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Barrier tissues are highly innervated by sensory and autonomic nerves that are positioned in close proximity to both stromal and immune cell populations. Together with a growing awareness of the far-reaching consequences of neuroimmune interactions, recent studies have uncovered key mechanisms through which they contribute to organ homeostasis and immunity. It has also become clear that dysregulation of such interactions is implicated in the development of chronic lung diseases. This review describes the characteristics of the lung nervous system and discusses the molecular mechanisms that underlie lung neuroimmune interactions in infection and disease. We have contextualized the current literature and identified opportune areas for further investigation. Indeed, both the lung-brain axis and local neuroimmune interactions hold enormous potential for the exploration and development of novel therapeutic strategies targeting lung diseases. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Pain-sensing neurons detect environmental insults and tissue injury, driving avoidance behavior and the local release of neuropeptides. Two related papers in this issue of Cell report that gut-innervating pain neurons sense bacterial presence to both shape the constituents of the gut microbiome and protect against excessive inflammation.
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Microbioma Gastrointestinal , Neuropéptidos , Humanos , Dolor , Inflamación , EmocionesRESUMEN
The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.
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Anticuerpos/metabolismo , Bacterias/metabolismo , Cresoles/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiología , Pulmón/metabolismo , Neumonía/prevención & control , Hipersensibilidad Respiratoria/prevención & control , Ésteres del Ácido Sulfúrico/metabolismo , Tirosina/metabolismo , Administración Oral , Alérgenos , Animales , Anticuerpos/inmunología , Diversidad de Anticuerpos , Bacterias/inmunología , Células Cultivadas , Quimiocina CCL20/metabolismo , Técnicas de Cocultivo , Cresoles/administración & dosificación , Modelos Animales de Enfermedad , Receptores ErbB/metabolismo , Femenino , Interacciones Huésped-Patógeno , Inyecciones Intravenosas , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/microbiología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/microbiología , Transducción de Señal , Ésteres del Ácido Sulfúrico/administración & dosificación , Receptor Toll-Like 4/metabolismo , Tirosina/administración & dosificaciónRESUMEN
Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.
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Antibacterianos , Asma , Disbiosis , Microbioma Gastrointestinal , Indoles , Pyroglyphidae , Animales , Ratones , Disbiosis/inmunología , Indoles/farmacología , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Asma/inmunología , Pyroglyphidae/inmunología , Pulmón/inmunología , Pulmón/patología , Ratones Endogámicos C57BL , Femenino , Inflamación/inmunología , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Citocinas/metabolismo , Hipersensibilidad/inmunología , PropionatosRESUMEN
The last decade of microbiome research has highlighted its fundamental role in systemic immune and metabolic homeostasis. The microbiome plays a prominent role during gestation and into early life, when maternal lifestyle factors shape immune development of the newborn. Breast milk further shapes gut colonization, supporting the development of tolerance to commensal bacteria and harmless antigens while preventing outgrowth of pathogens. Environmental microbial and lifestyle factors that disrupt this process can dysregulate immune homeostasis, predisposing infants to atopic disease and childhood asthma. In health, the low-biomass lung microbiome, together with inhaled environmental microbial constituents, establishes the immunological set point that is necessary to maintain pulmonary immune defense. However, in disease perturbations to immunological and physiological processes allow the upper respiratory tract to act as a reservoir of pathogenic bacteria, which can colonize the diseased lung and cause severe inflammation. Studying these host-microbe interactions in respiratory diseases holds great promise to stratify patients for suitable treatment regimens and biomarker discovery to predict disease progression. Preclinical studies show that commensal gut microbes are in a constant flux of cell division and death, releasing microbial constituents, metabolic by-products, and vesicles that shape the immune system and can protect against respiratory diseases. The next major advances may come from testing and utilizing these microbial factors for clinical benefit and exploiting the predictive power of the microbiome by employing multiomics analysis approaches.
