Asthma and the Airway Microbiome: New Insights and Hypotheses

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1 Asthma and the Airway Microbiome: New Insights and Hypotheses Yvonne J. Huang, MD Division of Pulmonary and Critical Care Medicine Department of Internal Medicine University of Michigan, Ann Arbor 3 rd Microbiome orum, Sept. 11, 2015

2 Objectives Asthma Overview Origins of childhood asthma (microbiome) Adult asthma and the importance of phenotypes Adult asthma and the airway microbiome Unanswered questions, new lines of investigation

3 Global Prevalence of Asthma Masoli et al. Allergy 2004; Science million globally have asthma; 22 million in U.S. In 2013, asthma-related medical costs and lost days of productivity in the U.S. amounted to $56 billion.

4 Links between the microbiome and development of allergy or asthma Marsland, Annals ATS 2013 Shaping of gut and airway microbiota, Immune development

5 The Complexity of Asthma GINA 2014 new definition: Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation. Huang and Boushey, J Allerg Clin Immunol 2015

6 Asthma Susceptibility Genes Vercelli, Nature Rev Immunol 2008

7 Asthma Susceptibility Genes Microbial recognition, Immunoregulation Epithelial cells: Chemokines, antimicrobial peptides Type 2 effector functions Vercelli, Nature Rev Immunol 2008

8 Asthma has many different phenotypes Onset/triggers Clinical severity Airway inflammation Disease control Disease risk Response to therapy

9 Asthma has many different phenotypes Onset/triggers Disease control Clinical severity Disease risk Airway inflammation Response to therapy T H 2 Non-T H 2 Haldar et al. Am J Respir Crit Care Med 2008 Wenzel, Nature Medicine 2012

10 Relevance of type 2- high vs. type 2- low inflammatory phenotypes in asthma type 2- responsive epithelial genes Woodruff et al, Am J Respir Crit Care Med 2009

11 A large subgroup of mild-moderate asthma is persistently non-eosinophilic ICS-negative ICS-positive Mcgrath et al, AJRCCM 2012

12 A significant proportion of adult asthmatics do not have type 2-driven asthma (50%) Inhaled corticosteroids (ICS) and newer biologics (type 2-targeting) do not work as well in type 2- low asthma A survey of 1000 patients indicated 86% of asthmatics on controller therapies (i.e. ICS) still had sub-optimal or poor asthma control (Colice et al. Annals Allerg Asthma Immnol 2012) What are the drivers of type 2- low asthma?

13 Adult Asthma and Potential Influence of the Microbiome Microbiome Asthma clinical features Type 2- high Type 2- low Asthma Treatment What are the known relationships between asthma, the airway microbiome, and inflammation?

14 1. Does lower airway microbiota composition differ between asthmatic and healthy adults? Bronchial brushings, Huang JACI 2011 Sputum (no ICS), Marri JACI 2013 Some asthmatics harbor higher bacterial burden and diversity in the lower airways

15 In mild asthma, the lower respiratory tract is enriched in certain bacteria (Proteobacteria) compared to healthy controls Sputum Marri et al. JACI 2013

16 2. Are patterns of lower airway microbiota composition associated with phenotypic features of asthma? β- and γ- Proteobacteria = 60% of taxa correlated with worse airway hyper-response. Huang et al. JACI 2011 In mild-moderate asthma, greater diversity (β- and γ-proteobacteria) is correlated with more severe airway hyper-responsiveness.

17 Shannon diversity Characteristics of the airway microbiota may play a role in asthma therapeutic response (example: macrolide) No Yes Improvement in bronchial reactivity (PC 20 ) with clarithromycin x 16 wks Huang et al. JACI 2011

18 In severe asthma, bacterial microbiota patterns are differentially associated with phenotypic features NMDS ACQdiff BxEos SputTotNonEpi NMDS 1 BMI NMDS 2 Asthma control Obesity Steroid-response Non-type 2 inflammation Huang et al. J Allerg Clin Immunol, in press

19 Prevotella copy# Obese severe asthmatics demonstrate increased bronchial abundance of certain bacteria -log10 p-value Phylum (amily) Bacteroidetes (lavobacteriaceae) * Bacteroidetes (Prevotellaceae) * Bacteroidetes (Rikenellaceae II) Chlorobi (OPB56) irmicutes (Clostridiales amily XI. Incertae Sedis) * irmicutes (Clostridiales amily XIII. Incertae Sedis) irmicutes (Lachnospiraceae) * usobacteria (usobacteriaceae) Proteobacteria (Desulfobacteraceae) Proteobacteria (Helicobacteraceae) * Spirochaetes (Spirochaetaceae) Tenericutes (Erysipelotrichaceae) Tenericutes (Mycoplasmataceae) Bacteroidetes Prevotella lavobacteria irmicutes Clostridiales Lachnospiraceae usobacteria Decreased in obese Increased in obese Difference in taxon relative abundance (log2) obese vs. nonobese Severe Asthma Prevotella spp. copy number (log10) 7.0 R s = 0.61, p < BMI (severe BMI asthma grp)

