Microbiome-immune interactions and relationship to asthma severity

Microbial-derived factors are integral components of the molecular circuitry that regulates immune and metabolic functions required for host fitness and survival. Recent advances in culture-based methods and sequencing technologies have revealed previously unappreciated complex communities of bacteria, fungi, and viruses that inhabit the respiratory tract and whose composition and activity are correlated with acute and chronic inflammatory responses. In this article, we will summarize our knowledge to date on the role of the microbiota in severe asthma, acknowledging that data specific to severe asthma are currently limited. Disrupted communication between the microbiota and the host because of altered microbiota composition and/or metabolism is thought to negatively influence immune homeostatic networks, as the balance between immune tolerance and inflammation within tissues is regulated in part by the cross talk between immune cells and the microbiota. In addition to the microbial cell structures that activate host pattern recognition receptors, many microbial-derived metabolites, including short-chain fatty acids, biogenic amines and polyamines, aryl hydrocarbon receptor ligands, modified bile acids, and a wide range of G protein–coupled receptor ligands, have all been shown to exert immunomodulatory effects. Importantly, recent microbiota surveys in humans consistently show reduced species diversity and richness in industrialized populations. At the same time, a shift away from diets rich in plant-based dietary fibers has occurred, and this is thought to be important for both microbial diversity and immunologic tolerance.1Fragiadakis G.K. Smits S.A. Sonnenburg E.D. Van Treuren W. Reid G. Knight R. et al.Links between environment, diet, and the hunter-gatherer microbiome.Gut Microbes. 2019; 10: 216-227Crossref PubMed Scopus (50) Google Scholar Thus, changes in microbiota diversity and changes in dietary habits that occur simultaneously may interact in unanticipated ways, resulting in additive detrimental effects on the host immune system. Following birth, infants acquire microbes from their mother, other family members, animals, and their environmental exposures. The complexity of the infant microbiome develops and matures during the first years of life and is supported by the introduction of diverse complementary and solid foods. Several studies have demonstrated that delayed maturation of the infant microbiome is associated with an increased risk of asthma later in life. Lower abundance of gut microbes, including Bifidobacterium, Akkermansia, Lachnospira, Veillonella, Faecalibacterium, and Rothia, were associated with the development of asthma later in life. In addition, changes in the infant fecal metabolome have also been correlated with asthma risk, where 12,13-dihydroxy-9Z-octadecenoic acid (which decreases regulatory T [Treg] cell abundance and increases TH2 cytokine numbers) has been associated with increased risk, whereas short-chain fatty acid levels (which increase Treg cell abundance and decrease TH2 cytokine numbers) have been associated with reduced risk of later life asthma.2Fujimura K.E. Sitarik A.R. Havstad S. Lin D.L. Levan S. Fadrosh D. et al.Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation.Nat Med. 2016; 22: 1187-1191Crossref PubMed Scopus (450) Google Scholar,3Roduit C. Frei R. Ferstl R. Loeliger S. Westermann P. Rhyner C. et al.High levels of butyrate and propionate in early life are associated with protection against atopy.Allergy. 2019; 74: 799-809Crossref PubMed Scopus (126) Google Scholar Microbiota composition in children is also correlated with changes in asthma control and asthma severity. One study suggested that 15 bacterial genera and 7 fungal genera show a significant difference in overall abundance between severe asthma and nonasthma bronchoalveolar lavage samples, whereas another study found that Moraxella is the most commonly associated genus in the nasal airways of children with severe persistent asthma (the average patient age in both studies was 11 years).4Goldman D.L. Chen Z. Shankar V. Tyberg M. Vicencio A. Burk R. Lower airway microbiota and mycobiota in children with severe asthma.J Allergy Clin Immunol. 2018; 141: 808-811Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,5Chun Y. Do A. Grishina G. Grishin A. Fang G. Rose S. et al.Integrative study of the upper and lower airway microbiome and transcriptome in asthma.JCI Insight. 2020; 5e133707Crossref PubMed Scopus (14) Google Scholar Microbial dysbiosis of the airways and the gut is increasingly being associated with the incidence and severity of asthma in adults (Fig 1).6Abdel-Aziz M.I. Brinkman P. Vijverberg S.J.H. Neerincx A.H. Riley J.H. Bates S. et al.Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months.J Allergy Clin Immunol. 2021; 147: 123-134Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,7Sokolowska M. Frei R. Lunjani N. Akdis C.A. O'Mahony L. Microbiome and asthma.Asthma Res Pract. 