Lung microbiota predict chronic rejection in healthy lung transplant recipients: a prospective cohort study

Combs, M.P.; Wheeler, David; Luth, J.; Falkowski, Nicole R.; Walker, Neff; Erb-Downward, John R.; Lama, Vibha N.; Dickson, Robert P.

doi:10.1016/s2213-2600(20)30405-7

Cited by 59 publications

(48 citation statements)

References 64 publications

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“…However, it is essential to consider relative enrichment of specific taxa in the context of the total microbial burden, particularly in the lung, where the microbial burden varies over many orders of magnitude. Indeed, bacterial burden may be as important as composition, as described in studies where total bacterial burden in bronchoalveolar lavage fluid (BALF) predicted chronic lung allograft dysfunction or death following lung transplantation (24), progression of interstitial pulmonary fibrosis (25,26), and outcomes during critical illness (27).…”

Section: The Healthy Lung Microbiomementioning

confidence: 99%

The lung microbiome: progress and promise

Whiteside¹,

McGinniss²,

Collman³

2021

Journal of Clinical Investigation

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Section: The Healthy Lung Microbiomementioning

confidence: 99%

The lung microbiome: progress and promise

Whiteside¹,

McGinniss²,

Collman³

2021

Journal of Clinical Investigation

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“…[1][2][3][4][5] Infectious complications are among the strongest risk factors for acute and chronic lung allograft dysfunction (CLAD), the primary cause of mortality following lung transplantation. [6][7][8][9] Lung allograft injury and CLAD are more frequent in lung transplant recipients (LTR) with clinical infection or colonization of the lung with specific pathogens, particularly de novo Pseudomonas aeruginosa [10][11][12] Emerging data suggest that increased bacterial burden, decreased bacterial diversity, and prominence of Proteobacteria, such as PsA, are associated with, graft failure, and CLAD through pathogen-driven inflammatory triggers and impaired innate responses impacting bacterial clearance. [6][7][8]11,[13][14][15] Regarding innate immune signaling, elevated IL-1β has been associated with a decline in lung function, injury in murine models of infection, and the development of CLAD; [16][17][18][19][20][21] but, few studies have examined the role of pathogen-driven inflammatory triggers on human innate immune responses in lung transplantation.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9] Lung allograft injury and CLAD are more frequent in lung transplant recipients (LTR) with clinical infection or colonization of the lung with specific pathogens, particularly de novo Pseudomonas aeruginosa [10][11][12] Emerging data suggest that increased bacterial burden, decreased bacterial diversity, and prominence of Proteobacteria, such as PsA, are associated with, graft failure, and CLAD through pathogen-driven inflammatory triggers and impaired innate responses impacting bacterial clearance. [6][7][8]11,[13][14][15] Regarding innate immune signaling, elevated IL-1β has been associated with a decline in lung function, injury in murine models of infection, and the development of CLAD; [16][17][18][19][20][21] but, few studies have examined the role of pathogen-driven inflammatory triggers on human innate immune responses in lung transplantation. [6][7][8]11,[13][14][15] Recent work has shown that Proteobacteria can enhance inflammatory M1 macrophage activation with excess inflammation or tissue injury and that resolution of Pseudomonas-lung injury in other lung disease models is mediated by a shift of macrophage responses.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8]11,[13][14][15] Regarding innate immune signaling, elevated IL-1β has been associated with a decline in lung function, injury in murine models of infection, and the development of CLAD; [16][17][18][19][20][21] but, few studies have examined the role of pathogen-driven inflammatory triggers on human innate immune responses in lung transplantation. [6][7][8]11,[13][14][15] Recent work has shown that Proteobacteria can enhance inflammatory M1 macrophage activation with excess inflammation or tissue injury and that resolution of Pseudomonas-lung injury in other lung disease models is mediated by a shift of macrophage responses. [22][23][24] However, the role of PsA in the lung microbiome and its activation of alveolar macrophage (AM) innate immune signaling following lung transplantation is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

