Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Microbiome and asthma Sokolowska, Milena ; Frei, Remo ; Lunjani, Nonhlanhla ; Akdis, Cezmi A ; O’Mahony, Liam Abstract: The mucosal immune system is in constant communication with the vast diversity of microbes present on body surfaces. The discovery of novel molecular mechanisms, which mediate host-microbe communication, have highlighted the important roles played by microbes in influencing mucosal immune responses. Dendritic cells, epithelial cells, ILCs, T regulatory cells, effector lymphocytes, NKT cells and B cells can all be influenced by the microbiome. Many of the mechanisms being described are bacterial strain- or metabolite-specific. Microbial dysbiosis in the gut and the lung is increasingly being associated with the incidence and severity of asthma. More accurate endotyping of patients with asthma may be assisted by further analysis of the composition and metabolic activity of an individual’s microbiome. In addition, the efficacy of specific therapeutics may be influenced by the microbiome and novel bacterial- based therapeutics should be considered in future clinical studies. DOI: https://doi.org/10.1186/s40733-017-0037-y Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148435 Journal Article Published Version The following work is licensed under a Creative Commons: Attribution 4.0 International (CC BY 4.0) License. Originally published at: Sokolowska, Milena; Frei, Remo; Lunjani, Nonhlanhla; Akdis, Cezmi A; O’Mahony, Liam (2018). Micro- biome and asthma. Asthma Research and Practice, 4:1. DOI: https://doi.org/10.1186/s40733-017-0037-y https://doi.org/10.1186/s40733-017-0037-y https://doi.org/10.5167/uzh-148435 http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/ https://doi.org/10.1186/s40733-017-0037-y REVIEW Open Access Microbiome and asthma Milena Sokolowska1,2, Remo Frei1,2, Nonhlanhla Lunjani1,2,3, Cezmi A. Akdis1,2 and Liam O’Mahony1* Abstract The mucosal immune system is in constant communication with the vast diversity of microbes present on body surfaces. The discovery of novel molecular mechanisms, which mediate host-microbe communication, have highlighted the important roles played by microbes in influencing mucosal immune responses. Dendritic cells, epithelial cells, ILCs, T regulatory cells, effector lymphocytes, NKT cells and B cells can all be influenced by the microbiome. Many of the mechanisms being described are bacterial strain- or metabolite-specific. Microbial dysbiosis in the gut and the lung is increasingly being associated with the incidence and severity of asthma. More accurate endotyping of patients with asthma may be assisted by further analysis of the composition and metabolic activity of an individual’s microbiome. In addition, the efficacy of specific therapeutics may be influenced by the microbiome and novel bacterial-based therapeutics should be considered in future clinical studies. Keywords: Asthma, Microbiome, Bacteria, Mucosal immune system, Immune tolerance, Short-chain fatty acids, Histamine Background An enormous number of microbes colonize the skin and mucosal body surfaces. These microbes are highly adapted to survive within complex community struc- tures, utilizing nutrients from other microbes and/or host processes. The microbiome is defined as the sum of these microbes, their genomic elements and interactions in a given ecological niche. The composition and diver- sity of the microbiome varies across body sites, resulting in a series of unique habitats within and between indi- viduals that can change substantially over time [1]. The establishment of stable microbial communities closely tracks host growth and immune development during the first few years of life. Factors that influence this evolu- tion include antibiotic use, birth mode, infant nutrition and biodiversity in the home, surrounding environment and in family members [2]. Delayed or altered establish- ment of these microbial communities’ leads to micro- biome immaturity and has been associated with increased risk of allergies and asthma later in life. Highly sophisticated mucosal immune cellular and molecular networks need to be constantly coordinated in order to tolerate the presence of a large number and diversity of bacteria, while protective immune responses to potential pathogens must be maintained and induced on demand. The balance between immune tolerance and inflammation within tissues is regulated in part by the crosstalk between immune cells and the microbiome [3]. Disrupted communication between the microbiome and the host due to altered microbiome composition and/or metabolism is thought to negatively influence immune homeostatic networks. This can be clearly seen