State of the Art Reviews
The lung microbiome in lung transplantation

https://doi.org/10.1016/j.healun.2021.04.014Get rights and content

Culture-independent study of the lower respiratory tract after lung transplantation has enabled an understanding of the microbiome – that is, the collection of bacteria, fungi, and viruses, and their respective gene complement – in this niche. The lung has unique features as a microbial environment, with balanced entry from the upper respiratory tract, clearance, and local replication. There are many pressures impacting the microbiome after transplantation, including donor allograft factors, recipient host factors such as underlying disease and ongoing exposure to the microbe-rich upper respiratory tract, and transplantation-related immunosuppression, antimicrobials, and postsurgical changes. To date, we understand that the lung microbiome after transplant is dysbiotic; that is, it has higher biomass and altered composition compared to a healthy lung. Emerging data suggest that specific microbiome features may be linked to host responses, both immune and non-immune, and clinical outcomes such as chronic lung allograft dysfunction (CLAD), but many questions remain. The goal of this review is to put into context our burgeoning understanding of the lung microbiome in the postlung transplant patient, the interactions between microbiome and host, the role the microbiome may play in post-transplant complications, and critical outstanding research questions.

Section snippets

Culture-Independent Sequencing

Microbial culture has been indispensable for understanding microbial pathogenesis but captures only a subset of the microbial landscape. Advances in sequencing technology (“next-generation” or “deep sequencing”) and computational methods have enabled a comprehensive, unbiased culture-independent approach.16 Sequence-based approaches quantify the relative abundances of specific microbes in a sample and readily identify both potential pathogens and the vast commensal landscape. The most

Composition and source of the lung bacterial microbiome in health

Traditionally, the lung below the glottis was thought to be sterile, but recent work has dispelled this dogma even in health.27,28 This is perhaps not surprising, as the lung is contiguous with the microbe-rich upper respiratory tract (URT). However, the microbial biomass in the lung is orders of magnitude lower than the oropharynx. Therefore, stringent approaches are required to distinguish authentic signal from artifact derived from both oropharyngeal carryover during bronchoscopy and the

Establishment of the Post-Transplantation Lung Microbiome

Studies of the post-transplantation lung microbiome8, 9, 10, 11, 12, 13, 14, 15,53,54 have uniformly found higher microbial biomass and dysbiosis55 characterized by lower alpha-diversity (a measure incorporating both the number of species and their evenness) and altered composition compared to healthy subjects. Dysbiosis likely results from donor-dependent, recipient-specific, and transplantation-related factors.

Microbiome dysbiosis post-transplantation

Multiple studies have found elevated bacterial burden compared to healthy controls, ranging from 15-fold to 1000-fold higher.8,9,15,53,54 Despite substantial methodological differences, studies indicate that a subset of post-transplant patients maintains a lung microbiome composition predominantly of oropharyngeal-type flora while most have a marked decrease in alpha-diversity accompanied an outgrowth of specific taxa.8,14,15,53Quantitative comparison of lung versus URT communities shows

Eukaryotic viruses

Herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV), are important pathogens after lung transplantation, and are targets of prophylactic antiviral regimens.74 Community-acquired respiratory viruses (CARV's), such as influenza, enteroviruses, and rhinoviruses, lead to acute morbidity and increased risk of later CLAD.3,88,89 These viruses are typically identified by targeted PCR methods. While there is a burgeoning literature probing the human virome through

Mechanisms of Lung Microbiome-Host Interactions and Injury

Both microbial pathogen-associated molecular patterns (PAMPs) sensed by host pathogen-recognition receptors (PRRs) and microbial metabolites mediate microbiome-host interactions,37 and it is essential to understand these interactions after transplant (Figure 2).

Conclusions and future directions

The post-transplantation lung microbiome is dysbiotic, with markedly higher bacterial, fungal and viral abundance and altered composition compared to health. Emerging data suggest that the composition of bacterial communities is associated with adverse outcomes such as CLAD, although inconsistencies between reports limit conclusions, and the mycobiome and virome remain under-studied. Critical issues in understanding the microbiome in relation to outcomes include the need to account for

Disclosure statement

The authors have no conflicts of interest to declare.

Acknowledgments

This work was supported by NIH grants R01-HL113252 and R61/33-HL137063 to RGC, and JEM was supported by KL2-TR001879. Figures created with the assistance of BioRender.com.

References (109)

  • B Baumann et al.

    Postoperative swallowing assessment after lung transplantation

    Ann Thorac Surg

    (2017)
  • AA Abbas et al.

    The perioperative lung transplant virome: torque teno viruses are elevated in donor lungs and show divergent dynamics in primary graft dysfunction

    Am J Transpl

    (2017)
  • AA Abbas et al.

    Bidirectional transfer of Anelloviridae lineages between graft and host during lung transplantation

    Am J Transpl

    (2019)
  • I De Vlaminck et al.

    XTemporal response of the human virome to immunosuppression and antiviral therapy

    Cell

    (2013)
  • VN Ahya et al.

    Lung Transplantation

    Med Clin North Am

    (2019)
  • AB Mitchell et al.

    Transplanting the pulmonary virome: dynamics of transient populations

    J Hear Lung Transplant

    (2018)
  • S Aslam et al.

    Early clinical experience of bacteriophage therapy in 3 lung transplant recipients

    Am J Transplant

    (2019)
  • AA Abbas et al.