2018; 4: 1Crossref PubMed Google Scholar Within the airways, the phylum Proteobacteria is often associated with worse asthma control, whereas Actinobacteria can be correlated with improvement or with no change in asthma control. Mycoplasma pneumoniae, Chlamydophila pneumoniae, Neisseria haemophilus, Campylobacter, and Leptotrichia species are also often found in the airways of patients with severe asthma or in corticosteroid-resistant patients. The mechanisms responsible for changes in the airway microbiota are not well understood, and it is possible that in addition to medications, the type of inflammatory response (ie, eosinophilic versus neutrophilic), changes in host secretions (eg, lipids), and cellular metabolism might influence microbial colonization and growth within the airways. Interestingly, neutrophilic exacerbations of asthma and chronic obstructive pulmonary disease were correlated with the presence of Proteobacteria in the sputum, whereas increased eosinophil numbers in patients with asthma, regardless of their body mass index, were associated with an increased relative abundance of the genera Rothia, Dorea, Lautropia, and Haemophilus within bronchoalveolar lavage samples.8Michalovich D. Rodriguez-Perez N. Smolinska S. Pirozynski M. Mayhew D. Uddin S. et al.Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients.Nat Commun. 2019; 10: 5711Crossref PubMed Scopus (55) Google Scholar The gut microbiota is also altered in patients with severe asthma. A significant reduction in the levels of bacteria of the family Verrucomicrobiaceae was observed in the gut microbiota of patients with severe asthma versus in patients with mild-to-moderate asthma, which was primarily due to reduced levels of Akkermansia muciniphila.8Michalovich D. Rodriguez-Perez N. Smolinska S. Pirozynski M. Mayhew D. Uddin S. et al.Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients.Nat Commun. 2019; 10: 5711Crossref PubMed Scopus (55) Google Scholar In experimental models, A muciniphila protected mice from respiratory inflammatory responses to acute and chronic house dust mite extract exposure, associated with higher numbers of lung Treg cells and reduced accumulation of the IL-5–dependent Siglec Fhigh eosinophils within lung tissue.8Michalovich D. Rodriguez-Perez N. Smolinska S. Pirozynski M. Mayhew D. Uddin S. et al.Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients.Nat Commun. 2019; 10: 5711Crossref PubMed Scopus (55) Google Scholar This mechanism was MyD88 independent but did require viable bacterial cells, suggesting that heat-sensitive factors or metabolites secreted in vivo are required for the protective effects of A muciniphila. In contrast, increased levels of histamine-secreting microbes, in particular Morganella morganii, were observed in the gut microbiota of patients with severe asthma.9Barcik W. Pugin B. Westermann P. Perez N.R. Ferstl R. Wawrzyniak M. et al.Histamine-secreting microbes are increased in the gut of adult asthma patients.J Allergy Clin Immunol. 2016; 138: 1491-1494Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Recently, there has been significant attention focused on defining asthma disease endotypes on the basis of a range of host factors. However, a more detailed and accurate endotyping of patients with asthma may be facilitated by including an analysis of the composition and metabolic activity of an individual's respiratory and gut microbiota (Fig 2). In particular, the potential for analysis of the microbiota to assist in the early prediction and differentiation of severe from nonsevere asthma, perhaps even in early life, opens exciting new areas of research and clinical applications in the management of severe asthma. However, to correctly interpret their findings, researchers conducting future studies must carefully include demographic, clinical, exposure, and lifestyle factors as possible confounders in their analysis. Specific microbes, as well as their metabolites, are being examined for their preventive and therapeutic effects, but given the explosion in knowledge regarding disease endotypes, it is possible that specific microbes will need to be carefully selected to mechanistically fit with specific disease endotypes, and it is likely that 1 intervention will not work for everyone with severe asthma. In addition, the efficacy of existing therapeutics may be significantly influenced by the microbiota. Therefore, microbiota profiling should be included in future clinical studies examining novel asthma medications. Responsiveness to glucocorticosteroids may be microbiota dependant, whereas the optimal choice of biologic may be heavily influenced by microbial factors. In other fields, such as cancer immunotherapy using checkpoint inhibitors, the importance of the microbiota in therapy success is well established.10Zhou C.B. Zhou Y.L. Fang J.Y. Gut microbiota in cancer immune response and immunotherapy.Trends Cancer. 2021; 7: 647-660Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In conclusion, it remains unclear whether and, if so, the extent to which patterns of microbial dysbiosis actually drive rather than merely reflect associated patterns of immune reactivity within the lung. However, interactions between the host and microbiota are almost certainly bidirectional, with species- and strain-specific behaviors shaped by the genetic background and microenvironment in which they exist. Microbial factors are evolutionarily hardwired into the molecular circuitry governing immune cell decision-making processes, and we expect that research focused on the mechanisms that contribute to this intimate and sophisticated interkingdom dialogue will yield important diagnostic and therapeutic advances for patients with severe asthma.