in mice bred under germ-free (GF) or sterile conditions, whereby mucosal tolerance mechanisms do not fully develop and these mice display increased allergic responses to aller- gen challenge. In this review, we will examine the potential mechanisms by which the microbiome influences immune responses within the lung and assess the evidence for a dysbiotic microbiome in the gut and the respiratory tract of asthma patients. In addition, we will summarize the current thera- peutic approaches and challenges associated with microbial-based therapies in asthma patients and highlight the future research and clinical needs in the field. Immune mechanisms influenced by the microbiome Multiple mechanisms have now been described, through which bacteria can induce regulatory responses or dampen inflammatory processes. Both bacterial cell wall components and metabolites from the microbiome have * Correspondence: liam.omahony@siaf.uzh.ch 1Swiss Institute of Allergy and Asthma Research, University of Zürich, Obere Strasse 22, 7270 Davos, Switzerland Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sokolowska et al. Asthma Research and Practice (2018) 4:1 DOI 10.1186/s40733-017-0037-y http://crossmark.crossref.org/dialog/?doi=10.1186/s40733-017-0037-y&domain=pdf mailto:liam.omahony@siaf.uzh.ch http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/publicdomain/zero/1.0/ been associated with immunoregulatory effects within the mucosa. Certain commensal microbes such as spe- cific Bifidobacterium, Lactobacillus and Clostridium strains have been shown to increase the proportion of T regulatory cells in mice [4–8]. In addition, Clostridia have been shown to stimulate ILC3s to produce IL-22, which helps to reinforce the epithelial barrier and reduces the permeability of the intestine to dietary pro- teins [9]. Furthermore, Bifidobacteria and Lactobacilli can stimulate metabolic processes in dendritic cells, such as vitamin A metabolism, tryptophan metabolism and heme oxygenase-1, which promote induction of T regu- latory cells [10–12]. The capsular polysaccharide A from Bacteroides fragilis has been shown to interact directly with mouse plasmacytoid dendritic cells and thereby promoted IL-10 secretion from CD4+ T cells [13]. In addition, an exopolysaccharide from Bifidobacterium longum was recently shown to suppress Th17 responses within the gut and within the lung [14, 15]. Notably, consumption of Bifidobacterium longum 35,624 by healthy human volunteers increased Foxp3+ T regula- tory cells in peripheral blood, while administration of this bacterial strain to psoriasis patients, chronic fatigue syndrome patients or ulcerative colitis patients consist- ently resulted in reduced levels of serum proinflamma- tory biomarkers such as CRP, possibly mediated by increased numbers of T regulatory cells [12, 16]. In addition to bacterial-associated components, bacterial-derived metabolites have significant effects on immunoregulatory processes. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are produced by the gut microbiota and have been shown to influence dendritic cell and T cell responses, via their binding to G protein-coupled receptors and their inhib- ition of histone deacetylases, thereby promoting epigen- etic changes [17]. Bacteria within the human gut can produce a wide range of biogenic amines (due to metab- olism of amino acids), which can also influence immune and inflammatory responses [18]. Interestingly, in murine models, microbiota-derived taurine, histamine, and spermine were shown to influence host-microbiome interactions by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide secretion [19]. Microbiome in animal models of asthma A number of different animal studies support the con- cept for a role of the microbiome in development of airway diseases. In particular, valuable insights for the mechanistic role of the microbiome in the development of allergic airway inflammation comes from GF animals, lacking any exposure to pathogenic or nonpathogenic microorganisms. Herbst et al. observed that OVA- induced type 2 airway inflammation and airway hypersensitivity is much stronger in GF mice as com- pared to the mice from a specific pathogen-free environ- ment (SPF) that were colonized with commensal microbes. Moreover, the exaggerated allergic inflamma- tion in GF mice could be reduced to the same level observed in SPF mice, when GF mice were co-housed for 3 weeks with SPF mice, suggesting that gut and airways recolonization with commensal microbes had protective effects [20]. In addition, early life colonization of GF mice prevented invariant natural killer T cell accu- mulation in the gut lamina propria and the lungs thereby reducing the severity of