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Although eosinophilic asthma has been connected with the Th2 response, neutrophilic asthma is believed to be a non-Th2 immune response [38]. It is recognized that this potent innate immune response can be stimulated by Gram-negative and Gram-positive
bacteria and their products, including endotoxins, with cell wall and outer membrane components all potentially acting as pathogen-associated molecular patterns (PAMPs), which are recognized by TLRs, G protein-coupled receptors (GPCRs), CD14, and
collectins. Activation of TLRs leads to inflammatory cascades that result in production of the proinflammatory cytokines IL-8 [also known as chemokine CXC ligand (CXCL)8], IL-1, and TNF-α, generating a shift toward a Th1 and Th17 response, extensive
neutrophil recruitment, and a change in inflammatory cell differential profile. Consistent with this, there is evidence in treatment-resistant severe asthma of increased TNF-α gene and protein expression within the airways compared to that in mild
asthma [39]. Some members of the GPCR family transduce signals through cytoplasmic G proteins to cytoskeletal proteins controlling the movement of leukocytes. The GPCRs FPR1 and FPR2 (human formyl peptide receptor 1 and 2) as well as GPCRs 41 and 43 (
GPR41 and GPR43) are all expressed by neutrophils and can detect PAMPs. Activation of these receptors results in the recruitment of neutrophils from the bloodstream to sites of infection, activation of the oxidative burst and IL-8 release [40].

An intriguing hypothesis that is gaining notoriety is that sustained microbial colonization of the airway could promote the neutrophilia observed in asthma. Studies lend strength to this argument by showing that S. aureus, M. catarrhalis, and H.
influenzae are detected in sputum from neutrophilic and stable severe asthmatics [13,41]. Furthermore, strong associations have been revealed between increased bacterial load and higher concentrations of airway neutrophils and the neutrophil
chemoattractant IL-8. Also linked to neutrophilic asthmatics is the resistance to corticosteroid treatment. Although only a small number of studies have been carried out, it appears that patients resistant to corticosteroid treatment are predominantly
colonized by the same communities of bacteria as neutrophilic asthmatics are. Work investigating the influence of H. parainfluenzae on the expression of corticosteroid-regulated genes of BAL macrophages in an in vitro co-culture model concluded that the
presence of H. parainfluenzae resulted in inhibition of the steroid response as opposed to the presence of commensal members of the genus Prevotella[21].

A recent study examining bronchial biopsies implicated IL-17 in causing substantial neutrophil recruitment in the airways suggesting that the neutrophilic asthmatic response is more complex than believed [42]. IL-17 drives Th17 responses, which provide
protection from infection at mucosal surfaces. Further work provides evidence that the Th17 lineage of T cells has a role in controlling pulmonary bacterial infections and have already been implicated in those caused by Klebsiella pneumoniae infection [
43]. Furthermore, Th17 cytokines are associated with moderate and severe asthma with IL-17A, IL-17F, and IL-22, functioning to increase smooth muscle mass, mucus production, and the indirect recruitment of neutrophils to the airways by inducing the
release of the chemokines CXCL1 and IL-8 from epithelial cells [44]. It should be noted that recent work looking at bronchial biopsies failed to find an association with IL-17A/IL-17F and neutrophilia [42]. Interestingly, the cytokine profile and
presence of microbial products at a site of infection can determine the lifespan of neutrophils. Activation of pattern recognition receptors (PRRs) on the surface of neutrophils such as TLR 1, 2, 4, 5, 6, 8, and 9 have been shown to enhance neutrophil
survival where nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling is important [45]. The pattern recognition function of neutrophils may represent an important pathway directly linking the detection of lung microbiota members
and neutrophil survival in the airway.

