The Human Microbiome in Chronic Obstructive Pulmonary Disease (COPD)

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1 The Human Microbiome in Chronic Obstructive Pulmonary Disease (COPD) Jeffrey L. Curtis, M.D. University of Michigan & Ann Arbor VA Healthsystem Ning Shen, M.D. Peking University Third Hospital

2 Outline Importance of increasing understanding of COPD pathogenesis Concept of the human microbiome Microbiome research to advance understanding of COPD risk

3 COPD: a world-wide problem 1 3 rd leading cause of death: USA: >130,000 deaths/year (2008) (~40 deaths/10 5 ) 2 China: >1.3 million deaths/year (2000) (~100 deaths/10 5 ) 3 global incidence increasing rapidly the leading worldwide cause of death by 2050 (World Health Organization prediction) 1 Mannino & Buist Lancet Minono et al. Nat Vital Stat Reports MOH Dis Control Dept & NCDC 2006

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5 China faces all three potential causes of COPD

6 Oxidative stress starts an inflammatory cascade leading to emphysema, bronchitis & small airway fibrosis Shapiro N Engl J Med 2005

7 present in every alveolus Alveolar macrophages express receptors to detect infectious agents or their products previously believed to assure sterility of healthy lungs guard your lungs

8 Why study COPD pathogenesis? No available therapies can stop COPD progression or alter its mortality Not all smokers develop COPD why some do is largely unknown so far, mostly unexplained by genetics Major component of COPD pathogenesis must still be missing

9 What is the Human Microbiome? The micro-organisms that live on our skin and mucosal surfaces our microbes outnumber us 10-fold more microbial cells in your colon than cells in your entire body >10,000 types of bacteria most cannot be cultured currently Turnbaugh et al. Nature 2007

10 Analyzing the microbiome Traditional, culture-dependent methods Culture-independent methods bacterial 16S rrna 454 pyrosequencing

11 Progress to date UM group published paper linking lung microbiome to COPD first to stratify by smoking status & lung function UM & PKUTH groups working together on 2 nd manuscript advanced methods to analyze in greater detail human samples already collected PKUTH group submitted human study

12 Erb-Downward et al. PLOS One 2011

13 qpcr of 16S rrna reveals normal human lungs are not sterile Erb-Downward et al. PLOS One 2011

14 454-analysis of human lung microbiome at phylum level Erb-Downward et al. PLOS One 2011

15 Erb-Downward et al. PLOS One 2011

16 Principal Component Analysis (PCA) to reduce dataset complexity Transforms data that might correlate into values without correlation called principal components The variable that contributed most to variance positions the sample along the first axis the next most along the second axis, etc. usually displayed as first two principal components (x vs. y axes)

17 PCA of human lung microbiome (at genus level) Erb-Downward et al. PLOS One 2011

18 Erb-Downward & Wang Unpublished

19 Modeling host-microbiome interactions Correspondence analysis correlates bacterial species to anatomic site and to murine epithelial cell gene expression Erb-Downward Unpublished

20 Big Picture How variations in the lung microbiome could explain individual susceptibility to COPD Curtis & Shen Unpublished

21 Conclusions Our two teams of Pulmonary investigators are collaborating to make significant discoveries into COPD pathogenesis comparing & contrasting results from our two sites developing yet more novel analytical techniques training next generation of researchers