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. 2019 Nov;16(11):1383-1391.
doi: 10.1513/AnnalsATS.201904-299OC.

Upper Respiratory Dysbiosis with a Facultative-dominated Ecotype in Advanced Lung Disease and Dynamic Change after Lung Transplant

Aurea Simon-Soro  1 , Michael B Sohn  2 , John E McGinniss  1 , Ize Imai  1 , Melanie C Brown  1 , Vincent R Knecht  1 , Aubrey Bailey  3 , Erik L Clarke  3 , Edward Cantu  4 , Hongzhe Li  2 , Kyle Bittinger  5   6 , Joshua M Diamond  1 , Jason D Christie  1 , Frederic D Bushman  3 , Ronald G Collman  1
Affiliations

Upper Respiratory Dysbiosis with a Facultative-dominated Ecotype in Advanced Lung Disease and Dynamic Change after Lung Transplant

Aurea Simon-Soro et al. Ann Am Thorac Soc. 2019 Nov.

Abstract

Rationale: The oropharyngeal microbiome is a primary source of lung microbiota, contributes to lower respiratory infection, and is also a driver of oral health.Objectives: We sought to understand oropharyngeal microbial communities in advanced lung disease, community dynamics after lung transplantation, and ecological features of dysbiosis.Methods: Oropharyngeal wash samples were obtained from individuals with end-stage disease awaiting transplantation (n = 22) and longitudinally from individuals at 6 weeks, 3 months, and 6 months after transplantation (n = 33), along with healthy control subjects (n = 14). Bacterial 16S and fungal internal transcribed spacer rRNA regions were deep-sequenced, and bacterial community respiratory patterns were imputed from taxonomic composition.Results: Healthy subjects' oropharyngeal microbiomes showed a gradient of community types reflecting relative enrichment of strictly anaerobic, aerobic, or facultative anaerobic bacteria. Patients with end-stage lung disease showed severe dysbiosis by both taxonomic composition and respiration phenotypes, with reduced richness and diversity, increased facultative and decreased aerobic bacteria, and absence of communities characterized by obligate aerobes. In patients at 6 weeks and 3 months post-transplant, richness and diversity were intermediate between healthy and pretransplant subjects, with near-normal distribution of community types. However, by 6 months post-transplant, oropharyngeal wash resembled the low-diversity facultative-dominated profile of pretransplant subjects. Community ecotype correlated with Candida abundance.Conclusions: End-stage lung disease is associated with marked upper respiratory tract dysbiosis involving both community structure and respiratory metabolism profiles of constituent bacteria. Dynamic changes occur after lung transplantation, with partial normalization early but later appearance of severe dysbiosis similar to pretransplant patients. Aberrant oropharyngeal communities may predispose to abnormal lung microbiota and infection risk both in advanced lung disease and after transplantation.

Keywords: bacteria; dysbiosis; fungi; lung transplantation; microbiome.

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Figures

Figure 1.
Figure 1.
Oropharyngeal microbiome richness and diversity in health and lung disease. (A) Richness is represented by Chao1 index (upper panel) and diversity by Shannon index (lower panel). Samples are grouped by subject category and, for post-transplant, by time of sampling. Dots in each category show the distribution within group. Asterisks indicate statistical significance (Wilcoxon rank sum test; ** P < 0.01 and **** P < 0.001). (B) Principal coordinate analysis (PCoA) of weighted UniFrac distances among oropharyngeal wash samples. Colors correspond to disease status: Healthy (green), pretransplant (PreTx) (red), and post-transplant (PostTx) (purple). Vectors show the taxa present at >5% abundance that are responsible for ordination on the PCoA plot. UniFrac distances were significantly different between healthy and disease groups: Healthy versus PreTx (P = 0.002) and PostTx (P < 0.0001); there were no significant differences between PreTx and PostTx (permutational multivariate analysis of variance). PC1 = principal coordinate axis 1; PC2 = principal coordinate axis 2.
Figure 2.
Figure 2.
Disease groups differ in relative dominant oral bacteria. (A) Principal coordinate analysis on the basis of weighted UniFrac distances colored to show relative abundances of Neisseria, Prevotella, and Streptococcus. The shapes correspond to disease groups. (B) Box plots showing relative abundances of the three dominant genera. There were significant differences for Neisseria, but not for Prevotella and Streptococcus, between time points (P = 0.048, P = 0.059, and P = 0.08, respectively; Kruskal-Wallis). Individual differences between sample groups are indicated by *P < 0.05 (Dunn’s multiple comparison test). PC1 = principal coordinate axis 1; PC2 = principal coordinate axis 2; PostTx = post-transplant; PreTx = pretransplant.
Figure 3.
Figure 3.
Bacterial respiration phenotype identifies differences between groups. (A) Principal coordinate analysis on the basis of weighted UniFrac distances colored based on relative abundances of strictly aerobic, obligate anaerobic, and facultative anaerobic bacteria respiration phenotypes. The shapes correspond to disease groups. (B) Box plots show relative abundances of bacterial respiration phenotypes by disease groups. There were significant differences for facultative and anaerobic bacteria between sample groups and a trend for aerobic bacteria (P = 0.001, P = 0.016, and P = 0.057, respectively; Kruskal-Wallis). Individual differences between sample groups are indicated by *P < 0.05 or ***P < 0.001 (Dunn’s multiple comparison test). PC1 = principal coordinate axis 1; PC2 = principal coordinate axis 2; PostTx = post-transplant; PreTx = pretransplant.
Figure 4.
Figure 4.
Oral pH is correlated with bacterial respiration phenotype. Relative abundances of bacterial taxa belonging to three respiration phenotypes (strictly aerobe, obligate anaerobe, and facultative anaerobe bacteria) are shown relative to oral pH. Aerobic bacteria and pH are positively correlated (first panel), anaerobe abundance is not significantly correlated with oral pH (middle panel), and facultative abundance and pH are inversely correlated (third panel). Lines indicate the tendency, and the gray area corresponds to standard error. P values were obtained from a linear model (Wilcoxon rank sum test). PostTx = post-transplant; PreTx = pretransplant.
Figure 5.
Figure 5.
Oropharyngeal fungi and relation to bacterial communities. Fungal communities were analyzed using internal transcribed spacer (ITS) marker gene sequencing. (A) Box plot shows relative abundance of Candida albicans, Candida dubliniensis, and Aspergillus among sample sets (H = healthy; Pre = pretransplant; 6w = 6 weeks post-transplant; 3m = 3 months post-transplant; 6m = 6 month post-transplant). (B) Relationship between Candida albicans abundance and abundance of respiratory bacterial phenotypes. Each point corresponds to a sample, and shapes represent time points. Gradient color indicates Candida albicans abundance per sample. Location of the point into the ternary plot depicts the relative abundance of facultative, anaerobic, and aerobe bacteria in each sample. Samples with relative abundance of facultative near to 100% (right corner of the triangle) have higher Candida albicans population (P = 0.0049, analysis of variance). Samples dominated by aerobic bacterial populations (left area of the plot) have the lowest fungi abundances (P = 0.0038, ANOVA).
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