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Asma , Microbiota , Recién Nacido , Humanos , Niño , Pulmón/microbiología , Inflamación/patología , Bacterias/metabolismo , HomeostasisRESUMEN
The revolution in microbiota research over the past decade has provided invaluable knowledge about the function of the microbial species that inhabit the human body. It has become widely accepted that these microorganisms, collectively called 'the microbiota', engage in networks of interactions with each other and with the host that aim to benefit both the microbial members and the mammalian members of this unique ecosystem. The lungs, previously thought to be sterile, are now known to harbor a unique microbiota and, additionally, to be influenced by microbial signals from distal body sites, such as the intestine. Here we review the role of the lung and gut microbiotas in respiratory health and disease and highlight the main pathways of communication that underlie the gut-lung axis.
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Microbioma Gastrointestinal , Enfermedades Pulmonares/microbiología , Pulmón/microbiología , Microbiota , Probióticos/uso terapéutico , Acinetobacter , Animales , Bifidobacterium , Suplementos Dietéticos , Femenino , Interacciones Huésped-Patógeno , Humanos , Lactobacillus , Pulmón/inmunología , Enfermedades Pulmonares/dietoterapia , Enfermedades Pulmonares/inmunología , Exposición Materna , EmbarazoRESUMEN
The gut microbiome is well-known to shape local and distal immune responses, both in health and disease. In a recent issue of Nature, Hosang et al. demonstrate how the lung microbiome regulates the magnitude of autoimmune inflammation in the brain.
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Microbioma Gastrointestinal , Microbiota , Encéfalo , Interacciones Microbiota-Huesped , Pulmón , Microbiota/fisiologíaRESUMEN
In this issue of Immunity, Tyagi et al. (2018) report that the microbial metabolite butyrate orchestrates the interplay between regulatory T cells and CD8+ T cells, increasing Wnt signaling, and promoting bone formation in young mice.
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Butiratos , Linfocitos T Reguladores , Animales , Linfocitos T CD8-positivos , Ratones , Osteogénesis , Transducción de Señal , Proteínas WntRESUMEN
Dietary fiber protects against chronic inflammatory diseases by dampening immune responses through short-chain fatty acids (SCFAs). Here we examined the effect of dietary fiber in viral infection, where the anti-inflammatory properties of SCFAs in principle could prevent protective immunity. Instead, we found that fermentable dietary fiber increased survival of influenza-infected mice through two complementary mechanisms. High-fiber diet (HFD)-fed mice exhibited altered bone marrow hematopoiesis, characterized by enhanced generation of Ly6c- patrolling monocytes, which led to increased numbers of alternatively activated macrophages with a limited capacity to produce the chemokine CXCL1 in the airways. Blunted CXCL1 production reduced neutrophil recruitment to the airways, thus limiting tissue immunopathology during infection. In parallel, diet-derived SCFAs boosted CD8+ T cell effector function by enhancing cellular metabolism. Hence, dietary fermentable fiber and SCFAs set an immune equilibrium, balancing innate and adaptive immunity so as to promote the resolution of influenza infection while preventing immune-associated pathology.
