Summary
Background
Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium (C.) difficile colonization might be associated with ...allergic disease. Previous studies of infant gut microbiota in relation to subsequent allergy development have mostly employed culture‐dependent techniques, studied genera of bacteria and the follow‐up period was limited to 2 years.
Objective
To relate gut microbiota in early infancy, notably bifidobacteria and lactobacilli at species level, to allergy development during the first 5 years of life and study if environmental factors influence the early infant gut microbiota.
Methods
Fecal samples were collected at 1 week, 1 month and 2 months after birth from 47 Swedish infants, followed prospectively to 5 years of age. Bacterial DNA was analysed with real‐time PCR and related to allergy development, family size as well as endotoxin and Fel d 1 levels in house dust samples. Primers binding to C. difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis were used. Children regarded as allergic manifested allergic symptoms and were skin prick test positive during their first 5 years while non‐allergic children were neither.
Results
Children who developed allergy were significantly less often colonized with lactobacilli group I (Lactobacillus (L.) rhamnosus, L. casei, L. paracasei), Bifidobacterium adolescentis and C. difficile during their first 2 months. Infants colonized with several Bifidobacterium species had been exposed to higher amounts of endotoxin and grew up in larger families than infants harbouring few species.
Conclusion
A more diverse gut microbiota early in life might prevent allergy development and may be related to the previously suggested inverse relationship between allergy, family size and endotoxin exposure.
The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and diversity of microbial stimulation, resulting in abnormal postnatal immune maturation. Most studies ...investigating the underlying immunomodulatory mechanisms have focused on postnatal microbial exposure, for example demonstrating that the gut microbiota differs in composition and diversity during the first months of life in children who later do or do not develop allergic disease. However, it is also becoming increasingly evident that the maternal microbial environment during pregnancy is important in childhood immune programming, and the first microbial encounters may occur already in utero. During pregnancy, there is a close immunological interaction between the mother and her offspring, which provides important opportunities for the maternal microbial environment to influence the immune development of the child. In support of this theory, combined pre‐ and postnatal supplementations seem to be crucial for the preventive effect of probiotics on infant eczema. Here, the influence of microbial and immune interactions within the mother–offspring dyad on childhood allergy development will be discussed. In addition, how perinatal transmission of microbes and immunomodulatory factors from mother to offspring may shape appropriate immune maturation during infancy and beyond, potentially via epigenetic mechanisms, will be examined. Deeper understanding of these interactions between the maternal and offspring microbiome and immunity is needed to identify efficacious preventive measures to combat the allergy epidemic.
Summary
Background
Low total diversity of the gut microbiota during the first year of life is associated with allergic diseases in infancy, but little is known how early microbial diversity is ...related to allergic disease later in school age.
Objective
To assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to the prevalence of different allergic diseases in school age, such as asthma, allergic rhinoconjunctivitis (ARC) and eczema.
Methods
The microbial diversity and composition was analysed with barcoded 16S rDNA 454 pyrosequencing in stool samples at 1 week, 1 month and 12 months of age in 47 infants which were subsequently assessed for allergic disease and skin prick test reactivity at 7 years of age (ClinicalTrials.gov ID NCT01285830).
Results
Children developing asthma (n = 8) had a lower diversity of the total microbiota than non‐asthmatic children at 1 week (P = 0.04) and 1 month (P = 0.003) of age, whereas allergic rhinoconjunctivitis (n = 13), eczema (n = 12) and positive skin prick reactivity (n = 14) at 7 years of age did not associate with the gut microbiota diversity. Neither was asthma associated with the microbiota composition later in infancy (at 12 months). Children having IgE‐associated eczema in infancy and subsequently developing asthma had lower microbial diversity than those that did not. There were no significant differences, however, in relative abundance of bacterial phyla and genera between children with or without allergic disease.
Conclusion and Clinical Relevance
Low total diversity of the gut microbiota during the first month of life was associated with asthma but not ARC in children at 7 years of age. Measures affecting microbial colonization of the infant during the first month of life may impact asthma development in childhood.
Background Although a reduced gut microbiota diversity and low mucosal total IgA levels in infancy have been associated with allergy development, IgA responses to the gut microbiota have not yet been ...studied. Objective We sought to determine the proportions of IgA coating together with the characterization of the dominant bacteria, bound to IgA or not, in infant stool samples in relation to allergy development. Methods A combination of flow cytometric cell sorting and deep sequencing of the 16S rDNA gene was used to characterize the bacterial recognition patterns by IgA in stool samples collected at 1 and 12 months of age from children staying healthy or having allergic symptoms up to 7 years of age. Results The children with allergic manifestations, particularly asthma, during childhood had a lower proportion of IgA bound to fecal bacteria at 12 months of age compared with healthy children. These alterations cannot be attributed to differences in IgA levels or bacterial load between the 2 groups. Moreover, the bacterial targets of early IgA responses (including coating of the Bacteroides genus), as well as IgA recognition patterns, differed between healthy children and children with allergic manifestations. Altered IgA recognition patterns in children with allergy were observed already at 1 month of age, when the IgA antibodies are predominantly maternally derived in breast-fed children. Conclusion An aberrant IgA responsiveness to the gut microbiota during infancy precedes asthma and allergy development, possibly indicating an impaired mucosal barrier function in allergic children.