allergic airway re- sponses. Later life colonization had no effect on disease phenotypes nor on the development of regulatory T cells or on invariant natural killer T cells [21]. Furthermore, antibiotic treatment of neonatal mice resulted in fewer regulatory T cells and a more pronounced T helper cell type 2 response, which was prevented by re-introducing a commensal intestinal microbiota [22–24]. Gollwitzer et al. examined the susceptibility to house dust mite (HDM)-induced allergic airway inflammation in mice of different ages (3, 15 and 60 days), simulating the conditions of gradual colonisation of the human infant airways [25]. Neonatal mice were prone to de- velop exaggerated airway eosinophilia, they released more type 2 cytokines and exhibited higher airway hyper-responsiveness following exposure to HDM com- pared to mice that were older. This protective effect in older mice was associated with the colonization of the mouse lungs with increased numbers of bacteria and the shift from a predominance of Gammaproteobacteria and Firmicutes to Bacteroidetes. The maturation of the lung microbiota was associated with the PDL-1-dependent emergence of Helios-negative T regulatory cells. This study suggests that the absence of specific bacterial species early in life could influence appropriate regulatory mechanisms later in life and subsequently shift the immunological balance towards allergy instead of tolerance [25]. Oral supplementation of mice with specific microbes such as Bifidobacterium breve, Clostridium clade IV and XIV species, or with the capsular polysaccharide PSA of Bacteroides fragilis induced an anti-inflammatory re- sponse associated with induction of regulatory T cells and IL-10 secretion that attenuated allergic airway in- flammation [21, 26]. In addition to the gut-induced regulatory T cells that could migrate to the lungs to pro- vide anti-inflammatory effects, there are metabolites produced by the microbiome such as SCFAs that are absorbed and potentially have direct effects on lung im- mune responses [27]. Deliberate administration of SCFAs, or dietary fibers that are metabolized to SCFAs, has repeatedly been shown to reduce airway inflamma- tion in murine models. A high-fiber diet increased the Sokolowska et al. Asthma Research and Practice (2018) 4:1 Page 2 of 9 level of colonic Bacteroidetes and Actinobacteria species and decreased Firmicutes and Proteobacteria, which was associated with increased SCFA serum levels and sup- pression of allergic airway-inflammation in mice [28]. The beneficial effect was transferred to the offspring after treatment of pregnant mice via epigenetic mecha- nisms [26, 29]. The influence of the microbiota on D- tryptophan, Vitamin A or biogenic amine metabolism can also modulate T helper cell type 2 mediated allergic airway inflammation within the lung [3, 26, 30, 31]. Several studies have suggested that direct exposure of the murine respiratory tract to microbial products such as endotoxin, CpG-containing oligonucleotides or other Toll-like receptor ligands could inhibit the classical fea- tures of asthma [32, 33]. For example, intranasal exposure to the bacterium Escherichia coli was protective in the OVA-induced allergic airway inflammation model [34]. These studies were recently expanded by novel findings that linked the protective effect of the farm environment with the microbiota and endotoxin levels in the house dust. Schuijs et al. demonstrated that prolonged exposure to low-dose endotoxin or farm dust protected mice from HDM-induced asthma via A20 (TNFAIP3)-dependent air- way epithelial cells-dendritic cells interactions [35]. Stein et al. further demonstrated that intranasal installation of the dust from Amish houses, but not dust from Hutterite homes, reduced OVA-induced allergic airway inflamma- tion in mice, via Myd88 and Trif-dependent mechanisms [36]. The dust from the Amish homes had different bacterial populations (especially higher in Bartonellaceae) and higher endotoxin levels as compared to Hutterite houses’ dust [36]. The role of the gut microbiome in asthma The human gut microbiome is the largest collection of bacteria in the body, consisting of 500–1000 distinct bacterial species with more than 8 million genes poten- tially influencing the host immune system [21, 37]. Euro- pean adults’ gut microbiota is predominantly colonized by Bacteroidetes, Firmicutes, Actinobacteria, Proteobac- teria, and Verrucomicrobia. The stomach, duodenum, and proximal small intestine are mainly colonized with aerobic bacteria including Streptococci species, Lactoba- cilli species, and Enterobacteriaceae while anaerobes such as Bacteroides, Bifidobacterium, Prevotellaceae, Rikenellaceae, Lachnospiraceae, Ruminococcaceae, and