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Antígenos Ly/inmunología , Linfocitos T CD8-positivos/inmunología , Fibras de la Dieta/farmacología , Hematopoyesis/inmunología , Monocitos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Inmunidad Adaptativa/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Fibras de la Dieta/administración & dosificación , Ácidos Grasos Volátiles/inmunología , Ácidos Grasos Volátiles/metabolismo , Hematopoyesis/efectos de los fármacos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacologíaRESUMEN
Intestinal helminth infection triggers a type 2 immune response that promotes a 'weep-and sweep' response characterised by increased mucus secretion and intestinal hypermotility, which function to dislodge the worm from its intestinal habitat. Recent studies have discovered that several other pathogens cause intestinal dysmotility through major alterations to the immune and enteric nervous systems (ENS), and their interactions, within the gastrointestinal tract. However, the involvement of these systems has not been investigated for helminth infections. Eosinophils represent a key cell type recruited by the type 2 immune response and alter intestinal motility under steady-state conditions. Our study aimed to investigate whether altered intestinal motility driven by the murine hookworm, Nippostrongylus brasiliensis, infection involves eosinophils and how the ENS and smooth muscles of the gut are impacted. Eosinophil deficiency did not influence helminth-induced intestinal hypermotility and hypermotility did not involve gross structural or functional changes to the ENS. Hypermotility was instead associated with a dramatic increase in smooth muscle thickness and contractility, an observation that extended to another rodent nematode, Heligmosomoides polygyrus. In summary our data indicate that, in contrast to other pathogens, helminth-induced intestinal hypermotility is driven by largely by myogenic, rather than neurogenic, alterations with such changes occurring independently of eosinophils. (<300 words).
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Sistema Nervioso Entérico , Eosinófilos , Motilidad Gastrointestinal , Músculo Liso , Nippostrongylus , Animales , Ratones , Eosinófilos/inmunología , Músculo Liso/parasitología , Sistema Nervioso Entérico/parasitología , Sistema Nervioso Entérico/inmunología , Motilidad Gastrointestinal/fisiología , Nematospiroides dubius/fisiología , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Parasitosis Intestinales/inmunología , Parasitosis Intestinales/parasitología , Helmintiasis/inmunología , Helmintiasis/parasitología , Neuronas/parasitología , Neuronas/metabolismo , Ratones Endogámicos C57BLRESUMEN
Pulmonary immune homeostasis is maintained by a network of tissue-resident cells that continually monitor the external environment, and in health, instruct tolerance to innocuous inhaled particles while ensuring that efficient and rapid immune responses can be mounted against invading pathogens. Here we review the multiple pathways that underlie effective lung immunity in health, and discuss how these may be affected by external environmental factors and contribute to chronic inflammation during disease. In this context, we examine the current understanding of the impact of the microbiota in immune development and function and in the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung. We propose that host interactions with microbes are critical for establishing the immune landscape of the lungs.
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Envejecimiento/inmunología , Homeostasis/inmunología , Sistema Inmunológico/inmunología , Pulmón/inmunología , Microbiota/inmunología , Animales , Interacciones Huésped-Patógeno/inmunología , Humanos , Sistema Inmunológico/microbiología , Inflamación/inmunología , Inflamación/fisiopatología , Pulmón/microbiología , Microbiota/fisiología , Modelos InmunológicosRESUMEN
The Gastroenterology Immunology Neuroscience (GIN) Discovery Program represents a new model for research that overcomes the limitations imposed by traditional "research silos" in science. By uniting these three fields, the GIN Program aims to enhance the understanding and treatment of chronic conditions through a system-wide perspective focusing on the gut-immune-brain axis. Key initiatives include monthly interdisciplinary seminars, an annual symposium, and GINnovate, a commercialization and entrepreneurship event. Additionally, the program offers a seed grant competition for early and mid-career researchers, promoting advancements in gut-immune-brain axis research through the power of collaboration. The GIN Program in a short period of time has facilitated the formation of a vibrant community, captivating attention from both national and international institutions. This effort to break down barriers in research aims to inspire similar models that prioritize open communication, mutual respect and a commitment to impactful science.