Although investigation into the microbial contributions to these various subtypes of asthma are in the initial stages, they provide confidence that research should be undertaken to link microbial burden and community composition with specific immune
responses. The categorization of asthmatics based on the immune cell profile of the sputum is an invaluable tool that should be utilized to elucidate the functional properties of the lung microbiota. However, there are many questions regarding the
stability of these inflammatory phenotypes over time, especially in children with asthma, and more longitudinal studies are required. This variability may be partly explained by variations in environmental exposure over time. Other complementary
approaches are required to understand these complex immunopathologies. A recent study looking at differential expression of host genes found a six-gene signature that could be used as a biomarker to distinguish different inflammatory subtypes [39]. In
the future, these clinically measurable outputs should be combined with sputum metabolomics data, patient genetics, and patient information (including history of infection) to better define asthma endotypes, as outlined in a recent review [46], and the
contribution of the lung microbiota to each of these. Ultimately, this will lead to the replacement of asthma as an umbrella term for a range of inter-related but distinct conditions [38].

Asthma treatment in the light of improved understanding of the associated airway microbiota
Many research groups have begun to devise and test methods to exploit and convert this newfound knowledge of the microbiota of the respiratory tract into improved or even new treatment strategies for asthma and other inflammation-based diseases. Below,
we discuss some of the approaches that have been proposed in potentially improving treatment of asthma.

Predication of onset of asthma exacerbation
The asthma severity correlates with microbiota dysfunction and inflammation in the airways [47,48]. Acute periods of exacerbation are one of the most important causes of morbidity in asthma sufferers. Consequently, the control of asthma has depended on
the management of inflammation. The precise triggers of exacerbation are complex but it has become clear that the current techniques to measure dysfunction and inflammation in asthma patients (history, physical examination, and spirometry) are somewhat
insensitive [49]. One of the key objectives of asthma clinicians now is to improve the ability to accurately monitor airway inflammation through noninvasive means. Although several inflammatory-marker-based methods have been developed, such factors are
typically only elevated during the inflammatory/exacerbation process, providing limited periods where treatment intervention will be useful. Advances in our understanding of microbiota in asthma and the rapid diagnostic tools that are being developed in
tandem now allow the examination of these microbial communities, with the likelihood of identifying potential microbial signatures on which rapid diagnostic assays can be based. To date, there is little work carried out examining if microbial signatures
can predict the onset of asthma exacerbation [50]. However, studies that have mapped the bacterial community structure during periods of stability and exacerbation in the airways of CF patients suggest this approach may be feasible. For example, a recent
study has identified several orders of anaerobic bacteria that are more predominant in CF patient airways undergoing exacerbation [50]. Although it is unlikely that the microorganisms colonizing the CF airway are the sole contributors to exacerbation,
further longitudinal studies could establish if the changes identified preceded the onset of exacerbation as measured by clinical parameters. The identification and deployment of microbial signatures in asthma diagnosis is less advanced than other
diseases but at this point longitudinally collected sample sets need to be investigated for their potential.

Immune manipulation using prebiotics, probiotics, and other microbiological supplements
There is increasing evidence to suggest that the intestinal microbiota, particularly during early infancy, plays a critical role in regulating immune responses [51]. Several studies have shown that modulations of the resident gut commensal microbiota can
shape the global immune response of the host, reducing sensitization and inflammation [51]. Several recent studies have illustrated that microbiota manipulation via oral prebiotics, probiotics, and other supplementation promotes healthy gut microbiota
and reduces overt airway immune responses in asthma patients [52,53]. Studies examining the impact of prebiotics on the immunogenicity of asthma are summarized in Table 2. Although data from these tests are not altogether convincing, they do give
strength to the possibility of promoting a healthy microbiota in asthmatics, which may have potential health benefits. These approaches show some merit in treatment of other inflammation-based diseases such as obesity and juvenile diabetes but specific
work on asthmatics is still required to surmount the scientific, health, and regulatory concerns.

