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Schematic overview of the hygiene/''old friends'' hypothesis. Several microbial signals, such as environmental exposure (rural/farm environment) and an archaic microbiota (containing more diverse and abundant bacteria and typical helminth parasites), provide strong signals to develop regulatory responses (tolerance), whereas an urbanized environment and/or a westernized microbiota does not, tipping the immune balance more toward inflammation. Tolerance leads to good health, whereas in its absence, an inflammatory profile leads to airway diseases, such as respiratory allergies and asthma. Composition and diversity of the microbiota are affected by diet. Viral infections, sinusitis, and air pollution trigger the immune system to move toward inflammation, whereas a diverse microbiota might reduce these inflammatory signals.
Source publication
The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic target...
Contexts in source publication
Context 1
... the last years, interactions of microbes, including worm parasites, with their host have been identified: exposure to microorganisms not only triggers but also effectively suppresses immune responses, and beneficial effects of microorganisms are increasingly recognized and mechanistically understood. Strate- gies are emerging to potentially implement these effects in novel interventions to prevent or treat allergic diseases, such as allergic asthma (Fig 1). A better understanding of the disease in its many guises at a basic level is needed to endorse such strategies and improve and refine interventions. ...
Context 2
... hypothesis has its origins in observations published in 1989 by Strachan, 5 who noted that decreasing family size was associated with hay fever in developed countries and suggested that this might be related to a lower degree of sibling-related childhood infections and mi- crobial exposure. In extension of the hygiene hypothesis, Rook 6 has postulated the ''old friends'' hypothesis, in which many infec- tious agents and microbes in their coevolution with human sub- jects have developed mechanisms to modulate and evade the host immune system (Fig 1). Immunomodulatory microorgan- isms have been described to activate various cells of the regulato- ry network, such as regulatory T (Treg) cells and regulatory B cells, and to modulate or even reprogram certain antigen- presenting cells, leading to tolerogenic dendritic cells (DCs), alternatively activated macrophages, or both. ...
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Citations
... Although the underlying pathophysiological mechanisms of asthma are now well described, existing treatment options are purely symptomatic rather than curative. The microbiome and its interactions with the immune system are promising starting points in the search for new therapies [3]. ...
Background
It has previously been shown that the Helicobacter pylori ( H. pylori )-derived molecule vacuolating cytotoxin A (VacA) could be suitable for the treatment of allergic airway disease. The therapeutic activity of the protein, which acts through modulation of dendritic cells (DC) and regulatory T cells (Tregs), was demonstrated in murine short-term acute models. The aim of this study is to further evaluate the therapeutic potential of VacA by determining the effectiveness of different application routes and the suitability of the protein for treating the chronic phase of allergic airway disease.
Methods
VacA was administered by the intraperitoneal (i.p.), oral (p.o.) or intratracheal (i.t.) routes, and long-term therapeutic effectiveness, allergic airway disease hallmarks, and immune phenotype were analyzed in murine models of acute and chronic allergic airway disease.
Results
Administration of VacA via the i.p., p.o or i.t. routes was associated with a reduction in airway inflammation. The i.p. route showed the most consistent effect in reducing airway inflammation and i.p. treatment with VacA was the only treatment that significantly reduced mucus cell hyperplasia. In a murine model of chronic allergic airway disease, both short- and long-term treatment with VacA showed a therapeutic effect, with a reduction in a variety of asthma hallmarks, including bronchoalveolar lavage eosinophilia, lung inflammation and goblet cell metaplasia. Short-term treatment was associated with induction of Tregs, while repetitive long-term administration of VacA influenced immunological memory in the lung.
Conclusions
In addition to showing therapeutic efficacy in short-term models, treatment with VacA also appeared to be effective in suppressing inflammation in a chronic airway disease model. The observation that treatment was effective after administration via several different routes highlights the potential of VacA as a therapeutic agent with different routes of administration in humans.