20 Log relative abundance positive-correlated taxa Worse symptom control in severe asthma is correlated with greater abundance of predominantly Proteobacteria members 448 taxa; R = , DR-adj p < 0.05 Change in ACQ

21 Log relative abundance negative-correlated taxa Better symptom control in severe asthma is correlated with greater relative abundance of Actinobacteria Change in ACQ 362 taxa; R = -0.5 to -0.8, DR-adj p < 0.05

22 Phylogenetic Diversity Expression levels of a steroid-responsive gene in airway epithelial cells correlate with greater bacterial diversity, mostly Actinobacteria Actinobacteria 8% Proteobacteria 27% 58% irmicutes Acidobacteria Bacteroidetes Chloroflexi Verrucomicrobia WPS-2 83 taxa, DR-adjusted q-value < 0.10 Huang et al. JACI in press

23 A distinct group of bacteria are associated with airway epithelial expression of genes related to Th17 inflammation Proteobacteria Cyanobacteria NMDS T T T T T T T TT TT T TT T T T T T T T TT T T TT Th17 T T T T KBP5 T 4% 5% 7% 8% Proteobacteria 73% Bacteroidetes irmicutes Deferribacteres Planctomycetes Synergistetes Actinobacteria TM6 Chlamydiae Armatimonadetes SAR406 Thermi Tenericutes Spirochaetes Actinobacteria Proteobacteria irmicutes Acidobacteria NMDS1 27% Proteobacteria 58% Actinobacteria Bacteroidetes Chloroflexi Verrucomicrobia WPS-2 R = , DR q-val < 0.20

24 Asthma Observable characteristics Phenotypes Endotypes Condition subtype defined by distinct functional or pathophysiological mechanism Microbiome

25 NIH AsthmaNet Microbiome Proof-of-Concept study (NCT ) 1. Allergic, Asthmatic 2. Allergic, Non-asthmatic 3. Healthy Oral wash Sputum Bronchoscopy Stool Airway microbiome analysis Effect of inhaled steroids Immune profiling (blood, lung)

26 University of Michigan Characterization of Adults for Asthma Microbiome Research Studies (CAARS) Asthmatics on ICS Screen (Q, Bld, S, MC, IS, Stl) Visit 1 Phone call (Q, S, AR, IS, Stl) Visit 2 Asthmatics, ICS-naive Healthy controls days to 30 days Key: ICS = inhaled corticosteroid; Q, questionnaires; S, spirometry; MC, methacholine challenge; AR, airway reversibility; IS, induced sputum; Stl, stool sample. Prospective observational, longitudinal Detailed subject characterization and sample/data collection: Lung function assessments Multiple questionnaires (asthma control, sino-nasal symptoms, environmental microbial exposures, detailed dietary history) Sputum, oral wash, stool, blood, urine

27 Some Research Questions (clinical) 1. Is airway enrichment in specific bacteria predictive of worse asthma outcomes? Bacterial biomarkers in clinically accessible sample types? 2. What is the stability of the airway microbiome in adult asthma, and its relationship to environmental exposures, even diet? 3. Does the respiratory microbiome differ between obese and non-obese individuals, with or without asthma? 4. Does the gut microbiome differ in adults with asthma? 5. Are patterns of gut dysbiosis associated with phenotypic features of asthma, including worse outcomes?

28 Microbiome Asthma clinical features Type 2- high Asthma Treatment Type 2- low Glucocorticoids What is the impact of pulmonary therapeutics on the microbiome? Do the above result in treatment-refractory asthma subtypes? Mechanisms? Does the respiratory microbiome play a role in therapeutic response? Biomarkers? microbial-derived therapeutics?

29 Alveolar macrophage responses to steroids may be altered in the presence of specific bacteria (H. parainfluenzae) Goleva et al. AJRCCM 2013 Steroids (beclomethasone) can alter behavior of H. influenzae in vitro in vivo Earl et al. EMBO Mol Med 2015

30 Summary 1. Mounting evidence implicates a role for the respiratory microbiome in the phenotypic heterogeneity of adult asthma. 2. Despite the known influence of gut microbiota in early life susceptibility to allergy or asthma, little is known about the GI microbiome in relation to adult asthma. 1. Potentially important interactions may exist between the respiratory microbiome and treatments used for asthma and other chronic airway diseases.

31 Acknowledgements UCS Homer Boushey MD Susan Lynch PhD Kei ujimura PhD (Mike Cox PhD) Lawrence Berkeley National Lab Eoin Brodie, PhD (Todd DeSantis MS) Asthma Clinical Research Network AsthmaNet Joe Arron MD PhD David Choy Jeff Harris MD PhD U. Michigan Gary Huffnagle, PhD Snehal Nariya unding: NHLBI