Microbial and Host Immune Factors as Drivers of Chronic Obstructive Pulmonary Disease

Background: We hypothesize that the inflammatory and emphysematous milieu in patients with Chronic Obstructive Pulmonary Disease (COPD) drives change in the respiratory tract microbiota and host macrophage gene expression. Methods: We performed a cross-sectional study to compare non-COPD controls (n=10) to COPD patients with different disease severity degrees (GOLD1 n=6, GOLD2 n=8, GOLD3 n=8, GOLD4 n=10). Samples (n=187) were obtained by conventional brushes and bronchoscopy, including broncho-alveolar lavage (BAL), of different sites of the respiratory tract. Microbiota analyses were performed by 16S rRNA sequencing and host gene expression analyses by quantitative real-time PCR of different inflammatory, immunomodulatory, and scavenging receptor and remodeling markers of BAL cells. Results: Overall, COPD GOLD3/GOLD4 patients clustered significantly different as compared to non-COPD controls and COPD GOLD1/GOLD2 patients illustrated by bacterial abundance based beta diversity analysis (permutational MANOVA; P=0.001). However, we found a gradual increase in dissimilarity by COPD severity degree (Mann-Whitney tests; P<0.0001, P<0.0001, and P=0.004) illustrating the great heterogeneity of the microbiome within COPD GOLD3/GOLD4 patients as compared to the controls and to COPD GOLD1/GOLD2 patients. As for the microibme, the chosen set of host gene expression markers separated COPD GOLD3/GOLD4 patients significantly. In addition, four markers of the host gene expression analyses were significantly correlated with alpha diversity measurements of the microbiota. Conclusions: COPD patients harbored a disordered microbiota that was associated with the disease severity and alteration of host gene expression profiles. Overall, this study provides an extensive description of host and microbiota factors that may influence the course of COPD. correlation of run accession and primer_set_id run_accession primer_set_id ERR1942968 28 ERR1942967 27 ERR1942966 26 ERR1942965 25 ERR1942964 24 ERR1942963 23 ERR1942962 22 ERR1942961 21 ERR1942960 21 ERR1942959 20 ERR1942958 19 ERR1942957 18 ERR1942956 18 ERR1942955 17 ERR1942954 17 ERR1942953 16 ERR1942952 15 ERR1942951 14 ERR1942950 13 ERR1942949 12 ERR1942948 11 ERR1942947 10 ERR1942946 