Clostridium species dominate the distal small intestine and the colon [26, 38]. The gut microbiota can influence immune responses at distant sites (such as the lung) via multiple mechanisms. For example, it was recently shown that there is an increase in the number of bac- teria capable of secreting histamine from the gut of adult asthma patients, compared to healthy volunteers [39]. However, it is not clear if increased secretion of histamine by gut microbes can have an overall detrimen- tal or protective effect as histamine can induce protect- ive responses in the lung via histamine 2 receptor and detrimental effects via histamine 1 and 4 receptors [40]. The composition of the gut microbiome is thought to reach an adult-like diversity by 3 years of age. Develop- ment of the early life gut microbiome is influenced by many environmental factors, such as living in microbial rich environments (e.g. on a farm or with frequent contact to livestock and pets), or a diverse diet, which have been inversely associated with childhood asthma [41–45]. It is thought that exposure to and colonization by certain mi- crobes at the correct time during early life is important for gut development, immune cell maturation and resistance to pathogens, all of which may protect against the devel- opment of asthma [22, 37, 46]. The mode of delivery has a significant influence on colonization. Babies delivered via caesarean section typically have more Staphylococcus spe- cies, Bacillales, Propionobacterineae, Corynebacterineae, Firmicutes and Acinetobacter species with fewer Actino- bacteria and Bacteroidetes, while vaginal delivery has been linked to increased colonization with Clostridia [38, 47]. Clostridia metabolize fibers to SCFAs, which can have systemic anti-inflammatory effects as described above. In addition to delivery mode and diet, maternal antibiotic use during pregnancy or antibiotic treatment in early childhood significantly disrupts the microbiota and was associated with long-lasting effects such as decreased Actinobacteria and increased Bacteroidetes and Proteo- bacteria [1]. Several studies have linked early life dysbiosis of the gut microbiota with an altered risk of asthma later in life. Colonization by Clostridium difficile at 1 month of age was associated with wheeze throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years [48]. Children that developed asthma at school age, had a lower gut microbiome diversity at 1 week or 1 month of age, but not at 1 year of age, compared to non-asthmatic children [49]. In another study, the early life relative abundance of the bacterial genera Lachnospira, Veillo- nella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This dysbiosis was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites [50]. In addition, neonates with the lowest relative abundance of Bifidobacteria, Akkermansia and Faecalibacterium and a higher relative abundance of particular fungi (Candida and Rhodotorula), had the highest risk to develop atopy and asthma [51]. Thus, early life dysbiosis of the gut microbiota has been consistently associated with an in- creased risk of asthma later in life. However, it remains unclear if microbial dysbiosis within the gut can actually drive relevant disease promoting mechanisms or if dys- biosis simply reflects associated phenomena such as Sokolowska et al. Asthma Research and Practice (2018) 4:1 Page 3 of 9 altered patterns of immune response to microbes and environmental stimuli. Role of the respiratory microbiome in asthma The Human Microbiome Project, launched in 2007, did not include airway tissue sampling as healthy human lung tissue at that time was assumed to be sterile [52]. However, shortly afterwards a number of pioneering publications in this field appeared and several research consortia and individual groups subsequently started in- tensive studies to characterize and understand the com- position and function of airway microbiota in health and disease [53–55]. Currently, it is known that the healthy respiratory mucosa is inhabited by niche-specific bacter- ial communities [56]. The highest densities of bacterial communities are found in the upper respiratory tract, reaching up to 103 viable bacteria per nasal swab from the nasal cavity and nasopharynx, with even up to 106/ ml viable cells from oropharynx lavages [56–58]. In the trachea and lungs, the estimated numbers of bacteria are lower with approximately 102 bacterial cells per ml being found in bronchoalveolar lavages (BAL) from healthy lungs [59]. The six dominant phyla routinely found in the lung are Firmicutes, Proteobacteria, Bacteroides, Fusobacteria, Acidobacteria, and Actinobacteria [60]. The original proof-of-concept