Summary
Introduction
Among sensitized infants, those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization ...with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development. Although animal and in vitro studies emphasize the role of the commensal gut microbiota in the development of the immune system, the influence of the gut microbiota on immune development in infants is unclear.
Objective
To assess whether early colonization with certain gut microbiota species associates with mucosal and systemic immune responses i.e. salivary SIgA and the spontaneous Toll‐like receptor (TLR) 2 and TLR4 mRNA expression and lipopolysaccharide (LPS)‐induced cytokine/chemokine responses in peripheral blood mononuclear cells (PBMCs).
Methods
Fecal samples were collected at 1 week, 1 month and 2 months after birth from 64 Swedish infants, followed prospectively up to 5 years of age. Bacterial DNA was analysed with real‐time PCR using primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis. Saliva was collected at age 6 and 12 months and at 2 and 5 years and SIgA was measured with ELISA. The PBMCs, collected 12 months after birth, were analysed for TLR2 and TLR4 mRNA expression with real‐time PCR. Further, the PBMCs were stimulated with LPS, and cytokine/chemokine responses were measured with Luminex.
Results
The number of Bifidobacterium species in the early fecal samples correlated significantly with the total levels of salivary SIgA at 6 months. Early colonization with Bifidobacterium species, lactobacilli groups or C. difficile did not influence TLR2 and TLR4 expression in PBMCs. However, PBMCs from infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of TLR4 mRNA spontaneously. Furthermore, LPS‐induced production of inflammatory cytokines and chemokines, e.g. IL‐6 and CCL4 (MIP‐1β), was inversely correlated to the relative amounts of Bacteroides fragilis in the early fecal samples.
Conclusion
Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system and early intense colonization with Bacteroides fragilis might down‐regulate LPS responsiveness in infancy.
Background
Allergic diseases have become a major public health problem in affluent societies. Microbial colonization early in life seems to be critical for instructing regulation on immune system ...maturation and allergy development in children. Even though the oral cavity is the first site of encounter between a majority of foreign antigens and the immune system, the influence of oral bacteria on allergy development has not yet been reported.
Objective
We sought to determine the bacterial composition in longitudinally collected saliva samples during childhood in relation to allergy development.
Methods
Illumina sequencing of the 16S rDNA gene was used to characterize the oral bacterial composition in saliva samples collected at 3, 6, 12, 24 months, and 7 years of age from children developing allergic symptoms and sensitization (n = 47) and children staying healthy (n = 33) up to 7 years of age.
Results
Children developing allergic disease, particularly asthma, had lower diversity of salivary bacteria together with highly divergent bacterial composition at 7 years of age, showing a clearly altered oral microbiota in these individuals, likely as a consequence of an impaired immune system during infancy. Moreover, the relative amounts of several bacterial species, including increased abundance of Gemella haemolysans in children developing allergies and Lactobacillus gasseri and L. crispatus in healthy children, were distinctive during early infancy, likely influencing early immune maturation.
Conclusion
Early changes in oral microbial composition seem to influence immune maturation and allergy development. Future experiments should test the probiotic potential of L. gasseri and L. crispatus isolates.
Early changes in oral microbial composition seem to influence immune maturation and allergy development. Oral microbiota increases in bacterial diversity and richness through time. By 7 years of age, allergic children have a lower diversity of salivary bacteria, as well as a highly divergent bacterial composition, compared to healthy children.
Summary
The gut microbiota are critical in the homoeostasis of multiple interconnected host metabolic and immune networks. If early microbial colonization is delayed, the gut‐associated lymphoid ...tissues (GALT) fail to develop, leading to persistent immune dysregulation in mice. Microbial colonization has also been proposed as a major driver for the normal age‐related maturation of both Th1 and T regulatory (Treg) pathways that appear important in suppressing early propensity for Th2 allergic responses. There is emerging evidence that resident symbionts induce tolerogenic gut‐associated Treg cells and dendritic cells that ensure the preferential growth of symbionts; keeping pathogenic strains in check and constraining proinflammatory Th1, Th2, and Th17 clones. Some effects of symbionts are mediated by short‐chain fatty acids, which play a critical role in mucosal integrity and local and systemic metabolic function and stimulate the regulatory immune responses. The homoeostatic IL‐10/TGF‐β dominated tolerogenic response within the GALT also signals the production of secretory IgA, which have a regulating role in mucosal integrity. Contrary to the ‘sterile womb’ paradigm, recent studies suggest that maternal microbial transfer to the offspring begins during pregnancy, providing a pioneer microbiome. It is likely that appropriate microbial stimulation both pre‐ and postnatally is required for optimal Th1 and Treg development to avoid the pathophysiological processes leading to allergy. Disturbed gut colonization patterns have been associated with allergic disease, but whether microbial variation is the cause or effect of these diseases is still under investigation. We are far from understanding what constitutes a ‘healthy gut microbiome’ that promotes tolerance. This remains a major limitation and might explain some of the inconsistency in human intervention studies with prebiotics and probiotics. Multidisciplinary integrative approaches with researchers working in networks, using harmonized outcomes and methodologies, are needed to advance our understanding in this field.