9 ERR1942945 8 ERR1942944 7 ERR1942943 6 ERR1942942 5 ERR1942941 4 ERR1942940 3 ERR1942939 2 ERR1942938 1 primer sets: ##1 P001_BAL TCGTCGCTCGACTCCTACGGGAGGCAGCAG P002_Lingula ACGCGAGTATACTCCTACGGGAGGCAGCAG P003_mBl ACTGTACAGTACTCCTACGGGAGGCAGCAG P001_Skin AGACTATACTACTCCTACGGGAGGCAGCAG P002_Pharynx AGTACGCTATACTCCTACGGGAGGCAGCAG P004_BAL ATAGAGTACTACTCCTACGGGAGGCAGCAG P002_Nasal TACACGTGATACTCCTACGGGAGGCAGCAG ##2 P001_Pharynx TCGTCGCTCGACTCCTACGGGAGGCAGCAG P002_LL ACGCGAGTATACTCCTACGGGAGGCAGCAG P003_OL ACTGTACAGTACTCCTACGGGAGGCAGCAG P001_Nasal AGACTATACTACTCCTACGGGAGGCAGCAG P004_Skin ATAGAGTACTACTCCTACGGGAGGCAGCAG P002_Trachea TACACGTGATACTCCTACGGGAGGCAGCAG ##3 P001_Trachea TCGTCGCTCGACTCCTACGGGAGGCAGCAG P003_BAL ACGCGAGTATACTCCTACGGGAGGCAGCAG P001_mBl AGACTATACTACTCCTACGGGAGGCAGCAG P004_Nasal ATAGAGTACTACTCCTACGGGAGGCAGCAG P002_mBl TACACGTGATACTCCTACGGGAGGCAGCAG ##4 P003_Skin ACGCGAGTATACTCCTACGGGAGGCAGCAG P001_LL AGACTATACTACTCCTACGGGAGGCAGCAG P004_Pharynx ATAGAGTACTACTCCTACGGGAGGCAGCAG P002_OL TACACGTGATACTCCTACGGGAGGCAGCAG ##5 P003_Nasal ACGCGAGTATACTCCTACGGGAGGCAGCAG P001_OL AGACTATACTACTCCTACGGGAGGCAGCAG P004_Trachea ATAGAGTACTACTCCTACGGGAGGCAGCAG ##6 P003_Pharynx ACGCGAGTATACTCCTACGGGAGGCAGCAG P001_Lingula AGACTATACTACTCCTACGGGAGGCAGCAG P004_mBl ATAGAGTACTACTCCTACGGGAGGCAGCAG P003_ML TACACGTGATACTCCTACGGGAGGCAGCAG ##7 P003_Trachea ACGCGAGTATACTCCTACGGGAGGCAGCAG P002_BAL AGACTATACTACTCCTACGGGAGGCAGCAG P004_OL ATAGAGTACTACTCCTACGGGAGGCAGCAG P004_LL TACACGTGATACTCCTACGGGAGGCAGCAG ##8 P002_Skin AGACTATACTACTCCTACGGGAGGCAGCAG P004_Lingula ATAGAGTACTACTCCTACGGGAGGCAGCAG ##9 P005_skin ACGAGtgcgtACTCCTACGGGAGGCAGCAG P006_ML ACGCTcgacaACTCCTACGGGAGGCAGCAG P006_LL AGACGcactcACTCCTACGGGAGGCAGCAG P007_OL AGCACtgtagACTCCTACGGGAGGCAGCAG P008_trachea ATCAGacacgACTCCTACGGGAGGCAGCAG P009_skin ATATCgcgagACTCCTACGGGAGGCAGCAG P010_skin CGTGTctctaACTCCTACGGGAGGCAGCAG P011_skin CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_skin TAGTAtcagcACTCCTACGGGAGGCAGCAG P010_trachea TCTCTatgcgACTCCTACGGGAGGCAGCAG P013_UL TGATAcgtctACTCCTACGGGAGGCAGCAG P006_nasal TACTGagctaACTCCTACGGGAGGCAGCAG P016_UL CGTCTAGTACACTCCTACGGGAGGCAGCAG ##10 P005_nasal ACGAGtgcgtACTCCTACGGGAGGCAGCAG P005_BAL ACGCTcgacaACTCCTACGGGAGGCAGCAG P006_BAL AGACGcactcACTCCTACGGGAGGCAGCAG P007_ML AGCACtgtagACTCCTACGGGAGGCAGCAG P009_nasal