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BACKGROUND AND AIM: In cystic fibrosis, gastrointestinal dysfunction and lower airway infection occur early and are independently associated with poorer outcomes in childhood. This study aimed to define the relationship between the microbiota at each niche during the first 2â years of life, its association with growth and airway inflammation, and explanatory features in the metabolome. MATERIALS AND METHODS: 67 bronchoalveolar lavage fluid (BALF), 62 plasma and 105 stool samples were collected from 39 infants with cystic fibrosis between 0 and 24â months who were treated with prophylactic antibiotics. 16S rRNA amplicon and shotgun metagenomic sequencing were performed on BALF and stool samples, respectively; metabolomic analyses were performed on all sample types. Sequencing data from healthy age-matched infants were used as controls. RESULTS: Bacterial diversity increased over the first 2â years in both BALF and stool, and microbial maturation was delayed in comparison to healthy controls from the RESONANCE cohort. Correlations between their respective abundance in both sites suggest stool may serve as a noninvasive alternative for detecting BALF Pseudomonas and Veillonella. Multisite metabolomic analyses revealed age- and growth-related changes, associations with neutrophilic airway inflammation, and a set of core systemic metabolites. BALF Pseudomonas abundance was correlated with altered stool microbiome composition and systemic metabolite alterations, highlighting a complex gut-plasma-lung interplay and new targets with therapeutic potential. CONCLUSION: Exploration of the gut-lung microbiome and metabolome reveals diverse multisite interactions in cystic fibrosis that emerge in early life. Gut-lung metabolomic links with airway inflammation and Pseudomonas abundance warrant further investigation for clinical utility, particularly in non-expectorating patients.
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Líquido del Lavado Bronquioalveolar , Fibrosis Quística , Heces , Microbioma Gastrointestinal , Pulmón , ARN Ribosómico 16S , Humanos , Fibrosis Quística/microbiología , Fibrosis Quística/metabolismo , Lactante , Líquido del Lavado Bronquioalveolar/microbiología , Heces/microbiología , Masculino , Femenino , ARN Ribosómico 16S/genética , Pulmón/microbiología , Pulmón/metabolismo , Recién Nacido , Estudios Longitudinales , Estudios de Casos y Controles , Metaboloma , Metabolómica , Antibacterianos/uso terapéutico , PreescolarRESUMEN
Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.
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Microbioma Gastrointestinal/inmunología , Helmintos/inmunología , Hipersensibilidad/inmunología , Inflamación/inmunología , Inflamación/parasitología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Adulto , Anciano , Animales , Asma/inmunología , Asma/microbiología , Asma/parasitología , Citocinas/inmunología , Ácidos Grasos/inmunología , Femenino , Humanos , Hipersensibilidad/microbiología , Hipersensibilidad/parasitología , Inflamación/microbiología , Mucosa Intestinal/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Nematospiroides dubius/inmunología , Receptores Acoplados a Proteínas G/inmunología , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/microbiología , Infecciones por Strongylida/parasitologíaRESUMEN
BACKGROUND: Early-life microbial colonization of the skin may modulate the immune system and impact the development of atopic dermatitis (AD) and allergic diseases later in life. To address this question, we assessed the association between the skin microbiome and AD, skin barrier integrity and allergic diseases in the first year of life. We further explored the evolution of the skin microbiome with age and its possible determinants, including delivery mode. METHODS: Skin microbiome was sampled from the lateral upper arm on the first day of life, and at 3, 6, and 12 months of age. Bacterial communities were assessed by 16S rRNA gene amplicon sequencing in 346 infants from the PreventADALL population-based birth cohort study, representing 970 samples. Clinical investigations included skin examination and skin barrier function measured as trans-epidermal water loss (TEWL) at the site and time of microbiome sampling at 3, 6, and 12 months. Parental background information was recorded in electronic questionnaires, and delivery mode (including vaginal delivery (VD), VD in water, elective caesarean section (CS) and emergency CS) was obtained from maternal hospital charts. RESULTS: Strong temporal variations in skin bacterial community composition were found in the first year of life, with distinct patterns associated with different ages. Confirming our hypothesis, skin bacterial community composition in the first year of life was associated with skin barrier integrity and later onsets of AD. Delivery mode had a strong impact on the microbiome composition at birth, with each mode leading to distinct patterns of colonization. Other possible determinants of the skin microbiome were identified, including environmental and parental factors as well as breastfeeding. CONCLUSION: Skin microbiome composition during infancy is defined by age, transiently influenced by delivery mode as well as environmental, parental factors and breastfeeding. The microbiome is also associated with skin barrier integrity and the onset of AD.