Table 2. Studies since 2011 showing the varied impact of prebiotics, probiotics, and other supplements on the immunogenicity of asthma or associated symptoms from a range of clinical trials, epidemiological studies, and murine models

Approach Objective Delivery Outcome Refs
Prebiotics
Bacteria oligosaccharides Examination of infants in the first six months of life without clinical evidence of allergy, both with and without risk factors for allergic disease and food allergy. Metadata assessing a collection of delivery methods. Evidence
suggested that the prebiotic supplement added to infant feeds potentially prevents eczema. It was unclear whether it may have an effect on asthma. [64]
Various nutrients & Mediterranean diet A total of 1428 subjects across 21 cohorts. Metadata assessing a collection of delivery methods. The evidence is supportive of vitamins A, D, and E; zinc; fruits and vegetables; and a Mediterranean diet contributing
to the prevention of asthma. [65]
Mediterranean diet A general population of children assessed in studies up to May 2012. Metadata assessing a collection of delivery methods Mediterranean diet tended to be associated with lower occurrence of the asthma symptoms. [66]
Antioxidant 2442 8-year-old children from the Swedish birth cohort study BAMSE. Oral Magnesium intake seems to have a protective effect on childhood asthma. [67]
Cord blood vitamin D 257 children from the Copenhagen prospective studies on asthma in childhood (COPSAC2000) at-risk mother-child cohort. Oral No association between cord blood 25(OH)-vitamin D level and changes in lung function, sensitization, rhinitis
or eczema were observed. [68]
Cord blood vitamin D 158 children at age 3 years. Oral Prenatal vitamin D supplementation in late pregnancy had a modest effect on cord blood vitamin D level. This study found that cord blood vitamin D level was not associated with decreased wheezing in
offspring at age three years. [69]
Fish oil 420 infants considered high atopic risk. Oral Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease including asthma. [70]
Probiotics
Single strain or mixture of bacterial strains – mainlyLactobacillus rhamnosusGG (LGG) 4031 subjects in 20 cohorts Metadata assessing a collection of delivery methods Early probiotic administration reduces the risk of atopic sensitization, but it does
not reduce the risk of developing asthma. [71]
Lactobacillus rhamnosusGG (LGG) Murine model of allergic asthma. Oral LGG had an anti-inflammatory effect on OVA-induced airway inflammation. [72]
Single strain or mixture of bacterial strains – mainlyLactobacillus rhamnosusGG (LGG) 4866 children. Metadata assessing a collection of delivery methods No evidence to support a protective association between perinatal use of probiotics and doctor
diagnosed asthma or childhood wheeze. [73]
Strains ofLactobacillusorBifidobacteriumwere mainly used 995 participants involving all age groups. Metadata assessing a collection of delivery methods Due to the high degree of heterogeneity in the data assess few solid outcomes can be ascertained. [74]
Lactobacillus reuteriATCC 55730 232 families with allergic disease, of whom 184 completed a 7-yr follow-up. Metadata assessing a collection of delivery methods The effect of L. reuteri on sensitization and IgE-associated eczema in infancy did not lead to
a lower prevalence of respiratory allergic disease in school age. Thus, the effect of L. reuteri on the immune system appeared to be transient. [75]
Lactobacillus paracaseisspparacaseiF19 171 children that completed the intervention, 121 were assessed at age 8–9 Oral No long-term effect of LF19 on any diagnosed allergic disease, airway inflammation or IgE sensitization. [76]
Microbial products
Lipopeptide Murine model of asthma. Intraperitoneal Protection against sensitization and airway inflammation was observed. [77]
Heat-killedBifidobacterium breveC50 andStreptococcus thermophilus065 (HKBBST) Infants at high risk of atopy. Oral Decreased the incidence of potentially allergic AE (PAAE)s. [75,78]
Tailored antimicrobial or vaccine therapy of specific microbiota community members
As discussed earlier, airway infections by specific microbiota or bacteria may induce, augment, or potentially even modify the predominant type of airway inflammation seen in asthma. It has been proposed that more focused antibiotic or vaccine therapies
based on comprehensive characterization of the microbiota present in the airway could inform the use of antimicrobials that target specific microbiota in asthmatics [49,54]. Conversely, microbiome-targeted treatment approaches could be interpreted from
the perspective of how to promote a more functionally balanced airway microbiome, such that pathogenic microbiota are not able to exert dominant effects. Thus, an understanding of microbiota that are negatively associated with features of asthma could be
useful toward developing approaches to promote these microbiota, or specific functions they express that counteract detrimental inflammatory processes. These approaches have been studied and highlighted more in the gut microbiome literature but suggest
that the approach may be feasible in the treatment of asthma [55].