ATATCgcgagACTCCTACGGGAGGCAGCAG P010_nasal CGTGTctctaACTCCTACGGGAGGCAGCAG P011_BAL CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_BAL TAGTAtcagcACTCCTACGGGAGGCAGCAG P013_BAL TGATAcgtctACTCCTACGGGAGGCAGCAG P007_skin TACTGagctaACTCCTACGGGAGGCAGCAG P016_BAL CGTCTAGTACACTCCTACGGGAGGCAGCAG ##11 P005_pharynx ACGAGtgcgtACTCCTACGGGAGGCAGCAG P006_skin ACGCTcgacaACTCCTACGGGAGGCAGCAG P007_LL AGCACtgtagACTCCTACGGGAGGCAGCAG P008_mBr ATCAGacacgACTCCTACGGGAGGCAGCAG P009_UL ATATCgcgagACTCCTACGGGAGGCAGCAG P010_pharynx CGTGTctctaACTCCTACGGGAGGCAGCAG P011_pharynx CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_pharynx TAGTAtcagcACTCCTACGGGAGGCAGCAG P014_skin TGATAcgtctACTCCTACGGGAGGCAGCAG P014_BAL TACTGagctaACTCCTACGGGAGGCAGCAG P015_pharynx CGAGAgatacACTCCTACGGGAGGCAGCAG P016_nasal ATACGACGTAACTCCTACGGGAGGCAGCAG P017_skin CGTCTAGTACACTCCTACGGGAGGCAGCAG ##12 P005_trachea ACGAGtgcgtACTCCTACGGGAGGCAGCAG P007_nasal AGACGcactcACTCCTACGGGAGGCAGCAG P007_BAL AGCACtgtagACTCCTACGGGAGGCAGCAG P009_BAL ATCAGacacgACTCCTACGGGAGGCAGCAG P009_pharynx ATATCgcgagACTCCTACGGGAGGCAGCAG P010_mBr CGTGTctctaACTCCTACGGGAGGCAGCAG P012_trachea TAGTAtcagcACTCCTACGGGAGGCAGCAG P013_pharynx TCTCTatgcgACTCCTACGGGAGGCAGCAG P014_nasal TGATAcgtctACTCCTACGGGAGGCAGCAG P008_nasal TACTGagctaACTCCTACGGGAGGCAGCAG P016_pharynx ATACGACGTAACTCCTACGGGAGGCAGCAG P017_nasal CGTCTAGTACACTCCTACGGGAGGCAGCAG ##13 P005_mBl ACGAGtgcgtACTCCTACGGGAGGCAGCAG P006_pharynx ACGCTcgacaACTCCTACGGGAGGCAGCAG P007_pharynx AGACGcactcACTCCTACGGGAGGCAGCAG P008_OL ATCAGacacgACTCCTACGGGAGGCAGCAG P009_trachea ATATCgcgagACTCCTACGGGAGGCAGCAG P010_OL CGTGTctctaACTCCTACGGGAGGCAGCAG P011_mBr CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_mBr TAGTAtcagcACTCCTACGGGAGGCAGCAG P013_trachea TCTCTatgcgACTCCTACGGGAGGCAGCAG P014_pharynx TGATAcgtctACTCCTACGGGAGGCAGCAG P008_mBl TACTGagctaACTCCTACGGGAGGCAGCAG P016_trachea ATACGACGTAACTCCTACGGGAGGCAGCAG P017_pharynx CGTCTAGTACACTCCTACGGGAGGCAGCAG ##14 P005_OL ACGAGtgcgtACTCCTACGGGAGGCAGCAG P006_trachea ACGCTcgacaACTCCTACGGGAGGCAGCAG P007_trachea AGACGcactcACTCCTACGGGAGGCAGCAG P008_ML ATCAGacacgACTCCTACGGGAGGCAGCAG P009_mBl ATATCgcgagACTCCTACGGGAGGCAGCAG P010_ML CGTGTctctaACTCCTACGGGAGGCAGCAG P011_OL CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_OL TAGTAtcagcACTCCTACGGGAGGCAGCAG P013_mBr TCTCTatgcgACTCCTACGGGAGGCAGCAG P016_lingula