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Dermatitis Atópica , Hipersensibilidad , Microbiota , Lactante , Recién Nacido , Humanos , Embarazo , Femenino , Cesárea , ARN Ribosómico 16S/genética , Estudios de Cohortes , Piel/microbiología , Bacterias/genética , AguaRESUMEN
The prevalence of asthma and other allergic diseases has rapidly increased in "Westernized" countries over recent decades. This rapid increase suggests the involvement of environmental factors, behavioral changes or lifestyle, rather than genetic drift. It has become increasingly clear that the microbiome plays a key role in educating the host immune system and, thus, regulation of disease susceptibility. This review will focus on recent advances uncovering immunological and microbial mechanisms that protect against allergies, in particular, within the context of a farming environment. A whole body of epidemiological data disclosed the nature of the protective exposures in a farm. Current evidence points toward an important role of the host microbiome in setting an immunological equilibrium that determines progression toward, or protection against allergic diseases. Conclusive mechanistic insights on how microbial exposures prevent from developing allergic diseases in humans are still lacking but findings from experimental models reveal plausible immunological mechanisms. Gathering further knowledge on these mechanisms and confirming their relevance in humans is of great importance to develop preventive strategies for children at risk of developing allergies.
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Hipersensibilidad/etiología , Hipersensibilidad/terapia , Inmunidad Adaptativa , Factores de Edad , Agricultura , Animales , Manejo de la Enfermedad , Susceptibilidad a Enfermedades/inmunología , Exposición a Riesgos Ambientales , Interacciones Huésped-Patógeno/inmunología , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/prevención & control , Inmunidad Innata , Microbiota/inmunologíaRESUMEN
RATIONALE: Lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). The mechanisms leading to CLAD remain elusive due to an insufficient understanding of the complex post-transplant adaptation processes. OBJECTIVES: To better understand these lung adaptation processes after transplantation and to investigate their association with future changes in allograft function. METHODS: We performed an exploratory cohort study of bronchoalveolar lavage samples from 78 lung recipients and donors. We analysed the alveolar microbiome using 16S rRNA sequencing, the cellular composition using flow cytometry, as well as metabolome and lipidome profiling. MEASUREMENTS AND MAIN RESULTS: We established distinct temporal dynamics for each of the analysed data sets. Comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. We further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. A decline in forced expiratory volume during the first second (FEV1) is a major characteristic of lung allograft dysfunction in transplant recipients. By using a machine learning approach, we could accurately predict future changes in FEV1 from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. CONCLUSION: Bronchoalveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The lung microbiome can predict future changes in lung function with high precision.
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Trasplante de Pulmón , Microbiota , Aloinjertos , Estudios de Cohortes , Humanos , Pulmón , ARN Ribosómico 16S/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Allergic skin inflammation often presents in early childhood; however, little is known about the events leading to its initiation and whether it is transient or long-term in nature. OBJECTIVE: We sought to determine the immunologic rules that govern skin inflammation in early life. METHODS: Neonatal and adult mice were epicutaneously sensitized with allergen followed by airway allergen challenge. Epicutaneous application of labeled allergen allowed for determination of antigen uptake and processing by antigen-presenting cells. RNAseq and microbiome analysis was performed on skin from neonatal and adult specific pathogen-free and germ-free mice. RESULTS: A mixed TH2/TH17 inflammatory response in the skin and the lungs of adult mice was observed following sensitization and challenge. Comparatively, neonatal mice did not develop overt skin inflammation, but exhibited systemic release of IL-17a and a TH2-dominated lung response. Mechanical skin barrier disruption was not sufficient to drive allergic skin inflammation, although it did promote systemic immune priming. Skin of neonatal mice and adult germ-free mice was seeded with low numbers of antigen-presenting cells and impaired chemokine and alarmin production. Enhanced chemokine and alarmin production, and seeding of the skin with antigen-presenting cells capable of instructing recruited cells to elicit their effector function, was, at least in part, dependent on formation of the microbiome, and consequently contributed to the development of overt skin disease. CONCLUSIONS: These data shed light on the principles that underlie allergic inflammation in different tissues and highlight a window of opportunity that might exist for early-life prevention of allergic diseases.