Although still in their infancy, these potential new approaches for the treatment of asthma, used in combination with other therapeutic measures including vaccines and steroid treatment, could improve, alleviate, and treat asthma symptoms. Many obstacles
exist to the use of these approaches but key among these is the complex heterogeneity of asthma as a disease and the variation in microbiome composition observed across this patient population. As discussed above, this heterogeneity of asthma reflects
different underlying clinical characteristics, biology, and genetics, which can all make different contributions to shaping microbial diversity found in the asthmatic airway. Therefore, it is becoming paramount that the phenotypes or subtypes of asthma
are more clearly defined to determine specifically when the microbiota plays an important role in asthma. As touched on above, a selection of schemes have been proposed to classify asthma phenotypes. It will become important that a stringent and more
feasible classification approach is adopted in order to enable more focused development of microbiota driven treatment in asthma.

Concluding remarks
It is now clear that high-resolution microbiota sequencing efforts and translational models of lung disease are providing new insight into the roles of microorganisms in asthma pathogenesis and exacerbation. Bacteria clearly have roles to play in the
disease progress and clinical outcome of asthma but also appear, in certain cases, to play protective functions. There is also vast experimental and clinical evidence that asthma can be viewed as a chronic inflammatory disease that can be initiated and
modulated by the airway microbiota. These interactions with the host immune system can involve commensal bacteria as well as pathogens that most likely mediate a range of molecular mechanisms. It may be that increases in asthma prevalence worldwide are
due in part to a changing relation with microbes in the lower respiratory tract. More research is needed to provide better mechanistic insights into interactions between the airway microbiota and host immune response, as well as address several
outstanding questions in the field (Box 3). Understanding the molecular basis and biological effect the airway microbiota has on the host immune response may lead to the discovery of microbial or immunological targets that are amenable to manipulation
for the development of new treatments.

Box 3
Outstanding questions

•
To what extent does an altered airway microbiota effect the development or worsening of asthma symptoms?

•
Do standard treatments, such as steroids, antibiotics or inhaled medication, contribute to the shaping of the asthma airway microbiota and does this have implications for disease symptoms?

•
Many microorganisms (virus, bacteria, and fungi) can coexist in the respiratory tract of an asthmatic patient. If interplay occurs between these organisms, what impact does it have on shaping the inflammatory response and the response to treatment?

•
How best can we classify phenotypes of asthma to determine precisely what role the microbiota plays in the development of disease and patient prognosis?

•
Many challenges apply to modeling asthma disease. However, with new translational models of asthmatic lung disease, can models of microbiota interactions with the host be developed?

•
Are changes in microbiota composition predictive of asthma exacerbation or respiratory tract infection? Will this provide a platform for preventative treatment using targeted interference strategies and antimicrobial therapy?

•
Can biotherapeutic strategies such as the use of prebiotics or probiotics be developed to counteract microbiota dysbiosis in asthmatic patients and could this have a knock-on effect on care?


Acknowledgments
We thank Susan Lynch, Yvonne McCarthy and the Ryan Laboratory for their helpful comments and critical reading of the manuscript. The work of the authors has been supported in part by grants awarded by the Wellcome Trust (WT100204AIA senior fellowship
grant to R.P.R.) and the European Union's Seventh Framework Programme (Grant No. 603038 to R.P.R.). We apologize to the colleagues whose work could not be cited due to space constraints.

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