    Redondoviridae, a family of small, circular DNA viruses of the human oro-respiratory tract associated with periodontitis and critical illness

    Cell Host Microbe

    (2019)
  • SS Weigt et al.

    Colonization with small conidia Aspergillus species is associated with bronchiolitis obliterans syndrome: a two-center validation study

    Am J Transplant

    (2013)
  • PA Corris et al.

    A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation

    Thorax

    (2015)
  • JR Marchesi et al.

    The vocabulary of microbiome research: a proposal

    Microbiome

    (2015)
  • G Berg et al.

    Microbiome definition re-visited: old concepts and new challenges

    Microbiome

    (2020)
  • KH Wilson et al.

    Human colonic biota studied by ribosomal DNA sequence analysis

    Appl Environ Microbiol

    (1996)
  • ES Charlson et al.

    Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant

    Am J Respir Crit Care Med

    (2012)
  • RP Dickson et al.

    Changes in the lung microbiome following lung transplantation include the emergence of two distinct pseudomonas species with distinct clinical associations. Davis IC, ed

    PLoS One

    (2014)
  • DL Willner et al.

    Reestablishment of recipient-associated microbiota in the lung allograft is linked to reduced risk of Bronchiolitis Obliterans Syndrome

    Am J Respir Crit Care Med

    (2013)
  • K Borewicz et al.

    Longitudinal analysis of the lung microbiome in lung transplantation

    FEMS Microbiol Lett

    (2013)
  • E Bernasconi et al.

    Airway microbiota determines innate cell inflammatory or tissue remodeling profiles in lung transplantation

    Am J Respir Crit Care Med

    (2016)
  • HMP Consortium et al.

    Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome

    Nature

    (2012)
  • GJ Olsen et al.

    Ribosomal RNA: a key to phylogeny

    FASEB J

    (1993)
  • DJ Lane et al.

    Rapid determination of 16S ribosomal RNA sequences for phylogenetic analyses

    Proc Natl Acad Sci

    (1985)
  • NR Pace

    A molecular view of microbial diversity and the biosphere

    Science (80-)

    (1997)
  • CR Woese

    Interpreting the universal phylogenetic tree

    Proc Natl Acad Sci U S A

    (2000)
  • XC Morgan et al.

    Chapter 12: human microbiome analysis

    PLoS Comput Biol

    (2012)
  • D Kim et al.

    Optimizing methods and dodging pitfalls in microbiome research

    Microbiome

    (2017)
  • EL Clarke et al.

    Microbial lineages in sarcoidosis a metagenomic analysis tailored for low-microbial content samples

    Am J Respir Crit Care Med

    (2018)
  • CA Marotz et al.

    Improving saliva shotgun metagenomics by chemical host DNA depletion

    Microbiome

    (2018)
  • W Gu et al.

    Depletion of Abundant Sequences by Hybridization (DASH): using Cas9 to remove unwanted high-abundance species in sequencing libraries and molecular counting applications

    Genome Biol

    (2016)
  • M Mac Aogáin et al.

    Metagenomics reveals a core macrolide resistome related to microbiota in chronic respiratory disease

    Am J Respir Crit Care Med

    (2020)
  • RP Dickson et al.

    Bacterial topography of the healthy human lower respiratory tract

    MBio

    (2017)
  • ES Charlson et al.

    Topographical continuity of bacterial populations in the healthy human respiratory tract

    Am J Respir Crit Care Med

    (2011)
  • SJ Salter et al.

    Reagent and laboratory contamination can critically impact sequence-based microbiome analyses

    BMC Biol

    (2014)
  • RP Dickson et al.

    Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography

    Ann Am Thorac Soc

    (2015)
  • ES Charlson et al.

    Assessing bacterial populations in the lung by replicate analysis of samples from the upper and lower respiratory tracts. Highlander SK, ed

    PLoS One

    (2012)
  • L Glendinning et al.

    Comparing microbiotas in the upper aerodigestive and lower respiratory tracts of lambs

    Microbiome

    (2017)
  • CM Bassis et al.

    Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. Ravel J, ed

    MBio

    (2015)
  • NDJJ Ubags et al.

    Mechanistic insight into the function of the microbiome in lung diseases

    Eur Respir J

    (2017)
  • CA Thaiss et al.

    The microbiome and innate immunity

    Nature

    (2016)
  • SK Cribbs et al.

    Pathogenesis of HIV-related lung disease: immunity, infection, and inflammation

    Physiol Rev

    (2020)
  • AP Hakansson et al.

    Bacterial-host interactions: physiology and pathophysiology of respiratory infection

    Physiol Rev

    (2018)

    • Cited by (18)

    • High throughput sequencing technology reveals alteration of lower respiratory tract microbiome in severe aspiration pneumonia and its association with inflammation

      2023, Infection, Genetics and Evolution

    • My time to say goodbye to JHLT

      2023, Journal of Heart and Lung Transplantation

    • General anesthesia alters the diversity and composition of the lung microbiota in rat

      2023, Biomedicine and Pharmacotherapy

    • Alterations of lung microbiota in lung transplant recipients with pneumocystis jirovecii pneumonia

      2024, Respiratory Research

    • Bacterial infections in solid organ transplant recipients

      2024, Current Opinion in Organ Transplantation

    • Unique Changes in the Lung Microbiome following the Development of Chronic Lung Allograft Dysfunction

      2024, Microorganisms
    View all citing articles on Scopus
    View full text
    © 2021 International Society for Heart and Lung Transplantation. All rights reserved.