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Analysis of the Lung Microbiome in Idiopathic Pulmonary Fibrosis Jin, Boyang Tom; Ng, Raymond; Tanabe, Naoya; Kinose, Daisuke; Hogg, James C. 2016-03-30

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Introduction• Bacteria and other microorganisms that normally reside in the lung is collectively known as the lung microbiome (3)• The microbiome does not usually elicit an immune response in healthy humans (3)• Role of the lung microbiome in IPF has not been extensively studied (3)• Changes in the microbiome composition may be associated with an immune response in IPF patients (3)Methods• Microbiome Sequencing (performed by HLI group): Performed on the bacteria-specific 16S rRNA gene in samples from 10 IPF patients and 6 healthy controls• Sequence Alignment: Performed using the mothur tool and the GreenGenes and Silva reference databases• Data Cleaning: Filtered and normalised by subsampling the data. Negative controls (background bacteria) were also subtracted• Analysis: Statistical analysis performed with R and PythonReferences1. Zolak JS, de Andrade JA. 2012. Idiopathic pulmonary fibrosis. Immunology and Allergy Clinics of North America. 32:473-485.2. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. 2012. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. European Respiratory Review. 21:355-361.3. Morris A, Gibson K, Collman RG. 2014. The lung microbiome in idiopathic pulmonary fibrosis. What does it mean and what should we do about it? American Journal of Respiratory and Critical Care Medicine. 190:850.0.0013033170.500.550.600.650.70Control IPFDistance to Centroid0.50.60.7Control IPFDistance to Centroid0.50.60.7Control IPFDistance to Centroid0.500.550.600.650.70Control IPFDistance to CentroidOVERALL LOWER LUNG MIDDLE LUNG UPPER LUNGIDIOPATHIC PULMONARY FIBROSIS (IPF)• Serious progressive lung disease with a poor prognosis (1)• Interstitial tissue scarring results in impaired respiratory capacity (1)• Higher occurrence in older male adults although still relatively rare with an incidence of 1.25 to 27.9 cases per 100,000 population (2)• Cause is unknown although fibrotic process may be a result of an aberrant wound repair response to a lung epithelial injury (1)• Risk factors may include smoking, viral infections, or certain genetic backgrounds (2)MICROBIOME12Control IPF Non-Elevated VvCD68 IPF Elevated VvCD68Alpha DiversityP = 0.03512Control IPF Non-Elevated VvCD79a IPF Elevated VvCD79aAlpha Diversity12Control IPF Non-Elevated VvCD4 IPF Elevated VvCD4Alpha DiversityAlpha DiversityMACROPHAGES B-CELLS T-CELLSMeasure of both richness (the number of species present) and evenness (how evenly distributed the species are within each sample) • An elevated immune cell level is defined as being in the top 25th percentile of all samples• Alpha diversities for IPF samples were significantly lower than that of the control samples • IPF samples with elevated macrophages and B-cells levels had a lower alpha diversity• IPF is characterised by the presence of fewer species than a healthy individualBeta Diversity Measure of the change in species composition between two samples within a group with similar disease states• IPF lung samples were more dissimilar to each other when compared with how similar the control lung samples were to each other• Of the three lung locations, only the lower lung IPF samples were significantly more dissimilar to each other when compared with that of the controls. This is consistent with the increased IPF disease severity in the lower lungs.• Higher dissimilarity in IPF indicate that different bacteria dominant in different IPF samples• Thus it is unlikely that a specific bacteria is the sole contributor to the IPF disease state0.001303317Identifying IPF-Associated Bacteria1. Convert bacteria count data into percent abundances2. Keep percent abundance values that are greater than 25%3. Filter any bacteria that do not have a single sample with an elevated value4. Identify the bacteria that are present in the IPF samples but not the control samples (exclude completely unclassified)Phylum GenusActinobacteria Tropheryma, unclassified (x2)BacteroidetesCytophaga, Chryseobacterium, Flavobacterium, Pedobacter, unclassified (x2)Proteobacteria Acinetobacter, Bacteriovorax, Stenotrophomonas, unclassified (x4)Firmicutes Clostridium, Streptococcus, StaphylococcusTABLE 1. BACTERIA IDENTIFIED (19 TOTAL)IDENTIFICATION PROCESSConclusion-2.50.02.55.07.5-2.5 0.0 2.5 5.0 7.5PCA Axis 1PCA Axis 2metadataControlIPF1 2 3 4 5 6 7 8 9 105.56.06.57.07.58.0Principle ComponentVariance %PCA OF IDENTIFIED BACTERIA VARIANCE CAPTURED BY PCA• IPF samples exhibit more variation unlike the control samples which are clustered around (0,0)IPF-Associated Bacteria AnalysisP = 1.53662e-05Elevated-Macrophage Bacteria Analysis0.000.250.500.75Control IPF Non-Elevated CD68 IPF Elevated CD68Percent AbundancePhylum GenusActinobacteria TropherymaBacteroidetes unclassifiedProteobacteria Acinetobacter, Bacteriovorax, unclassified (x2)Firmicutes Clostridium, Streptococcus• A subset of the 19 bacteria genus focused on opportunistic pathogenic bacteria were selected to investigate the association with elevated macrophage levelsP = 0.000280652P = 0.001676699TABLE 2. SUBSETTED BACTERIA (8 TOTAL)• Significantly higher total percent abundance was observed for IPF non-elevated macrophage samples when only this subset of bacteria was used• Percent abundance of each bacteria genus identified as being elevated in IPF (Table 1) was summed across each sample • IPF samples had a significantly higher total percentage abundance when compared to that of the control samples• Several identified bacteria in Table 1 are pathogens or opportunistic pathogens including Clostridium, Staphylococcus, and Acinetobacter0.000.250.500.751.00Control IPFDiseasePercent Abundance• The role of the microbiome in IPF is likely to be very multifaceted as different bacteria are elevated in IPF while the overall number of different bacteria is decreased• Certain groups of bacteria can be identified as being elevated as a whole in IPF • Elevated macrophage response in IPF samples could potentially result in the low percent abundance of the bacteria identified in Table 2 • As several bacteria identified were opportunistic pathogens, the fibrotic response could be a product of the immune system response against these pathogensAnalysis of the Lung Microbiome in Idiopathic Pulmonary FibrosisBoyang Tom Jin, Dr. Raymond Ng, Dr. Naoya Tanabe, Dr. Daisuke Kinose, Dr. James C. HoggP = 0.036 P = 0.0497 P = 0.022 N.SP = 0.0026N.S.P = 0.042P = 0.0013 N.S.Note: Elevated is defined as being in the top 25th percentile of all samplesCPSC 449  |  March 30, 2016

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