... Bacteria are known to interact with the host through symbiotic, commensal or pathogenic host-bacteria relationships and can exert immune-modulatory effects. There is mounting evidence that interactions between microbes and the immune system are an important factor influencing susceptibility to allergic disease and asthma (3). The gastric bacterium Helicobacter pylori has the ability to induce immune suppression that, on one hand prevents clearance of the bacteria and on the other hand diminishes the risk of allergic diseases (4). ...
... Data from epidemiological studies (5-8) that has been corroborated by studies in murine models (3,9) suggest a protective effect of H. pylori to reduce the incidence of allergic asthma, hay fever, and other allergic disease manifestations. In addition, animal data suggest that exposure of mothers to H. pylori during pregnancy can induce a tolerogenic immunophenotype in their pups that attenuates the development of allergic diseases later in life (10). ...
... In addition, animal data suggest that exposure of mothers to H. pylori during pregnancy can induce a tolerogenic immunophenotype in their pups that attenuates the development of allergic diseases later in life (10). In this setting, the effects of H. pylori on allergic airway disease were found to be mediated by the modulation of dendritic cell (DC) and T cell responses (3,9). However, all currently available data come from postnatal prophylactic models in which infection or administration of bacterial lysates were performed long before allergen sensitization and/or challenge. ...
Background
Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori -derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions.
Methods
Murine models of allergic airway diseases, and murine and human in vitro models were used.
Results
In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori -derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo .
Conclusion
H. pylori -derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease.
... The low proportions of Moraxella spp., Staphylococcus spp., and Haemophilus spp. in the wheezing group were different from the increased proportions of Staphylococcus spp., Moraxella spp., and Haemophilus spp., which have been previously reported to increase the risk of chronic wheezing in children [35][36][37][38][39][40], and require further investigation. The high proportion of Phyllobacterium spp. ...
Background
The bacterial load of the human lower respiratory tract is at least several times lower than that of the other parts of the body. This study aimed to identify the bacterial composition and colony structure of the lower respiratory tract in infants and children with recurrent wheezing compared with those of children with a bronchial foreign body and clarify whether the length of wheezing in infants can contribute to differences in the lower respiratory tract’s bacterial colony structure.
Methods
We collected specimens of alveolar lavage fluid from 48 infants and children who underwent fiberoptic bronchoscopy and were divided into groups: A1 (multiple wheezing: wheezing more than three times in < 1 month), A2 (persistent wheezing: > 1 month), and B (bronchial foreign body; control group). We analyzed the bacterial community structure of alveolar lavage fluid using high-throughput sequencing. The richness and diversity of the microbial communities were assessed by α and β diversity analyses.
Results
A total of 6,644 operational taxonomic units (OTUs) were obtained based on the Illumina Nova sequencing platform and clustered according to those that met the 97% identity threshold, followed by species annotation of the OTU sequences. In the annotation results, 2,608 (39.25%) OTUs were annotated at the genus level. At the genus level, Sphingomonas and Phyllobacterium were significantly higher in group A1 than in group B. There were significantly more Phyllobacterium in group A2 than in group B. Prevotella , Neisseria , and Haemophilus were higher in group B than in groups A1 and A2. The differences in the between-group α and β diversity analyses were statistically significant. The microbial diversity in groups A1 and A2 was significantly less than that in group B, but there was no statistical difference in bacterial community diversity between groups A1 and A2.
Conclusion
Recurrent wheezing in infants and children is more likely due to alterations in the overall bacterial microecology and disruption of host respiration and immune homeostasis than the effects of a single bacterium.
... Additionally, we believe that integrating microbiome with other omics data-such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics-will provide further insights into the pathobiology of asthma and its subtypes. Taken together, these efforts will facilitate the development of an early life microbiometargeted prevention and intervention strategies for the primary prevention of childhood asthma (84). ...
