Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung

Stéphane Mouraux; Eric Bernasconi; Céline Pattaroni; Angela Koutsokera; John-David Aubert; Johanna Claustre; Christophe Pison; Pierre-Joseph Royer; Antoine Magnan; Romain Kessler; Christian Benden; Paola M Soccal; Benjamin J Marsland; Laurent P Nicod; SysCLAD Consortium

doi:10.1016/j.jaci.2017.06.022

Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung

J Allergy Clin Immunol. 2018 Feb;141(2):718-729.e7. doi: 10.1016/j.jaci.2017.06.022. Epub 2017 Jul 18.

Authors

Collaborators

SysCLAD Consortium:
J Jougon, J-F Velly, H Rozé, E Blanchard, C Dromer, M Antoine, M Cappello, M Ruiz, Y Sokolow, F Vanden Eynden, G Van Nooten, L Barvais, J Berré, S Brimioulle, D De Backer, J Créteur, E Engelman, I Huybrechts, B Ickx, T J C Preiser, T Tuna, L Van Obberghe, N Vancutsem, J-L Vincent, P De Vuyst, I Etienne, F Féry, F Jacobs, C Knoop, J L Vachiéry, P Van den Borne, I Wellemans, G Amand, L Collignon, M Giroux, D Angelescu, O Chavanon, R Hacini, A Pirvu, P Porcu, P Albaladejo, C Allègre, A Bataillard, D Bedague, E Briot, M Casez-Brasseur, D Colas, G Dessertaine, M Durand, G Francony, A Hebrard, M R Marino, B Oummahan, D Protar, D Rehm, S Robin, M Rossi-Blancher, C Augier, P Bedouch, A Boignard, H Bouvaist, A Briault, B Camara, J Claustre, S Chanoine, M Dubuc, S Quétant, J Maurizi, P Pavèse, C Pison, C Saint-Raymond, N Wion, C Chérion, R Grima, O Jegaden, J-M Maury, F Tronc, C Flamens, S Paulus, J-F Mornex, F Philit, A Senechal, J-C Glérant, S Turquier, D Gamondes, L Chalabresse, F Thivolet-Bejui, C Barnel, C Dubois, A Tiberghien, F Le Pimpec-Barthes, A Bel, P Mordant, P Achouh, V Boussaud, R Guillemain, D Méléard, M O Bricourt, B Cholley, V Pezella, G Brioude, X B D'Journo, C Doddoli, P Thomas, D Trousse, S Dizier, M Leone, L Papazian, F Bregeon, A Basire, B Coltey, N Dufeu, H Dutau, S Garcia, J Y Gaubert, C Gomez, S Laroumagne, A Nieves, L C Picard, M Reynaud-Gaubert, V Secq, G Mouton, O Baron, P Lacoste, C Perigaud, J C Roussel, I Danner, A Haloun, A Magnan, A Tissot, T Lepoivre, M Treilhaud, K Botturi-Cavaillès, S Brouard, R Danger, J Loy, M Morisset, M Pain, S Pares, D Reboulleau, P-J Royer, D Fabre, E Fadel, O Mercier, S Mussot, F Stephan, P Viard, J Cerrina, P Dorfmuller, S M Ghigna, Ph Hervén, F Le Roy Ladurie, J Le Pavec, V Thomas de Montpreville, L Lamrani, Y Castier, P Mordant, P Cerceau, P Augustin, S Jean-Baptiste, S Boudinet, P Montravers, O Brugière, G Dauriat, G Jébrak, H Mal, A Marceau, A-C Métivier, G Thabut, E Lhuillier, C Dupin, V Bunel, P Falcoz, G Massard, N Santelmo, G Ajob, O Collange, O Helms, J Hentz, A Roche, B Bakouboula, T Degot, A Dory, S Hirschi, S Ohlmann-Caillard, L Kessler, R Kessler, A Schuller, K Bennedif, S Vargas, J Stauder, S Ali-Azouaou, P Bonnette, A Chapelier, P Puyo, E Sage, J Bresson, V Caille, C Cerf, J Devaquet, V Dumans-Nizard, M-L Felten, M Fischler, A-G Si Larbi, M Leguen, L Ley, N Liu, G Trebbia, S De Miranda, B Douvry, F Gonin, D Grenet, A M Hamid, H Neveu, F Parquin, C Picard, A Roux, M Stern, F Bouillioud, P Cahen, M Colombat, C Dautricourt, M Delahousse, B D'Urso, J Gravisse, A Guth, S Hillaire, P Honderlick, M Lequintrec, E Longchampt, F Mellot, A Scherrer, L Temagoult, L Tricot, M Vasse, C Veyrie, L Zemoura, J Berjaud, L Brouchet, M Dahan, F O Mathe, H Benahoua, M DaCosta, I Serres, V Merlet-Dupuy, M Grigoli, A Didier, M Murris, L Crognier, O Fourcade, J Jougon, J-F Velly, H Rozé, E Blanchard, C Dromer, M Antoine, M Cappello, M Ruiz, Y Sokolow, F Vanden Eynden, G Van Nooten, L Barvais, J Berré, S Brimioulle, D De Backer, J Créteur, E Engelman, I Huybrechts, B Ickx, T J C Preiser, T Tuna, L Van Obberghe, N Vancutsem, J-L Vincent, P De Vuyst, I Etienne, F Féry, F Jacobs, C Knoop, J L Vachiéry, P Van den Borne, I Wellemans, G Amand, L Collignon, M Giroux, D Angelescu, O Chavanon, R Hacini, A Pirvu, P Porcu, P Albaladejo, C Allègre, A Bataillard, D Bedague, E Briot, M Casez-Brasseur, D Colas, G Dessertaine, M Durand, G Francony, A Hebrard, M R Marino, B Oummahan, D Protar, D Rehm, S Robin, M Rossi-Blancher, C Augier, P Bedouch, A Boignard, H Bouvaist, A Briault, B Camara, J Claustre, S Chanoine, M Dubuc, S Quétant, J Maurizi, P Pavèse, C Pison, C Saint-Raymond, N Wion, C Chérion, R Grima, O