TGATAcgtctACTCCTACGGGAGGCAGCAG P015_skin TACTGagctaACTCCTACGGGAGGCAGCAG P017_trachea CGTCTAGTACACTCCTACGGGAGGCAGCAG ##15 P005_lingula ACGAGtgcgtACTCCTACGGGAGGCAGCAG P006_mBr ACGCTcgacaACTCCTACGGGAGGCAGCAG P007_mBr AGACGcactcACTCCTACGGGAGGCAGCAG P008_pharynx AGCACtgtagACTCCTACGGGAGGCAGCAG P009_OL ATATCgcgagACTCCTACGGGAGGCAGCAG P011_ML CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_ML TAGTAtcagcACTCCTACGGGAGGCAGCAG P013_OL TCTCTatgcgACTCCTACGGGAGGCAGCAG P015_nasal TACTGagctaACTCCTACGGGAGGCAGCAG P016_OL CGAGAgatacACTCCTACGGGAGGCAGCAG P017_mBl CGTCTAGTACACTCCTACGGGAGGCAGCAG ##16 P005_LL ACGAGtgcgtACTCCTACGGGAGGCAGCAG P006_OL ACGCTcgacaACTCCTACGGGAGGCAGCAG P008_BAL ATCAGacacgACTCCTACGGGAGGCAGCAG P010_BAL CGTGTctctaACTCCTACGGGAGGCAGCAG P011_UL CTCGCgtgtcACTCCTACGGGAGGCAGCAG P012_UL TAGTAtcagcACTCCTACGGGAGGCAGCAG P013_ML TCTCTatgcgACTCCTACGGGAGGCAGCAG P015_trachea TACTGagctaACTCCTACGGGAGGCAGCAG P015_UL CGAGAgatacACTCCTACGGGAGGCAGCAG P017_BAL CGTCTAGTACACTCCTACGGGAGGCAGCAG ##17 P018_pharynx ACGAGtgcgtACTCCTACGGGAGGCAGCAG P019_skin ACGCTcgacaACTCCTACGGGAGGCAGCAG P019_UL AGACGcactcACTCCTACGGGAGGCAGCAG P021_nasal AGCACtgtagACTCCTACGGGAGGCAGCAG P021_mBr ATCAGacacgACTCCTACGGGAGGCAGCAG P022_nasal ATATCgcgagACTCCTACGGGAGGCAGCAG P022_BAL CGTGTctctaACTCCTACGGGAGGCAGCAG P023_BAL CTCGCgtgtcACTCCTACGGGAGGCAGCAG P025_nasal TAGTAtcagcACTCCTACGGGAGGCAGCAG P025_BAL TCTCTatgcgACTCCTACGGGAGGCAGCAG P026_nasal TGATAcgtctACTCCTACGGGAGGCAGCAG P027_nasal TACTGagctaACTCCTACGGGAGGCAGCAG P028_pharynx CATAGtagtgACTCCTACGGGAGGCAGCAG P029_pharynx CGAGAgatacACTCCTACGGGAGGCAGCAG P029_mBl ATACGACGTAACTCCTACGGGAGGCAGCAG P030_pharynx CGTCTAGTACACTCCTACGGGAGGCAGCAG P031_skin TGTACTACTCACTCCTACGGGAGGCAGCAG ##18 P020_lingula ACGAGtgcgtACTCCTACGGGAGGCAGCAG P019_nasal ACGCTcgacaACTCCTACGGGAGGCAGCAG P019_BAL AGACGcactcACTCCTACGGGAGGCAGCAG P021_pharynx AGCACtgtagACTCCTACGGGAGGCAGCAG P021_BAL ATCAGacacgACTCCTACGGGAGGCAGCAG P022_pharynx ATATCgcgagACTCCTACGGGAGGCAGCAG P023_trachea CGTGTctctaACTCCTACGGGAGGCAGCAG P024_pharynx CTCGCgtgtcACTCCTACGGGAGGCAGCAG P025_pharynx TAGTAtcagcACTCCTACGGGAGGCAGCAG P023_mBl TCTCTatgcgACTCCTACGGGAGGCAGCAG P026_pharynx TGATAcgtctACTCCTACGGGAGGCAGCAG P027_pharynx TACTGagctaACTCCTACGGGAGGCAGCAG P029_trachea CGAGAgatacACTCCTACGGGAGGCAGCAG P029_OL ATACGACGTAACTCCTACGGGAGGCAGCAG P030_BAL CGTCTAGTACACTCCTACGGGAGGCAGCAG