Asthma is a chronic and heterogeneous respiratory disease with many risk factors that typically originate during early childhood. A complex interplay between environmental factors and genetic predisposition is considered to shape the lung and gut microbiome in early life. The growing literature has identified that changes in the relative abundance of microbes (microbial dysbiosis) and reduced microbial diversity, as triggers of the airway-gut axis crosstalk dysregulation, are associated with asthma development. There are several mechanisms underlying microbial dysbiosis to childhood asthma development pathways. For example, a bacterial infection in the airway of infants can lead to the activation and/or dysregulation of inflammatory pathways that contribute to bronchoconstriction and bronchial hyperresponsiveness. In addition, gut microbial dysbiosis in infancy can affect immune development and differentiation, resulting in a suboptimal balance between innate and adaptive immunity. This evolving dysregulation of secretion of pro-inflammatory mediators has been associated with persistent airway inflammation and subsequent asthma development. In this review, we examine current evidence around associations between the airway and gut microbial dysbiosis with childhood asthma development. More specifically, this review focuses on discussing the integrated roles of environmental exposures, host metabolic and immune responses, airway and gut microbial dysbiosis in driving childhood asthma development.
... This pathology usually develops after the onset of bronchial asthma (BA) or cystic fibrosis [1] and prevalence rates of ABPA among adult asthmatic patients have been estimated as 2.5% in China and 7-22% in India [2]. Rates differ among countries but appear to be increasing around the world with the increase of BA [3]. Several diagnostic criteria for ABPA have been proposed, such as a history of BA or cystic fibrosis, characteristic radiographic pulmonary opacities including central dilatation of the bronchus, elevated immunoglobulin (Ig)E levels, and hypersensitivity reaction to Aspergillus including elevated IgE antibodies against Aspergillus fumigatus and/or IgG antibodies for Aspergillus [2,4]. ...
Background
Allergic bronchopulmonary aspergillosis (ABPA) and chronic eosinophilic pneumonia (CEP) both display peripheral eosinophilia as well as pulmonary infiltration, together described as pulmonary eosinophilia, and differentiation is sometimes problematic. This study therefore examined the distinctions between ABPA with and without CEP-like shadows.
Methods
This retrospective cohort study from a single center included 25 outpatients (median age, 65 years) with ABPA diagnosed between April 2015 and March 2019, using criteria proposed by the International Society of Human and Animal Mycology (ISHAM), which focuses on positive specific IgE for Aspergillus fumigatus . Patients were assigned to either the eosinophilic pneumonia (EP) group or Non-EP group, defined according to findings on high-resolution computed tomography (HRCT). The EP group included patients with HRCT findings compatible with CEP; i.e., the presence of peripheral consolidation (p-consolidation) or ground-glass opacities (GGO), with no evidence of high-attenuation mucus. The Non-EP group comprised the remaining patients, who showed classical findings of ABPA such as mucoid impaction. Differences between the groups were analyzed.
Results
Baseline characteristics, frequency of a history of CEP (EP, 50% vs. Non-EP, 26%) and tentative diagnosis of CEP before diagnosis of ABPA (67% vs. 16%) did not differ significantly between groups. Although elevated absolute eosinophil count and Aspergillus -specific immunoglobulin E titers did not differ significantly between groups, the Non-EP group showed a strong positive correlation between these values (R = 0.7878, p = 0.0003). The Non-EP group displayed significantly higher levels of the fungal marker beta-D glucan (median, 11.7 pg/ml; interquartile range, 6.7–18.4 pg/ml) than the EP group (median, 6.6 pg/ml; interquartile range, 5.2–9.3 pg/ml). Both groups exhibited frequent recurrence of shadows on X-rays but no cases in the EP group had progressed to the Non-EP group at the time of relapse.
Conclusions
The ABPA subgroup with imaging findings resembling CEP experienced frequent recurrences, as in typical ABPA. In pulmonary eosinophilia, even if there are no shadows indicating apparent mucous change, the Aspergillus -specific immunoglobulin E level is important in obtaining an accurate diagnosis and in the selection of appropriate therapies for this type of ABPA.