study from Hilty et al., with microbiome assessments of the nose, oropharynx, bronchial brushings and BAL samples from the lower airways revealed that the Proteobacteria phylum and es- pecially Haemophilus species are more often present in upper and lower airways of asthmatic and COPD adults and asthmatic children [53]. The study performed by Huang et al. in patients with suboptimal controlled asthma, defined as persistent symptoms on the Asthma Control Questionnaire after 4 weeks of standardized treatment with inhaled fluticasone, showed a greater air- way microbiota diversity in these patients compared to control subjects that correlated positively with bronchial hyperresponsiveness [61]. Specifically, there was an increase in the phylum Proteobacteria in asthma patients, including Comamonadaceae, Sphingomonada- ceae, Nitrosomonadaceae, Oxalobacteraceae, and Pseu- domonadaceae families [61]. Interestingly, adult patients who benefited most from clarithromycin treatment, as assessed by the reduction in bronchial hyperactivity to methacholine were those who had significantly greater bacterial diversity prior the intervention [61]. Subse- quent studies also confirmed that Proteobacteria were present in higher proportions in the asthmatic airways [59, 62]. In addition, Klebsiella species were enriched in patients with severe asthma as compared to patients with mild-to-moderate asthma and controls [63]. More- over, within severe asthma patients, Proteobacteria was associated with TH17-related gene signature in airway epithelium, worsening asthma control and total leuco- cytes in the sputum, while Bacteroides/Firmicutes were more abundant in obese patients with severe asthma. In contrast, the presence of Actinobacteria correlated with improvement and/or no change in asthma control [63]. Severe asthma had long been associated with the pres- ence of Mycoplasma pneumoniae and Chlamydophila pneumoniae, resulting in several clinical trials with macrolide antibiotics in this group of patients [64]. Yet, in the face of controversial study results and the possi- bility that beneficial microbial species are also affected, further clinical trials that include detailed microbiome studies are needed [65, 66]. The composition of the airway microbiome develops ex- ponentially very early in life and later in life can be influ- enced by the environment, health status and age. Birth mode (vaginal or via caesarean section), the exposures during the first hours of life and the environment of the following 3–4 months of life have been shown to be of utmost importance in shaping the development of stable respiratory and gut microbiota to ensure respiratory health later in life [50, 67–69]. Both human and animal studies have shown that inhaled dust particles can carry a complex mixture of microbes and microbial factors, which influence susceptibility to asthma development via their effects on innate and adaptive immune responses [35, 36]. The important research questions that are currently being addressed in children include: i) what is the longitudinal process of upper airways colonization in healthy infants? ii) how do environmental factors such as breast feeding, living on a farm, number of siblings, day-care, pets at home, smoking and antibiotic usage impact the respira- tory microbiome? iii) are there correlations between pat- terns of respiratory microbial colonization in early life with the occurrence of acute respiratory infections such as respiratory syncytial virus (RSV), rhinovirus and influenza virus and their further impact on chronic non infectious- associated recurrent wheeze, atopic sensitization and asthma? [58, 70–74]. Teo et al. analyzed the nasopharynx microbiome in a prospective cohort of children at several time-points up to 2 years of age and correlated the presence of specific groups of bacteria with acute respiratory infections [68]. Healthy infants from this cohort were initially colonized with Staphylococcus or Corynebacterium species up to 2 months of age with subsequent stable colonization by Allociococcus or Moraxella. In contrast, Streptococcus, Moraxella or Haemophilus colonization were correlated with virus-associated acute respiratory infections in the first 60 weeks of life. Early asymptomatic Streptococcus colonization, rare in children from dog and cat-owning families, increased the risk of asthma at 5 years of age [68]. Early upper respiratory tract colonization with S. pneumoniae, H. influenzae and/or M. catarrhalis in Sokolowska et al. Asthma Research and Practice (2018) 4:1 Page 4 of 9 children at 4 weeks of age from other prospective birth cohorts was also found to be associated with an increased risk of pneumonia and bronchiolitis