P031_nasal TGTACTACTCACTCCTACGGGAGGCAGCAG ##19 P020_BAL ACGAGtgcgtACTCCTACGGGAGGCAGCAG P019_pharynx ACGCTcgacaACTCCTACGGGAGGCAGCAG P020_skin AGACGcactcACTCCTACGGGAGGCAGCAG P026_BAL ATCAGacacgACTCCTACGGGAGGCAGCAG P022_trachea ATATCgcgagACTCCTACGGGAGGCAGCAG P023_OL CGTGTctctaACTCCTACGGGAGGCAGCAG P028_skin CTCGCgtgtcACTCCTACGGGAGGCAGCAG P021_trachea TAGTAtcagcACTCCTACGGGAGGCAGCAG P026_trachea TGATAcgtctACTCCTACGGGAGGCAGCAG P028_ML TACTGagctaACTCCTACGGGAGGCAGCAG P029_lingula ATACGACGTAACTCCTACGGGAGGCAGCAG P031_pharynx TGTACTACTCACTCCTACGGGAGGCAGCAG ##20 P021_skin ACGAGtgcgtACTCCTACGGGAGGCAGCAG P019_trachea ACGCTcgacaACTCCTACGGGAGGCAGCAG P020_pharynx AGACGcactcACTCCTACGGGAGGCAGCAG P022_mBr ATATCgcgagACTCCTACGGGAGGCAGCAG P023_lingula CGTGTctctaACTCCTACGGGAGGCAGCAG P028_nasal CTCGCgtgtcACTCCTACGGGAGGCAGCAG P021_OL TAGTAtcagcACTCCTACGGGAGGCAGCAG P028_UL TACTGagctaACTCCTACGGGAGGCAGCAG P029_UL ATACGACGTAACTCCTACGGGAGGCAGCAG P031_trachea TGTACTACTCACTCCTACGGGAGGCAGCAG ##21 P026_mBr ACGAGtgcgtACTCCTACGGGAGGCAGCAG P019_mBl ACGCTcgacaACTCCTACGGGAGGCAGCAG P020_trachea AGACGcactcACTCCTACGGGAGGCAGCAG P022_UL ATATCgcgagACTCCTACGGGAGGCAGCAG P023_pharynx CGTGTctctaACTCCTACGGGAGGCAGCAG P028_trachea CTCGCgtgtcACTCCTACGGGAGGCAGCAG P022_skin TAGTAtcagcACTCCTACGGGAGGCAGCAG P028_BAL TACTGagctaACTCCTACGGGAGGCAGCAG ##22 P026_OL ACGAGtgcgtACTCCTACGGGAGGCAGCAG P019_OL ACGCTcgacaACTCCTACGGGAGGCAGCAG P023_nasal ATATCgcgagACTCCTACGGGAGGCAGCAG P028_mBr CTCGCgtgtcACTCCTACGGGAGGCAGCAG P022_OL TAGTAtcagcACTCCTACGGGAGGCAGCAG P029_BAL ATACGACGTAACTCCTACGGGAGGCAGCAG P031_lingula TGTACTACTCACTCCTACGGGAGGCAGCAG ##23 P026_ML ACGAGtgcgtACTCCTACGGGAGGCAGCAG P030_skin ATACGACGTAACTCCTACGGGAGGCAGCAG P031_nc TGTACTACTCACTCCTACGGGAGGCAGCAG ##24 P026_UL ACGAGtgcgtACTCCTACGGGAGGCAGCAG P030_nasal ATACGACGTAACTCCTACGGGAGGCAGCAG P031_BAL TGTACTACTCACTCCTACGGGAGGCAGCAG ##25 P032_pharynx ACGAGtgcgtACTCCTACGGGAGGCAGCAG P043_trachea2 ACGCTcgacaACTCCTACGGGAGGCAGCAG P044_OL AGACGcactcACTCCTACGGGAGGCAGCAG P033_skin ATCAGacacgACTCCTACGGGAGGCAGCAG P033_pharynx ATATCgcgagACTCCTACGGGAGGCAGCAG P034_pharynx CGTGTctctaACTCCTACGGGAGGCAGCAG P035_pharynx CTCGCgtgtcACTCCTACGGGAGGCAGCAG P035_nasal TAGTAtcagcACTCCTACGGGAGGCAGCAG P036_nasal TCTCTatgcgACTCCTACGGGAGGCAGCAG P036_mBr TGATAcgtctACTCCTACGGGAGGCAGCAG P037_nasal TACTGagctaACTCCTACGGGAGGCAGCAG P037_BAL