... Hygiene Hypothesis and Farm Environment After David Strachan associated increased microbial exposure with decreased prevalence of hay fever in developed countries in 1989 (Strachan 1989), the "hygiene hypothesis" was born. Several following studies showed that microbes play an important role in tolerance induction by activating regulatory immune cells like regulatory T and B cells (Smits et al. 2016). In addition to the observation of Strachan, rural living such as "traditional" farming was shown to be associated with a decreased risk of allergy development. ...
Since allergic diseases are of great public health relevance, effective primary prevention strategies are urgently needed. This chapter gives an overview of existing primary prevention programs on environmental exposures and dietary strategies based on epidemiological studies which have defined risk- and protective factors for the development of allergic diseases.The allergy protective effect mediated by growing up on a traditional farm environment is well studied. But the exact underlying mechanisms have still not been fully clarified and have not yet led to concrete prevention strategies. The beneficial effect of avoiding cigarette smoke exposure, indoor moisture and molds in pregnancy and childhood on the development of asthma is well documented. Whereas the avoidance of house dust mite exposure is not recommended to prevent eczema or allergy. Dietary supplementation with vitamins, pre- and probiotics in pregnant woman and their offspring is not harmful but evidence for the prevention of allergic diseases is still lacking. Fish oil consumption was shown to be asthma protective. The early introduction of peanuts and egg protein to prevent peanut and egg allergy in children with atopic dermatitis is promising. Further studies are needed to increase the overall evidence in allergy prevention. Most studies lack methodological standards such as randomization and blinding. More evidence is in demand on the potential beneficial impact of multifaceted interventional studies. The future of allergy prevention strategies might be based on individual risk assessment. Therefore, research in the immunological and molecular basis of allergic diseases needs to be promoted.
... For Belgium, the Netherlands and Luxembourg (whose usual acronym is Benelux) the prevalence of asthma varies between 10 and 15% of the population (3) and for allergic rhinitis it is estimated to be 10-30% (4)(5)(6). The increase in prevalence of these diseases may be related to improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle, dietary habit, and air pollution (7). In addition, the increase in amount of airborne allergenic pollen and prolonged pollen seasons caused by climate change and/or by changes in land use may also contribute (8,9). ...
Airborne pollen is a major cause of allergic rhinitis, affecting between 10 and 30% of the population in Belgium, the Netherlands, and Luxembourg (Benelux). Allergenic pollen is produced by wind pollinating plants and released in relatively low to massive amounts. Current climate changes, in combination with increasing urbanization, are likely to affect the presence of airborne allergenic pollen with respect to exposure intensity, timing as well as duration. Detailed analysis of long-term temporal trends at supranational scale may provide more comprehensive insight into these phenomena. To this end, the Spearman correlation was used to statistically compare the temporal trends in airborne pollen concentration monitored at the aerobiological stations which gathered the longest time-series (30–44 years) in the Benelux with a focus on the allergenic pollen taxa: Alnus, Corylus, Betula, Fraxinus, Quercus, Platanus, Poaceae, and Artemisia. Most arboreal species showed an overall trend toward an increase in the annual pollen integral and peak values and an overall trend toward an earlier start and end of the pollen season, which for Betula resulted in a significant decrease in season length. For the herbaceous species (Poaceae and Artemisia), the annual pollen integral and peak values showed a decreasing trend. The season timing of Poaceae showed a trend toward earlier starts and longer seasons in all locations. In all, these results show that temporal variations in pollen levels almost always follow a common trend in the Benelux, suggesting a similar force of climate change-driven factors, especially for Betula where a clear positive correlation was found between changes in temperature and pollen release over time. However, some trends were more local-specific indicating the influence of other environmental factors, e.g., the increasing urbanization in the surroundings of these monitoring locations. The dynamics in the observed trends can impact allergic patients by increasing the severity of symptoms, upsetting the habit of timing of the season, complicating diagnosis due to overlapping pollen seasons and the emergence of new symptoms due allergens that were weak at first.