or asthma at 5 years of age [54, 75]. Additional studies have also noted associations between H. influenza, Streptococcus species and S. aureus nasopharyngeal colonization with RSV infection and hospitalization in children independ- ently of their age [76–78]. Furthermore, early colonization of the upper respiratory tract of healthy in- fants with Staphylococcus species, subsequently followed by Corynbactrium/Dolosigranulum and Moraxella, were described for infants who were breastfed and who had lower rates of respiratory infections in the first 2 years of life [67, 79, 80]. Indeed, airway microbial diversity ap- pears to be inversely associated with sensitization to house dust mites in early childhood [81, 82]. Of particu- lar interest is a recent study comparing Amish children raised on traditional farms, who have a low prevalence of asthma and atopy, with Hutterite children coming from highly industrialized farms who have a higher prevalence of asthma and atopy, even though these two populations are genetically similar. One striking differ- ence was the microbial composition and endotoxin load of dust from those two housing environments, associ- ated with the enhanced induction of innate immune pathways in Amish children. The high-endotoxin dust from Amish houses was able to inhibit OVA-induced al- lergic airway inflammation in mice, as described above [36]. Several other studies have also confirmed that the farm environment is associated with increased bacterial diversity in the house dust samples and nasal micro- biome diversity of the same children who have lower risk of developing asthma [83–85]. It is currently unknown if the protective effect of the dust-associated microbiome is due to inhalation of multiple bacteria species and fur- ther colonization of the airways, or if inhaled bacterial metabolites may also play a role. Microbiome strategies for asthma prevention, treatment and management Alterations in the lung and gut microbiome of asthma patients have been well described previously in this review. The deliberate restoration of lung and gut micro- biota through the use of prebiotics; probiotics or synbio- tics is one potential strategy currently being assessed. Interest in probiotics and prebiotics for their potential benefits in protecting against airway inflammation is relatively recent but increasing significantly, particularly as several lines of evidence suggest that a “healthy” microbial community facilitates the development of im- mune tolerance [30]. In vitro studies and animal models have repeatedly shown the protective effects of certain probiotic strains on lung inflammatory responses, but have also shown that not all probiotics will induce the same effects [86]. Intervention and prevention studies in humans are inconsistent in their findings, possibly be- cause many factors complicate the analysis of dysbiosis in patients with asthma. Comparison between human studies are difficult, because of considerable heterogen- eity in the probiotics and/or prebiotics used, study design, sample size, age of study population, geographic location and lifestyle factors (including diet). One pre- liminary study did suggest that symbiotic (pre and pro- biotic) use improved peak expiratory flow and reduced the systemic production of Th2 cytokines in allergic asthmatics [87]. Another recent study using a combin- ation of nutritional interventions (fish oils and vegetable extracts) with a probiotic led to significant improvement in pulmonary function parameters and significantly reduced requirement for short-acting inhaled bronchodi- lators and inhaled corticosteroids in children with asthma, suggesting that the combination of multiple ap- proaches may lead to the most optimal benefits [88]. These findings are promising, however more definitive studies are needed to determine whether modification of gut and lung microbiota can be attributed to pre and/or probiotic use. Currently, there is no recommendation to use pre- or probiotics for treatment or prevention of asthma. Nevertheless, there is accumulating evidence that antenatal interactions between maternal diet, gut bacteria and bacterial metabolites may lead to immuno- logical imprinting on the developing fetal immune system that could influence the development of allergy and asthma later in life [89]. Thus, further studies are required to determine if appropriate prebiotic and pro- biotic use during pregnancy may functionally impact the maternal gut microbiome with subsequent effects on maternal immune function and risk of asthma in the offspring [90]. In addition to using single probiotic bacterial strains, the manipulation of the entire gut microbiome with fecal microbiota transplants (FMT) is currently being explored. FMT has been successfully used for the treatment of Clos- tridium difficile infection and research into its use for other inflammatory diseases such as type 2 diabetes, inflamma- tory bowel diseases and non-alcoholic steatohepatitis is well under way [91]. The use of FMT beyond intestinal dis- orders requires additional studies and currently there is no data supporting its use in allergic disease or asthma [1]. The role of the microbiome in influencing precision medicine approaches to patient care has been best explored to date in the oncology field. Accumulating evidence sug- gests that the microbiome not only influences the severity of treatment-associated side effects in cancer patients, but also has a dramatic effect on treatment efficacy via pharma- codynamic and immunological mechanisms [92]. Notably, a melanoma mouse model showed commensal microbe- derived antitumor immunity evidenced by higher Sokolowska et al. Asthma Research and Practice (2018) 4:1 Page 5 of 9 intratumoral CD8+ T cell accumulation. From this micro- biota, Bifidobacteria were identified as having the strongest association with antitumor T cell immunity and the ability to maximize the efficacy of the cancer immunotherapeutic anti-PD-L1-specific antibody treatment. Bifidobacteria aug- mented dendritic cell function leading to enhanced CD8+ T cell priming and accumulation within the tumor [93]. While there is a growing amount of data on the compos- itional differences in lung microbiota in health and disease, there is a dearth of research into the functional role of the microbiome on treatment efficacy in patients with chronic respiratory disorders [94]. One important study did correl- ate corticosteroid use and corticosteroid sensitivity in asthma patients with the presence of specific microbes in the lower airways. At the genus level, Neisseria species, Haemophilus species, Campylobacter species and Leptotri- chia species were present in the lower airways of patients with corticosteroid-resistant asthma, but not in patients with corticosteroid-sensitive asthma [59]. Others have dem- onstrated that corticosteroid use, particularly the combin- ation of inhaled and oral corticosteroids, is associated with an increased abundance of Proteobacteria and the genus Pseudomonas, and decreased abundance of Bacteroidetes, Fusobacteria, and Prevotella species [60]. One recent study suggests that microbiome-related functions might affect re- sponsiveness to corticosteroid treatment in asthma patients [95]. Pre-steroid treatment Haemophilus levels were in- creased in asthma patients with diminished responses to corticosteroids. Furthermore, the predicted metagenome metabolic functions in inhaled corticosteroid nonre- sponders suggested increased microbiome-associated xeno- biotic degradation capacity [95]. Further profiling and characterization of the micro- biome associated with different asthma phenotypes is necessary for identifying novel microbiota-related mech- anisms of disease. In addition, identification of these key microbial species and their associated functional effects will contribute to a more precise definition of asthma phenotypes and may help identify more suitable “pheno- type-specific” management strategies [96]. Future perspectives While it is clear that the microbiome significantly influ- ences host immune maturation and immune activity, the molecular basis for these immunomodulatory mecha- nisms are only beginning to be elucidated. It still remains unclear whether and, if so, to what extent pat- terns of airway microbial dysbiosis actually drives rather than merely reflects associated patterns of immune re- activity within the lung. Current studies in prospective birth cohorts and cross-sectional studies in children have heightened our awareness of time-sensitive patterns of colonization of seemingly protective or detrimental bacteria in the gut or airways of healthy and diseased children. However, further mechanistic and epidemio- logical studies are needed to uncover the functional, multidirectional associations between the specific bacter- ial strains, host, allergens and viruses. Respiratory micro- biome assessments in adults have so far been performed in a cross-sectional manner, comparing the airway microbiota composition between healthy controls and patients with asthma and often with other chronic airway diseases. Some studies have provided detailed clinical characteristics of patients, allowing for the cor- relation of microbiota differences across different asthma phenotypes. However, longitudinal and prospective ana- lyses of adult airway microbiome in bigger cohorts of well-characterized patients are still needed to under- stand