CGAGAgatacACTCCTACGGGAGGCAGCAG P038_trachea ATACGACGTAACTCCTACGGGAGGCAGCAG P038_UL CGTCTAGTACACTCCTACGGGAGGCAGCAG P035_trachea TGTACTACTCACTCCTACGGGAGGCAGCAG P036_UL ACGACTACAGACTCCTACGGGAGGCAGCAG P040_pharynx CGTAGACTAGACTCCTACGGGAGGCAGCAG P041_nasal TACTCTCGTGACTCCTACGGGAGGCAGCAG P041_mBl TAGAGACGAGACTCCTACGGGAGGCAGCAG P041_BAL TCGTCGCTCGACTCCTACGGGAGGCAGCAG P039_BAL ACGCGAGTATACTCCTACGGGAGGCAGCAG P043_nasal AGACTATACTACTCCTACGGGAGGCAGCAG P044_pharynx AGTACGCTATACTCCTACGGGAGGCAGCAG P019_PMA TAGTGTAGATACTCCTACGGGAGGCAGCAG P041_PMA TGACGTATGTACTCCTACGGGAGGCAGCAG P043_UL ACAGTATATAACTCCTACGGGAGGCAGCAG ##26 P043_BAL ACGCTcgacaACTCCTACGGGAGGCAGCAG P044_UL AGACGcactcACTCCTACGGGAGGCAGCAG P034_nasal ATCAGacacgACTCCTACGGGAGGCAGCAG P043_lingula ATATCgcgagACTCCTACGGGAGGCAGCAG P034_skin CGTGTctctaACTCCTACGGGAGGCAGCAG P035_UL CTCGCgtgtcACTCCTACGGGAGGCAGCAG P035_OL TAGTAtcagcACTCCTACGGGAGGCAGCAG P036_pharynx TCTCTatgcgACTCCTACGGGAGGCAGCAG P036_ML TGATAcgtctACTCCTACGGGAGGCAGCAG P037_pharynx TACTGagctaACTCCTACGGGAGGCAGCAG P038_skin CGAGAgatacACTCCTACGGGAGGCAGCAG P038_mBl ATACGACGTAACTCCTACGGGAGGCAGCAG P038_BAL CGTCTAGTACACTCCTACGGGAGGCAGCAG P035_lingula TGTACTACTCACTCCTACGGGAGGCAGCAG P041_pharynx TACTCTCGTGACTCCTACGGGAGGCAGCAG P041_OL TAGAGACGAGACTCCTACGGGAGGCAGCAG P042_pharynx TCGTCGCTCGACTCCTACGGGAGGCAGCAG P040_skin ACGCGAGTATACTCCTACGGGAGGCAGCAG P043_OL AGACTATACTACTCCTACGGGAGGCAGCAG P044_trachea AGTACGCTATACTCCTACGGGAGGCAGCAG P021_PMA TAGTGTAGATACTCCTACGGGAGGCAGCAG P043_PMA TGACGTATGTACTCCTACGGGAGGCAGCAG P044_ML ACAGTATATAACTCCTACGGGAGGCAGCAG ##27 P044_skin ACGCTcgacaACTCCTACGGGAGGCAGCAG P035_mBl TAGTAtcagcACTCCTACGGGAGGCAGCAG P036_trachea TCTCTatgcgACTCCTACGGGAGGCAGCAG P038_nasal CGAGAgatacACTCCTACGGGAGGCAGCAG P038_OL ATACGACGTAACTCCTACGGGAGGCAGCAG P039_pharynx CGTCTAGTACACTCCTACGGGAGGCAGCAG P041_trachea TACTCTCGTGACTCCTACGGGAGGCAGCAG P041_UL TAGAGACGAGACTCCTACGGGAGGCAGCAG P044_mBr AGTACGCTATACTCCTACGGGAGGCAGCAG P044_PMA TGACGTATGTACTCCTACGGGAGGCAGCAG P014_PMA ACAGTATATAACTCCTACGGGAGGCAGCAG ##28 P035_BAL TAGTAtcagcACTCCTACGGGAGGCAGCAG P038_pharynx CGAGAgatacACTCCTACGGGAGGCAGCAG P043_trachea1 ACTGTACAGTACTCCTACGGGAGGCAGCAG P044_BAL ATAGAGTACTACTCCTACGGGAGGCAGCAG P004_PMA CACGCTACGTACTCCTACGGGAGGCAGCAG P025_PMA TCGATCACGTACTCCTACGGGAGGCAGCAG P029_PMA TCGCACTAGTACTCCTACGGGAGGCAGCAG P038_PMA TCTATACTATACTCCTACGGGAGGCAGCAG