and the Met-Met group was fed the same diet and 70-mmoʟMet plus 11-mmoʟMet-Met was intraperitoneally injected. All animals were fed the Control diet after DP17 and during lactation. Mammogenesis, lactogenesis, transcriptome at DP17, and milk performance during lactation were examined. In experiment 2, 9-wk-old ICR mice (n = 55, ~30 g) at DP0 were injected through the teat with adeno-associated virus for overexpression/inhibition of phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), divided into the Control, Met, and Met-Met groups and received the same treatment as experiment 1 to examine mammogenesis and lactogenesis at DP17.
In experiment 1, compared with the Met group, the Met-Met group showed higher (P < 0.05) mammary epithelium percentage (42%) and aS1-casein expression (84%) at DP17, milk yield (34%) and energy concentrations (8.7%) during lactation; transcriptomic analysis illustrated activated phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling in the mammary glands of the Met-Met group (P-adj < 0.001). In experiment 2, overexpression ofPik3r1enhanced (P < 0.05) the protective effect of Met-Met over Met on mammogenesis and β-casein expression.
Met-Met is more effective than Met in promoting mammogenesis and lactogenesis mainly by activation of PI3K-AKT signaling in Met-deficient mice.
Background: Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given its ...sensitivity to diet and contribution to regulating food intake through the integration of hormonal and cognitive signals, hippocampus may play a role in these relationships. Methods: We conducted a secondary analysis of 149, 7-11-year-olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume (GMV) was extracted from structural scans using CAT12, weight status was assessed using age- and sex-adjusted body mass index (%BMIp85), and parents reported exclusive breastfeeding duration and satiety responsiveness (Child Eating Behavior Questionnaire). Separate path models for left and right hippocampus tested: 1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal GMV; 2) the direct effect of hippocampal GMV on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and prematurity while hippocampal GMV was adjusted for total intercranial volume, age, and study from which data were extracted. Results: Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal GMV. While better satiety responsiveness and greater left hippocampal GMV were both associated with lower %BMIp85, hippocampal GMV was not associated with satiety responsiveness. Conclusions: While exclusive breastfeeding duration was not directly associated with weight status in children, these results highlight the potential impact of exclusive breastfeeding on hippocampal structure. Future studies need to determine the relative impact that complimentary feeding has on regional brain development and satiety responsiveness.
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