Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory t cells
01 Aug 2011-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 121, Iss: 8, pp 3088-3093
TL;DR: Experimental evidence is provided for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma by utilizing mouse models of allergic airway disease induced by ovalbumin or house dust miteAllergen to experimentally examine a possible inverse correlation between H.pylori and asthma.
Abstract: Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correlation between H. pylori and asthma. H. pylori infection efficiently protected mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, which are hallmarks of asthma, and prevented allergen-induced pulmonary and bronchoalveolar infiltration with eosinophils, Th2 cells, and Th17 cells. Protection against asthma was most robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of lung-infiltrating dendritic cells and the accumulation of highly suppressive Tregs in the lungs. Systemic Treg depletion abolished asthma protection; conversely, the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. Our results thus provide experimental evidence for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma.
Citations
More filters
TL;DR: It is suggested that a holistic approach to studying the microbiota that goes beyond characterization of community composition and encompasses dynamic interactions between all components of the microbiota and host tissue over time will be crucial for building predictive models for diagnosis and treatment of diseases linked to imbalances in the microbiota.
2,832 citations
TL;DR: The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology, andiphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community.
Abstract: Interest in the role of the microbiome in human health has burgeoned over the past decade with the advent of new technologies for interrogating complex microbial communities. The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology. Deciphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community. Both the microbiome and metagenome probably have important functions in health and disease; their exploration is a frontier in human genetics.
2,650 citations
TL;DR: It is reported in a longitudinal human study that infants at risk of asthma have transient gut microbial dysbiosis during the first 100 days of life, and certain bacterial genera were decreased in these children, suggesting a potential causative role of the loss of these microbes.
Abstract: Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.
1,195 citations
Cites background from "Helicobacter pylori infection preve..."
...Early life gutmicrobial alterations not only are limited to shifts in the prevalence of gut microbes (10, 11) but also include changes in the production ofmicrobial-derivedmetabolites such as short-chain fatty acids (SCFAs) (13) and othermetabolites that interactwith host immune cells (13–15)....
[...]
TL;DR: Data support a neonatal, microbiota‐driven, specific increase in susceptibility to experimental murine allergic asthma, consistent with the ‘hygiene hypothesis’.
Abstract: Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics—streptomycin and vancomycin—and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the ‘hygiene hypothesis', our data support a neonatal, microbiota-driven, specific increase in susceptibility to experimental murine allergic asthma.
721 citations
Cites background from "Helicobacter pylori infection preve..."
...Several of these studies highlight the necessity of neonatal administration rather than adult, emphasizing that immune modulation is most effective during the developmental period [12,14]....
[...]
...Similarly, oral administrations of Mycobacterium vaccae [11], Helicobacter pylori [12] as well as conventional probiotic strains [13,14] have been shown to ameliorate symptoms of allergic airways disease in mice....
[...]
TL;DR: A greater understanding of how the early-life gut microbiota impacts the authors' immune development could potentially lead to novel microbial-derived therapies that target disease prevention at an early age.
Abstract: Human microbial colonization begins at birth and continues to develop and modulate in species abundance for about three years, until the microbiota becomes adult-like. During the same time period, children experience significant developmental changes that influence their current health status as well as their immune system. An ever-expanding number of articles associate several diseases with early life imbalances of the gut microbiota, also referred to as gut microbial dysbiosis. Whether early life dysbiosis precedes and plays a role in disease pathogenesis, or simply originates from the disease process itself is a question that is beginning to be answered in a few diseases, including IBD, obesity and asthma. This review describes the gut microbiome structure and function during the formative first years of life, as well as the environmental factors that determine its composition. It also aims to discuss the recent advances in understanding the role of the early life gut microbiota in the development of immune-mediated, metabolic, and neurological diseases. A greater understanding of how the early life gut microbiota impacts our immune development could potentially lead to novel microbial-derived therapies that target disease prevention at an early age.
684 citations
Cites background from "Helicobacter pylori infection preve..."
...show that infection of asthma-induced neonate mice versus adult mice with Helicobacter pylori protects these mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia (common asthma characteristics) (135)....
[...]
...asthma during childhood • Mycobacterium vaccae (134) and Helicobacter pylori (135)...
[...]
References
More filters
TL;DR: A possible explanation forHay fever trends over time is suggested, as well as a recent increase in the prevalence of asthma2 and childhood eczema.
Abstract: Hay fever has been described as a "post industrial
revolution epidemic,"' and successive morbidity
surveys from British general practice suggest that its
prevalence has continued to increase over the past 30
years.) Other evidence suggests a recent increase in the
prevalence of asthma2 and childhood eczema.3 This
paper suggests a possible explanation for these trends
over time.
4,728 citations
"Helicobacter pylori infection preve..." refers background in this paper
...modern sanitary practices and the widespread use of antibiotics (4)....
[...]
...The “hygiene hypothesis” postulates that early exposure to microbial antigens is essential for the normal maturation of the immune system and the prevention of allergic diseases (4); it was recently revisited by Blaser and Falkow (5), who propose that the loss of our ancestral indigenous microbiota, rather than a general decline in arbitrary childhood infections, is causally associated with the asthma epidemic....
[...]
[...]
TL;DR: Evidence of a plateau in the prevalence of asthma in many Western countries and the evidence of possible causal relations to factors such as air pollution, obesity, diet, and exposure to infections, antibiotics, and allergens is found.