Jegaden, J-M Maury, F Tronc, C Flamens, S Paulus, J-F Mornex, F Philit, A Senechal, J-C Glérant, S Turquier, D Gamondes, L Chalabresse, F Thivolet-Bejui, C Barnel, C Dubois, A Tiberghien, F Le Pimpec-Barthes, A Bel, P Mordant, P Achouh, V Boussaud, R Guillemain, D Méléard, M O Bricourt, B Cholley, V Pezella, G Brioude, X B D'Journo, C Doddoli, P Thomas, D Trousse, S Dizier, M Leone, L Papazian, F Bregeon, A Basire, B Coltey, N Dufeu, H Dutau, S Garcia, J Y Gaubert, C Gomez, S Laroumagne, A Nieves, L C Picard, M Reynaud-Gaubert, V Secq, G Mouton, O Baron, P Lacoste, C Perigaud, J C Roussel, I Danner, A Haloun, A Magnan, A Tissot, T Lepoivre, M Treilhaud, K Botturi-Cavaillès, S Brouard, R Danger, J Loy, M Morisset, M Pain, S Pares, D Reboulleau, P-J Royer, D Fabre, E Fadel, O Mercier, S Mussot, F Stephan, P Viard, J Cerrina, P Dorfmuller, S M Ghigna, Ph Hervén, F Le Roy Ladurie, J Le Pavec, V Thomas de Montpreville, L Lamrani, Y Castier, P Mordant, P Cerceau, P Augustin, S Jean-Baptiste, S Boudinet, P Montravers, O Brugière, G Dauriat, G Jébrak, H Mal, A Marceau, A-C Métivier, G Thabut, E Lhuillier, C Dupin, V Bunel, P Falcoz, G Massard, N Santelmo, G Ajob, O Collange, O Helms, J Hentz, A Roche, B Bakouboula, T Degot, A Dory, S Hirschi, S Ohlmann-Caillard, L Kessler, R Kessler, A Schuller, K Bennedif, S Vargas, J Stauder, S Ali-Azouaou, P Bonnette, A Chapelier, P Puyo, E Sage, J Bresson, V Caille, C Cerf, J Devaquet, V Dumans-Nizard, M-L Felten, M Fischler, A-G Si Larbi, M Leguen, L Ley, N Liu, G Trebbia, S De Miranda, B Douvry, F Gonin, D Grenet, A M Hamid, H Neveu, F Parquin, C Picard, A Roux, M Stern, F Bouillioud, P Cahen, M Colombat, C Dautricourt, M Delahousse, B D'Urso, J Gravisse, A Guth, S Hillaire, P Honderlick, M Lequintrec, E Longchampt, F Mellot, A Scherrer, L Temagoult, L Tricot, M Vasse, C Veyrie, L Zemoura, J Berjaud, L Brouchet, M Dahan, F O Mathe, H Benahoua, M DaCosta, I Serres, V Merlet-Dupuy, M Grigoli, A Didier, M Murris, L Crognier, O Fourcade, T Krueger, H B Ris, M Gonzalez, Ph Jolliet, C Marcucci, M Chollet, F Gronchi, C Courbon, C Berutto, O Manuel, A Koutsokera, J-D Aubert, L P Nicod, S Mouraux, E Bernasconi, C Pattaroni, B J Marsland, P M Soccal, T Rochat, L M Lücker, S Hillinger, I Inci, W Weder, R Schuepbach, M Zalunardo, C Benden, M M Schuurmans, A Gaspert, D Holzmann, N Müller, C Schmid, B Vrugt, A Fritz, D Maier, K Deplanche, D Koubi, F Ernst, T Paprotka, M Schmitt, B Wahl, J-P Boissel, G Olivera-Botello, C Trocmé, B Toussaint, S Bourgoin-Voillard, M Sève, M Benmerad, V Siroux, R Slama, C Auffray, D Charron, D Lefaudeux, J Pellet

Affiliations

¹ Service de Pneumologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
² Service de Pneumologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Electronic address: [email protected].
³ Clinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France; Institut National de la Santé et de la Recherche Médicale 1055, Saint Martin d'Hèes, France.
⁴ L'institut du Thorax, Service de Pneumologie, Centre Hospitalier Universitaire de Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Nantes, Nantes, France.
⁵ Service de Pneumologie, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France.
⁶ Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland.
⁷ Division of Pulmonary Medicine, Geneva University Hospitals, Geneva, Switzerland.

Abstract

Background: Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling.

Objective: This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation.

Methods: Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture.

Results: We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition.

Conclusions: Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.

Keywords: Airway remodeling; fibroblasts; macrophages; matrix; microbiota.

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Airway Remodeling / immunology*
Bacteria* / classification
Bacteria* / immunology
Extracellular Matrix / immunology
Extracellular Matrix / pathology
Female
Fibroblasts / immunology
Fibroblasts / pathology
Humans
Lung Transplantation*
Lung* / immunology
Lung* / microbiology
Lung* / pathology
Macrophages / immunology
Macrophages / pathology
Male
Microbiota / immunology*
Middle Aged
Signal Transduction / immunology*