Summary
Background Analyses of circulating chemokines offer novel tools to investigate the T helper (Th)1/Th2 imbalance in allergic disease in vivo.
Objective To relate circulating Th1‐ and ...Th2‐associated chemokines in infancy to allergic disease, sensitization and probiotic supplementation.
Methods Circulating levels of Th1‐associated CXC‐chemokine ligand (CXCL)9, CXCL10 and CXCL11 and Th2‐associated CC‐chemokine ligand (CCL)17 and CCL22 were assessed with Luminex and CCL18 with enzyme‐linked immunosorbent assay at birth (n=109), 6 (n=104), 12 (n=116) and 24 months (n=123) in 161 infants completing a double‐blind placebo‐controlled allergy prevention trial with Lactobacillus reuteri during the last month of gestation and through the first year of life. The infants were followed regarding the development of allergic disease and sensitization until 2 years of age.
Results The Th2‐associated chemokines CCL17 and CCL22 were the highest at birth and then decreased, whereas CCL18 and the Th1‐associated chemokines increased with age. High Th2‐associated chemokine levels were observed in children developing allergic disease. Sensitization was preceded by elevated levels of the Th2‐associated CCL22 and reduced levels of the Th1‐associated CXCL11 already at birth. The Th2‐associated CCL17 was also elevated at birth in infants developing recurrent wheeze. A high Th2/Th1 ratio (CCL22/CXCL10) at birth associated with both sensitization and eczema development. The presence of L. reuteri in stool in the first week of life was associated with low CCL17 and CCL22 and high CXCL11 levels at 6 months of age. High Th1‐associated chemokine levels were associated with day‐care.
Conclusion and Clinical Relevance Allergic disease and sensitization in infancy was associated with low circulating Th1‐ and high Th2‐associated chemokine levels already from birth. Circulating chemokines are useful for investigating the Th1/Th2 imbalance in allergic disease in vivo. Elucidation of the role of chemokines in allergic diseases may lead to future treatments (ClinicalTrials.gov NCT01285830).
Cite this as: T. R. Abrahamsson, M. Sandberg Abelius,, A. Forsberg, B. Björkstén and M. C. Jenmalm, Clinical & Experimental Allergy, 2011 (41) 1729–1739.
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•Decidual stromal cells induce and promote survival of decidual-type macrophages.•Decidual stomal cells induce regulatory T-cells in a paracrine manner.•Both 1st trimester and term ...stromal cells possess these immune regulatory abilities.•Protein profiling supports prominent regulatory functions of decidual stromal cells.•Decidual stromal cells may initiate and support fetal-maternal immune tolerance.
During pregnancy, the semi-allogeneic nature of the foetus requires maternal immune adaption and acquisition of tolerance at the foetal-maternal interface. Macrophages with regulatory properties and regulatory T (Treg) cells are central in promoting foetal tolerance and are enriched in the decidua (the uterine endometrium during pregnancy). Although tissue-resident decidual stromal cells (DSC) have been implicated in regulatory functions, it is not known if they are able to induce the regulatory phenotype of macrophages and T-cells. In this study we report that maternally derived DSC are able to induce homeostatic M2 macrophages and Treg cells. CD14+ monocytes and CD4+ T-cells from healthy non-pregnant women were cultured in the presence or absence of conditioned medium (CM) from DSC isolated from 1st trimester and term placentas. DSC-CM alone was able to promote the survival of macrophages and to induce a regulatory CD14brightCD163+CD209+CD86dim phenotype, typical for decidual macrophages and similar to that induced by M-CSF. Interestingly, DSC-CM was also able to overrule the pro-inflammatory effects of GM-CSF by upregulating CD14, CD163 and CD209. Protein-profiling showed that M-CSF was secreted by DSC, and blocking of M-CSF partially reversed the M2 phenotype and reduced viability. DSC-CM also expanded CD25brightFoxp3+ Treg cells, an expansion that was abolished by a SMAD3-inhibitor, indicating the contribution of TGF-β signaling. In conclusion, our findings collectively emphasize the role of tissue-resident stromal cells in shaping the tolerogenic environment at the foetal-maternal interface.
Background It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing ...incidence of allergic disease. The advent of powerful, cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts. Objective We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development. Methods Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool samples at 1 week, 1 month, and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age ( ClinicalTrials.gov ID NCT01285830 ). Results Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month ( P = .004) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month ( P = .02 and P = .01) and the phylum Proteobacteria at 12 months of age ( P = .02). The microbiota was less uniform at 1 month than at 12 months of age, with a high interindividual variability. At 12 months, when the microbiota had stabilized, Proteobacteria, comprising gram-negative organisms, were more abundant in infants without allergic manifestation (Empirical Analysis of Digital Gene Expression in R edgeR test: P = .008, q = 0.02). Conclusion Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema.
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