Perinatal Programming of Asthma: The Role of Gut Microbiota

Perinatal programming, a dominant theory for the origins of cardiovascular disease, proposes that environmental stimuli influence developmental pathways during critical periods of prenatal and postnatal development, inducing permanent changes in metabolism. In this paper, we present evidence for the perinatal programming of asthma via the intestinal microbiome. While epigenetic mechanisms continue to provide new explanations for the programming hypothesis of asthma development, it is increasingly apparent that the intestinal microbiota plays an independent and potentially interactive role. Commensal gut bacteria are essential to immune system development, and exposures disrupting the infant gut microbiota have been linked to asthma. This paper summarizes the recent findings that implicate caesarean delivery, breastfeeding, perinatal stress, probiotics, and antibiotics as modifiers of infant gut microbiota in the development of asthma

FUT2 secretor genotype and susceptibility to infections and chronic conditions in the ALSPAC cohort

Background: The FUT2 (fucosyltransferase-2) gene determines blood group secretor status. Being homozygous for the inactive “non-secretor” rs601338(A) allele confers resistance to certain infections (e.g. Norovirus, Rotavirus) and susceptibility to others (e.g. Haemophilus influenza, Streptococcus pneumonia). Non-secretors also have an increased risk of type 1 diabetes and inflammatory bowel disease. We examined FUT2 genotype, infections and chronic conditions in a population-based cohort. Methods: We studied 7,582 pregnant women from the ALSPAC pregnancy cohort. Infections (measles, mumps, chicken pox, whooping cough, meningitis, herpes, gonorrhea and urinary infections) and chronic conditions (kidney disease, hypertension, diabetes, rheumatism, arthritis, psoriasis, hay fever, asthma, eczema and allergies) were self-reported. FUT2 secretor status was determined from the rs601338 genotype. ABO blood type was obtained from clinical records. Results: Overall, 1920 women (25.3%) were homozygous for the non-secretor allele (AA). Secretor status was associated with mumps, with 68% of non-secretors experiencing this infection, compared to 48% of secretors (RR, 1.40; 95% CI, 1.34–1.46). A weaker association was observed for measles infection (76% vs. 72%; RR, 1.05; 95% CI, 1.02–1.09). Non-secretors also experienced an increased risk of kidney disease (5.4% vs. 3.9%; RR, 1.39; 95% CI, 1.11–1.75). Independent of secretor status, AB blood type was a risk factor for mumps (RR 1.15; 95%CI, 1.03, 1.28 compared to type O). We found no evidence of interaction between secretor status and blood type.  For some conditions, including asthma and arthritis, FUT2 heterozygosity (GA) appeared to confer an intermediate phenotype. There was no strong evidence of association between secretor status and other infections or chronic conditions, although statistical power was limited for rare outcomes. Conclusion: Our results identify an association between FUT2 secretor status and self-reported kidney disease, and confirm a recently reported association with susceptibility to mumps infection. The clinical implications of these associations warrant further investigation

The Prebiotic and Probiotic Properties of Human Milk: Implications for Infant Immune Development and Pediatric Asthma

The incidence of pediatric asthma has increased substantially in recent decades, reaching a worldwide prevalence of 14%. This rapid increase may be attributed to the loss of “Old Friend” microbes from the human microbiota resulting in a less diverse and “dysbiotic” gut microbiota, which fails to optimally stimulate immune development during infancy. This hypothesis is supported by observations that the gut microbiota is different in infants who develop asthma later in life compared to those who remain healthy. Thus, early life exposures that influence gut microbiota play a crucial role in asthma development. Breastfeeding is one such exposure; it is generally considered protective against pediatric asthma, although conflicting results have been reported, potentially due to variations in milk composition between individuals and across populations. Human milk oligosaccharides (HMOs) and milk microbiota are two major milk components that influence the infant gut microbiota and hence, development of the immune system. Among their many immunomodulatory functions, HMOs exert a selective pressure within the infant gut microbial niche, preferentially promoting the proliferation of specific bacteria including Bifidobacteria. Milk is also a source of viable bacteria originating from the maternal gut and infant oral cavity. As such, breastmilk has prebiotic and probiotic properties that can modulate two of the main forces controlling the gut microbial community assembly, i.e., dispersal and selection. Here, we review the latest evidence, mechanisms and hypotheses for the synergistic and/or additive effects of milk microbiota and HMOs in protecting against pediatric asthma

The human milk proteome and allergy of mother and child: Exploring associations with protein abundances and protein network connectivity

BackgroundThe human milk proteome comprises a vast number of proteins with immunomodulatory functions, but it is not clear how this relates to allergy of the mother or allergy development in the breastfed infant. This study aimed to explore the relation between the human milk proteome and allergy of both mother and child.MethodsProteins were analyzed in milk samples from a subset of 300 mother-child dyads from the Canadian CHILD Cohort Study, selected based on maternal and child allergy phenotypes. For this selection, the definition of “allergy” included food allergy, eczema, allergic rhinitis, and asthma. Proteins were analyzed with non-targeted shotgun proteomics using filter-aided sample preparation (FASP) and nanoLC-Orbitrap-MS/MS. Protein abundances, based on label-free quantification, were compared using multiple statistical approaches, including univariate, multivariate, and network analyses.ResultsUsing univariate analysis, we observed a trend that milk for infants who develop an allergy by 3 years of age contains higher abundances of immunoglobulin chains, irrespective of the allergy status of the mother. This observation suggests a difference in the milk’s immunological potential, which might be related to the development of the infant’s immune system. Furthermore, network analysis showed overall increased connectivity of proteins in the milk of allergic mothers and milk for infants who ultimately develop an allergy. This difference in connectivity was especially noted for proteins involved in the protein translation machinery and may be due to the physiological status of the mother, which is reflected in the interconnectedness of proteins in her milk. In addition, it was shown that network analysis complements the other methods for data analysis by revealing complex associations between the milk proteome and mother-child allergy status.ConclusionTogether, these findings give new insights into how the human milk proteome, through differences in the abundance of individual proteins and protein-protein associations, relates to the allergy status of mother and child. In addition, these results inspire new research directions into the complex interplay of the mother-milk-infant triad and allergy