Abstract: This review surveys the data on the increase in the prevalence of asthma in recent decades and finds evidence of a plateau in many Western countries. The authors examine the evidence of possible causal relations to factors such as air pollution, obesity, diet, and exposure to infections, antibiotics, and allergens, including exposures at very young ages. The most strongly supported preventive measure is the avoidance of passive and active exposure to smoke.
1,622 citations
"Helicobacter pylori infection preve..." refers background in this paper
...The growing prevalence of asthma has been attributed to pollution and tobacco smoke (3) and to a lack of infectious stimuli arising from...
[...]
...In recent decades, the incidence of asthma and associated allergic diseases has increased to epidemic proportions in developed countries, especially among children (3)....
[...]
...pylori infection rates has preceded a rise in the prevalence of asthma and other atopic diseases in developed countries (3)....
[...]
TL;DR: It is proposed that the disappearance of these ancestral indigenous organisms, which are intimately involved in human physiology, is not entirely beneficial and has consequences that might include post-modern conditions such as obesity and asthma.
Abstract: Humans and our ancestors have evolved since the most ancient times with a commensal microbiota. The conservation of indicator species in a niche-specific manner across all of the studied human population groups suggests that the microbiota confer conserved benefits on humans. Nevertheless, certain of these organisms have pathogenic properties and, through medical practices and lifestyle changes, their prevalence in human populations is changing, often to an extreme degree. In this Essay, we propose that the disappearance of these ancestral indigenous organisms, which are intimately involved in human physiology, is not entirely beneficial and has consequences that might include post-modern conditions such as obesity and asthma.
768 citations
"Helicobacter pylori infection preve..." refers background in this paper
...Blaser MJ, Falkow S....
[...]
...pylori–mediated asthma protection provides experimental support for the “disappearing microbiota” hypothesis (5), which postulates that the asthma and allergy epidemic of modern societies is a direct consequence of the disappearance of our ancestral indigenous microflora, which included H....
[...]
...The “hygiene hypothesis” postulates that early exposure to microbial antigens is essential for the normal maturation of the immune system and the prevention of allergic diseases (4); it was recently revisited by Blaser and Falkow (5), who propose that the loss of our ancestral indigenous microbiota, rather than a general decline in arbitrary childhood infections, is causally associated with the asthma epidemic....
[...]
TL;DR: It is proposed that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs, resulting in specific immune suppression and tolerance.
Abstract: Naturally occurring CD4(+)CD25(+) regulatory T cells (Treg) suppress in vitro the proliferation of other T cells in a cell-contact-dependent manner. Dendritic cells (DCs) appear to be a target of Treg-mediated immune suppression. We show here that, in coculture of dye-labeled Treg cells and CD4(+)CD25(-) naive T cells in the presence of T cell receptor stimulation, Treg cells, which are more mobile than naive T cells in vitro, out-compete the latter in aggregating around DCs. Deficiency or blockade of leukocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming aggregates, Treg cells specifically down-regulate the expression of CD80/86, but not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of strong DC-maturating stimuli, such as GM-CSF, TNF-alpha, IFN-gamma, type I IFN, and lipopolysaccharide. Taken together, as a possible mechanism of in vitro Treg-mediated cell contact-dependent suppression, we propose that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. Both steps prevent antigen-reactive naive T cells from being activated by antigen-presenting DCs, resulting in specific immune suppression and tolerance.
666 citations
"Helicobacter pylori infection preve..." refers background in this paper
..., who found that FoxP3+ Tregs form aggregates on DCs, actively downregulate their costimulatory molecules, and impair the DCs’ ability to activate antigen-specific T cells (15)....
[...]
TL;DR: Data support the contention that helminth infections elicit a regulatory T cell population able to down-regulate allergen induced lung pathology in vivo.
Abstract: Allergic diseases mediated by T helper type (Th) 2 cell immune responses are rising dramatically in most developed countries. Exaggerated Th2 cell reactivity could result, for example, from diminished exposure to Th1 cell‐inducing microbial infections. Epidemiological studies, however, indicate that Th2 cell‐stimulating helminth parasites may also counteract allergies, possibly by generating regulatory T cells which suppress both Th1 and Th2 arms of immunity. We therefore tested the ability of the Th2 cell‐inducing gastrointestinal nematode Heligmosomoides polygyrus to influence experimentally induced airway allergy to ovalbumin and the house dust mite allergen Der p 1. Inflammatory cell infiltrates in the lung were suppressed in infected mice compared with uninfected controls. Suppression was reversed in mice treated with antibodies to CD25. Most notably, suppression was transferable with mesenteric lymph node cells (MLNC) from infected animals to uninfected sensitized mice, demonstrating that the effector phase was targeted. MLNC from infected animals contained elevated numbers of CD4 � CD25 � Foxp3 � T cells, higher TGF- � expression, and produced strong interleukin (IL)-10 responses to parasite antigen. However, MLNC from IL-10‐deficient animals transferred suppression to sensitized hosts, indicating that IL-10 is not the primary modulator of the allergic response. Suppression was associated with CD4 � T cells from MLNC, with the CD4 � CD25 � marker defining the most active population. These data support the contention
607 citations
"Helicobacter pylori infection preve..." refers background in this paper
...In experimental models of asthma, infection with microorganisms possessing strong immunomodulatory properties has been negatively associated with allergic airway disease (6, 7)....
[...]
...and helminths, have been implicated in protection against asthma and allergy (6, 7, 16); additional observations point to H....
[...]