the relationships between the course of the disease, its phenotype and endotype, susceptibility to exacerbations and disease progression as well as its response to treatment. Compositional profiling needs to be complemented with metagenomics, transcriptomics, physiological, bio- chemical and function-oriented analyses of both the host response and microbial communities as interactions between the host and microbiome are almost certainly bidirectional, with species- and strain-specific behaviors shaped by the genetic background and microenviron- ment in which they exist. In addition, current compos- itional analysis at the genus level is not sufficient and future analysis needs to be conducted at greater depth to include information at the species and strain level. The immune response to a bacterium is often strain-specific and results from one strain cannot be extrapolated to other strains even within the same species. Thus, the traditional methods for microbiological classification, based on 16 s sequencing and certain biochemical prop- erties, of a bacterium into a given genus or species do not currently help us to predict immunological out- comes. Culturing methods need also to be improved in order to isolate and grow lung-derived bacterial strains in vitro, particularly the obligate anaerobes, in order to facilitate strain-specific immunological assessments. Conclusions The last few years have resulted in pivotal studies that clearly associate changes in gut or lung microbial popu- lations with asthma. However, mechanistic studies are still necessary to elucidate how members of the micro- biota induce or modulate inflammatory responses in asthmatic patients. We anticipate that the continuing identification of novel bacterial strains, their compo- nents and metabolites, which modulate mucosal immu- noregulatory responses, will open up new possibilities for a bug-to-drug approach in the treatment of asthma patients and the prevention of airway diseases. Sokolowska et al. Asthma Research and Practice (2018) 4:1 Page 6 of 9 Abbreviations BAL: Bronchoalveolar lavages; FMT: Fecal microbiota transplant; GF: Germ- free; HDM: House dust mite; NLRP6: NOD-like receptor family pyrin domain containing 6; RSV: Respiratory syncytial virus; SCFAs: Short-chain fatty acids; SPF: Specific pathogen-free Acknowledgements None Funding The authors are supported by Swiss National Science Foundation grants (project numbers CRSII3_154488, 310,030_144219, 310,030–127,356 and 310,030_144219) and Christine Kühne – Center for Allergy Research and Education (CK-CARE). Availability of data and materials Not applicable Authors’ contributions All authors contributed to the writing of the review. All authors read and approved the final manuscript. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests LOM is a consultant to Alimentary Health Ltd. and has received research funding from GlaxoSmithKline. CA has received research support from Novartis and Stallergenes and consulted for Actellion, Aventis and Allergopharma. MS, RF and NL have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1Swiss Institute of Allergy and Asthma Research, University of Zürich, Obere Strasse 22, 7270 Davos, Switzerland. 2Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland. 3University of Cape Town, Cape Town, South Africa. Received: 14 September 2017 Accepted: 18 December 2017 References 1. Huang Y, Marsland B, Bunyavanich S, O'Mahony L, Leung D, Muraro A, et al. (2017). The microbiome in allergic disease: current understanding and future opportunities—2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European academy of allergy and clinical immunology. J Allergy Clin Immunol. 2017;139:1099–110. 2. 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Curr Allergy Asthma Rep. 2017;17:62. • We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal • We provide round the clock customer support • Convenient online submission • Thorough peer review • Inclusion in PubMed and all major indexing services • Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit Submit your next manuscript to BioMed Central and we will help you at every step: Sokolowska et al. Asthma Research and Practice (2018) 4:1 Page 9 of 9 Abstract Background Immune mechanisms influenced by the microbiome Microbiome in animal models of asthma The role of the gut microbiome in asthma Role of the respiratory microbiome in asthma Microbiome strategies for asthma prevention, treatment and management Future perspectives Conclusions Abbreviations Funding Availability of data and materials Authors’ contributions Ethics approval and consent to participate Consent for publication Competing interests Publisher’s Note Author details References