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics

In May 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of nutritionists, physiologists and microbiologists to review the definition and scope of synbiotics. The panel updated the definition of a synbiotic to “a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host”. The panel concluded that defining synbiotics as simply a mixture of probiotics and prebiotics could suppress the innovation of synbiotics that are designed to function cooperatively. Requiring that each component must meet the evidence and dose requirements for probiotics and prebiotics individually could also present an obstacle. Rather, the panel clarified that a complementary synbiotic, which has not been designed so that its component parts function cooperatively, must be composed of a probiotic plus a prebiotic, whereas a synergistic synbiotic does not need to be so. A synergistic synbiotic is a synbiotic for which the substrate is designed to be selectively utilized by the co-administered microorganisms. This Consensus Statement further explores the levels of evidence (existing and required), safety, effects upon targets and implications for stakeholders of the synbiotic concept

Breastfeeding and the origins of health: Interdisciplinary perspectives and priorities

Breastfeeding and human milk (HM) are critically important to maternal, infant and population health. This paper summarizes the proceedings of a workshop that convened a multidisciplinary panel of researchers to identify key priorities and anticipated breakthroughs in breastfeeding and HM research, discuss perceived barriers and challenges to achieving these breakthroughs and propose a constructive action plan to maximize the impact of future research in this field. Priority research areas identified were as follows: (1) addressing low breastfeeding rates and inequities using mixed methods, community partnerships and implementation science approaches; (2) improving awareness of evidence-based benefits, challenges and complexities of breastfeeding and HM among health practitioners and the public; (3) identifying differential impacts of alternative modes of HM feeding including expressed/pumped milk, donor milk and shared milk; and (4) developing a mechanistic understanding of the health effects of breastfeeding and the contributors to HM composition and variability. Key barriers and challenges included (1) overcoming methodological limitations of epidemiological breastfeeding research and mechanistic HM research; (2) counteracting ‘breastfeeding denialism’ arising from negative personal breastfeeding experiences; (3) distinguishing and aligning research and advocacy efforts; and (4) managing real and perceived conflicts of interest. To advance research on breastfeeding and HM and maximize the reach and impact of this research, larger investments are needed, interdisciplinary collaboration is essential, and the scientific community must engage families and other stakeholders in research planning and knowledge translation

Integrated Analysis of Human Milk Microbiota With Oligosaccharides and Fatty Acids in the CHILD Cohort

Background: Human milk contains many bioactive components that are typically studied in isolation, including bacteria. We performed an integrated analysis of human milk oligosaccharides and fatty acids to explore their associations with milk microbiota.Methods: We studied a sub-sample of 393 mothers in the CHILD birth cohort. Milk was collected at 3–4 months postpartum. Microbiota was analyzed by 16S rRNA gene V4 sequencing. Oligosaccharides and fatty acids were analyzed by rapid high-throughput high performance and gas liquid chromatography, respectively. Dimension reduction was performed with principal component analysis for oligosaccharides and fatty acids. Center log-ratio transformation was applied to all three components. Associations between components were assessed using Spearman rank correlation, network visualization, multivariable linear regression, redundancy analysis, and structural equation modeling. P-values were adjusted for multiple comparisons. Key covariates were considered, including fucosyltransferase-2 (FUT2) secretor status of mother and infant, method of feeding (direct breastfeeding or pumped breast milk), and maternal fish oil supplement use.Results: Overall, correlations were strongest between milk components of the same type. For example, FUT2-dependent HMOs were positively correlated with each other, and Staphylococcus was negatively correlated with other core taxa. Some associations were also observed between components of different types. Using redundancy analysis and structural equation modeling, the overall milk fatty acid profile was significantly associated with milk microbiota composition. In addition, some individual fatty acids [22:6n3 (docosahexaenoic acid), 22:5n3, 20:5n3, 17:0, 18:0] and oligosaccharides (fucosyl-lacto-N-hexaose, lacto-N-hexaose, lacto-N-fucopentaose I) were associated with microbiota α diversity, while others (C18:0, 3′-sialyllactose, disialyl-lacto-N-tetraose) were associated with overall microbiota composition. Only a few significant associations between individual HMOs and microbiota were observed; notably, among mothers using breast pumps, Bifidobacterium prevalence was associated with lower abundances of disialyl-lacto-N-hexaose. Additionally, among non-secretor mothers, Staphylococcus was positively correlated with sialylated HMOs.Conclusion: Using multiple approaches to integrate and analyse milk microbiota, oligosaccharides, and fatty acids, we observed several associations between different milk components and microbiota, some of which were modified by secretor status and/or breastfeeding practices. Additional research is needed to further validate and mechanistically characterize these associations and determine their relevance to infant gut and respiratory microbiota development and health