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BRN Symposium 03/06/16 Respiratory microbiome in IPF: Pathogenesis, Progression and Exacerbations
- 1. Philip Molyneaux MBBS BSc. PhD Barcelona 2016 The respiratory microbiome in IPF: Pathogenesis, Progression and Exacerbations
- 2. Maher et al Clinics Chest Med 2012 Pathogenesis of IPF INJURY ACTIVATION IMBALANCE ENDOTHELIUM EPITHELIUM FIBROBLASTS FIBROSIS Particulates ▪ Chemicals ▪ Autoimmunity ▪ Viruses ▪ Bacteria Excessive extracellular matrix deposition EMT, transdifferentiation, proliferation, apoptosis, extra cellular matrix turnover Profibrotic mediators CTGF ▪ TGFβ ▪ PDGF FXa ▪ VEGF Antifibrotic mediators PGE2 ▪ IFNγ HGF Coagulation Cascades Anti-oxidant pathways Fibrocytes & circulating cells Macrophage stimulation GENETIC SUCEPTIBILITY MUC5B ▪ TOLLIP ▪ SpC ▪ TERT Pathogenetic Mechanisms in IPF
- 5. A protective effect of antibiotics?
- 7. DOES THE MICROBIOME PLAY A ROLE IN IPF?
- 8. BAL sample DNA extraction multiple bacterial genomes Universal PCR amplification 16s rRNA gene Identification of bacteria and community structure Barcoded PCR Pyrosequencing Data Curation and analysis
- 9. IPF Controls Number of Subjects 65 44 Age 67 years 64 years Men 69% 66% White 80% 82% Smoker (Ex or Current) 65% 60% FVC (% Predicted) 72% 98% DLCO (% Predicted) 40% NA 6MWT distance (m) 316 NA Recruitment & Demographics
- 10. Bacterial load in Stable IPF IPF patients have a significantly higher bacterial burden than both healthy controls and COPD patients.
- 11. Bacterial load & Disease Progression Individuals whose disease had progressed at six months demonstrated a significantly higher BAL bacterial burden when compared to subjects with stable disease.
- 12. Bacterial load predicts Survival
- 13. The Microbiome & Bacterial Burden
- 14. Respiratory Microbiome in IPF Increased numbers of potentially pathogenic bacteria in IPF
- 15. IPF subjects have a less Rich and Diverse Microbiome compared to Controls Loss of diversity and richness
- 17. Han et al Lancet Resp Med 2014 Bacterial Abundance and Survival
- 18. • IPF patients have a higher bacterial load in BAL and significant differences in their microbiota compared to control subjects • Baseline bacterial burden predicted lung function decline in IPF patients Microbiome & IPF
- 19. THE MICROBIOME IN ACUTE EXACERBATIONS OF IPF
- 20. Acute Exacerbations of IPF
- 21. Infection vs Exacerbation Song JW et al Eur Respir J 2011 Patients with acute exacerbation (AE) Patients with infection
- 22. Stable IPF AE-IPF Number of Subjects 14 18 Age 67 years 64 years Men 87% 90% Smoker (Ex or Current) 73% 80% FVC (% Predicted) 80% 76% DLCO (% Predicted) 70% 67% Recruitment & Demographics
- 23. AE-IPF subjects had a bacterial load more than four times higher than stable IPF subjects. A further increase in bacterial load Molyneaux et al (unpublished)
- 24. Molyneaux et al (unpublished) Stable vs. Exacerbation
- 25. Changes in an Individual
- 26. • Increase bacterial load during AE-IPF • Significant differences in the composition and diversity of the microbiota during AE-IPF compared to stable IPF • If an exacerbation is a result of changes in the microbiome, the causal bacteria may be specific to an individual subject. Microbiome & Exacerbations
- 27. WHY DOES THE MICROBIOME CHANGE IN IPF?
- 28. Maher (unpublished) Structural changes in IPF lungs
- 30. MUC5B and Disease Progression
- 31. Bacterial load and MUC5B Bacterial burden associated independently with the MUC5B genotype (P=0.01), with patients possessing the minor allele having a lower bacterial burden
- 32. Morris et al AJRCCM 2014
- 33. Conclusions • IPF is a progressive and inevitably fatal disease • The microbiome in IPF differs from health and COPD • Bacterial load independently predicts disease progression • Acute exacerbation is distinguished by further change in the microbiome • Genetic susceptibility may explain some change in microbiome
- 34. • Toby Maher • Miriam Moffatt • Bill Cookson • Dong Soon Kim • Mike Cox & Saffron Willis Owen • The Asmarley Trust Acknowledgments
- 35. PROFILE Study Annual patient involvement day Oct 2012 Thanks to...