... Proposed risk factors for asthma vary with the age of asthma onset and timing of exposures and behaviors relative to the onset of asthma. Microbes have long been postulated to play a role in asthma and might also shape its heterogeneity [73]. The early life microbiome likely influences the likelihood that an allergic predisposition results in asthma. ...
There is increasing recognition of the importance of both the microbiome and vitamin D in states of health and disease. Microbiome studies have already demonstrated unique microbial patterns in systemic autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. Dysbiosis also seems to be associated with allergies, in particular asthma, atopic dermatitis, and food allergy. Even though the effect of vitamin D supplementation on these pathologies is still unknown, vitamin D deficiency deeply influences the microbiome by altering the microbiome composition and the integrity of the gut epithelial barrier. It also influences the immune system mainly through the vitamin D receptor (VDR). In this review, we summarize the influence of the microbiome and vitamin D on the immune system with a particular focus on allergic diseases and we discuss the necessity of further studies on the use of probiotics and of a correct intake of vitamin D.
... After epidemiological studies had demonstrated an association between spending early life time in specific agricultural environments and protection against the development of allergies in childhood (35,36), functional investigations of various types started to clarify which elements of farming, such as contact with farm animals, consumption of raw cow's milk, exposure to so-called farm-dust, and others, mechanistically underlie this observation. DNA demethylation at the FOXP3-encoding locus related to higher expression of the gene and activation of Treg (37) has been associated in cord blood with maternal consumption of raw cow's milk (38) and in children's whole blood with early-life ingestion of raw cow's milk (39). ...
During its 30 years history, the Hygiene Hypothesis has shown itself to be adaptable whenever it has been challenged by new scientific developments and this is a still a continuously ongoing process. In this regard, the mini review aims to discuss some selected new developments in relation to their impact on further fine-tuning and expansion of the Hygiene Hypothesis. This will include the role of recently discovered classes of innate and adaptive immune cells that challenges the old Th1/Th2 paradigm, the applicability of the Hygiene Hypothesis to newly identified allergy/asthma phenotypes with diverse underlying pathomechanistic endotypes, and the increasing knowledge derived from epigenetic studies that leads to better understanding of mechanisms involved in the translation of environmental impacts on biological systems. Further, we discuss in brief the expansion of the Hygiene Hypothesis to other disease areas like psychiatric disorders and cancer and conclude that the continuously developing Hygiene Hypothesis may provide a more generalized explanation for health burden in highly industrialized countries also relation to global changes.
... Low microbial diversity in the lung with an increased proportion of Proteobacteria has been found in patients with asthma. In detail, colonization of the airways by some bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, was associated with higher risk of asthma and its exacerbations, suggesting some synergistic mechanisms between pathogenic viruses and bacteria [70]. Hilty et al. conducted a systematic study on microbiota in the nasopharynx, oropharynx and lower airways of children with asthma. ...
Respiratory tract infections (RTIs) are common in childhood because of the physiologic immaturity of the immune system, a microbial community under development in addition to other genetic, physiological, environmental and social factors. RTIs tend to recur and severe lower viral RTIs in early childhood are not uncommon and are associated with increased risk of respiratory disorders later in life, including recurrent wheezing and asthma. Therefore, a better understanding of the main players and mechanisms involved in respiratory morbidity is necessary for a prompt and improved care as well as for primary prevention. The inter-talks between human immune components and microbiota as well as their main functions have been recently unraveled; nevertheless, more is still to be discovered or understood in the above medical conditions. The aim of this review paper is to provide the most up-to-date overview on dysbiosis in pre-school children and its association with RTIs and their complications. The potential role of non-harmful bacterial-derived products, according to the old hygiene hypothesis and the most recent trained-innate immunity concept, will be discussed together with the need of proof-of-concept studies and larger clinical trials with immunological and microbiological endpoints.