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Células Presentadoras de Antígenos/inmunología , Hipersensibilidad/inmunología , Inflamación/inmunología , Pulmón/inmunología , Microbiota/inmunología , Piel/inmunología , Células Th2/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Movimiento Celular , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Vida Libre de Gérmenes , Humanos , Hipersensibilidad/microbiología , Inflamación/microbiología , Interleucina-17/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , PyroglyphidaeRESUMEN
BACKGROUND: Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population. METHODS: This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850. FINDINGS: 2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI -0·3 to 6·5) for skin intervention and 1·0% (-2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group. INTERPRETATION: Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants. FUNDING: The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vårdalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council-the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare-FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.
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Dermatitis Atópica/prevención & control , Emolientes/uso terapéutico , Hipersensibilidad a los Alimentos/prevención & control , Fenómenos Fisiológicos Nutricionales del Lactante , Administración Tópica , Análisis por Conglomerados , Dermatitis Atópica/terapia , Fármacos Dermatológicos/uso terapéutico , Femenino , Hospitales Universitarios , Humanos , Lactante , Recién Nacido , Masculino , Noruega , Estudios Prospectivos , Factores de Riesgo , Suecia , Resultado del TratamientoRESUMEN
The nutritional drivers for mother-child sharing of bacteria and the corresponding longitudinal trajectory of the infant gut microbiota development are not yet completely settled. We therefore aimed to characterize the mother-child sharing and the inferred nutritional utilization potential for the gut microbiota from a large unselected cohort. We analyzed in depth gut microbiota in 100 mother-child pairs enrolled antenatally from the general population-based Preventing Atopic Dermatitis and Allergies in Children (PreventADALL) cohort. Fecal samples collected at gestational week 18 for mothers and at birth (meconium), 3, 6, and 12 months for infants were analyzed by reduced metagenome sequencing to determine metagenome size and taxonomic composition. The nutrient utilization potential was determined based on the Virtual Metabolic Human (VMH, www.vmh.life) database. The estimated median metagenome size was â¼150 million base pairs (bp) for mothers and â¼20 million bp at birth for the children. Longitudinal analyses revealed mother-child sharing (P < 0.05, chi-square test) from birth up to 6 months for 3 prevalent Bacteroides species (prevalence, >25% for all age groups). In a multivariate analysis of variance (ANOVA), the mother-child-shared Bacteroides were associated with vaginal delivery (1.7% explained variance, P = 0.0001). Both vaginal delivery and mother-child sharing were associated with host-derived mucins as nutrient sources. The age-related increase in metagenome size corresponded to an increased diversity in nutrient utilization, with dietary polysaccharides as the main age-related factor. Our results support host-derived mucins as potential selection means for mother-child sharing of initial colonizers, while the age-related increase in diversity was associated with dietary polysaccharides.IMPORTANCE The initial bacterial colonization of human infants is crucial for lifelong health. Understanding the factors driving this colonization will therefore be of great importance. Here, we used a novel high-taxonomic-resolution approach to deduce the nutrient utilization potential of the infant gut microbiota in a large longitudinal mother-child cohort. We found mucins as potential selection means for the initial colonization of mother-child-shared bacteria, while the transition to a more adult-like microbiota was associated with dietary polysaccharide utilization potential. This knowledge will be important for a future understanding of the importance of diet in shaping the gut microbiota composition and development during infancy.