“…1–5 Infectious complications are among the strongest risk factors for acute and chronic lung allograft dysfunction (CLAD), the primary cause of mortality following lung transplantation. 6–9…”

Section: Introductionmentioning

confidence: 99%

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Pseudomonas aeruginosa Elicits Sustained IL-1β Upregulation in Alveolar Macrophages from Lung Transplant Recipients

Britton

Villabona-Rueda

Whiteside

et al. 2022

Preprint

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BackgroundIsolation of Pseudomonas aeruginosa (PsA) is associated with increased BAL (bronchoalveolar lavage) inflammation and lung allograft injury in lung transplant recipients (LTR). However, the effect of PsA on macrophage responses in this population is incompletely understood. We examined human alveolar macrophage (AM) responses to PsA and Pseudomonas dominant microbiome in healthy lung transplant recipients (LTR).MethodsWe stimulated THP-1 derived macrophages (THP-1M) and human AM from LTR with different bacteria and LTR BAL derived microbiome characterized as Pseudomonas-dominant. Macrophage responses were assessed by high dimensional flow cytometry, including their intracellular production of cytokines (TNF-α, IL-6, IL-8, IL-1β, IL-10, IL-1RA, and TGF-β). Pharmacological inhibitors were utilized to evaluate the role of the inflammasome in PsA-macrophages interaction.ResultsWe observed upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) following stimulation by PsA compared to other bacteria (Staphylococcus aureus, Prevotella melaninogenica, Streptococcus pneumoniae) in both THP-1 derived and LTR AM, predominated by IL-1β. IL-1β production from THP-1 was sustained after PsA stimulation for up to 96 hours and 48 hours in LTR AM. Treatment with the inflammasome inhibitor BAY11-7082 abrogated macrophage IL-1β and IL-18 production after PsA exposure. BAL Pseudomonas-dominant microbiota elicited an increased IL-1β, similar to PsA, an effect abrogated by the addition of antibiotics.ConclusionPsA and PsA-dominant lung microbiota induce sustained IL-1β production in LTR AM. Pharmacological targeting of the inflammasome reduces PsA-macrophage-IL1β responses, underscoring their use in lung transplant recipients.

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Microbiosis in lung allotransplantation and xenotransplantation: State of the art and future perspective

Jiao

Tian

et al. 2022

Health Care Science

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The respiratory tract is known to harbor a microbial community including bacteria, viruses, and fungi. New techniques contribute enormously to the identification of unknown or culture-independent species and reveal the interaction of the community with the host immune system. The existing respiratory microbiome and substantial equilibrium of the transplanted microbiome from donor lung grafts provide an extreme bloom of dynamic changes in the microenvironment in lung transplantation (LT) recipients. Dysbiosis in grafts are not only related to the modified microbial components but also involve the kinetics of the host-graft "talk," which signifies the destination of graft allograft injury, acute rejection, infection, and chronic allograft dysfunction development in short-and long-term survival. Microbiome-derived factors may contribute to lung xenograft survival when using genetically multimodified pig-derived organs. Here, we review the most advanced knowledge of the dynamics and resilience of microbial communities in transplanted lungs with various pretransplant indications. Conceptual and analytical points of view have been illustrated along the time series, gaining insight into the microbiome and lung grafts. Future endeavors on precise tools, sophisticated models, and novel targeted regimens are needed to improve the long-term survival in these patients.

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Lung microbiota predict chronic rejection in healthy lung transplant recipients: a prospective cohort study

Cited by 59 publications

References 64 publications

The lung microbiome: progress and promise

The lung microbiome: progress and promise

Pseudomonas aeruginosa Elicits Sustained IL-1β Upregulation in Alveolar Macrophages from Lung Transplant Recipients

Microbiosis in lung allotransplantation and xenotransplantation: State of the art and future perspective

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