Nontuberculous mycobacteria remodel lung microbiota in cystic fibrosis-associated respiratory infections

Abstract

Nontuberculous mycobacterial (NTM) infections in people with cystic fibrosis (pwCF) can have detrimental effects on prognosis and pose significant challenges to treatment. However, there are still questions regarding the contribution and influence of NTMs on the respiratory microbiome and the mechanisms by which NTMs cause infections. Here, we investigate the impact of NTM infection on microbiome composition and lung function (percent predicted forced expiratory volume in 1 second). Primary comparisons were between culture-positive cohorts for Mycobacterium avium complex and Mycobacterium abscessus complex and those who were culture-negative for NTMs and attending outpatient clinics. Additionally, the consequence of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy status and positive NTM culture was assessed in terms of microbiome change. Our data suggest that the presence of NTM significantly alters the diversity and the composition of the lung microbiota in pwCF, including those receiving CFTR modulator therapies. Importantly, significant associations were detected between NTM presence and changes in abundance of Pseudomonas aeruginosa and Burkholderia cepacia complex members, inferring modulatory effects of NTMs on respiratory microbiomes. This study contributes to the understanding of NTM infection and these organisms' interaction with the respiratory microbiome and CFTR modulator therapy, highlighting the need for further research in this area.IMPORTANCEThe influence of NTM infection in pwCF is still debated, and the extent of their contribution to mortality and morbidity is still questioned. Findings in this study highlight a link between the presence of NTMs and significant alterations in the composition of the respiratory microbiome, particularly with respect to some of the canonical CF pathogens, especially Pseudomonas aeruginosa and members of the Burkholderia cepacia complex. This indicates that complex relationships are occurring within the microbiome. This study further contributes to the understanding of NTM infection in pwCF, with and without CFTR modulator therapy, and highlights the need for further research in this area. The knowledge gained from this study has implications for treatment strategies and management, ultimately aiming to improve and prolong the lives of pwCF.

Keywords: Burkholderia cepacia complex; CFTR modulator therapy; Nontuberculous mycobacterium; Pseudomonas aeruginosa; cystic fibrosis; microbiome; respiratory infection.

Fig 1

Differences in microbiome diversity during NTM infection. Differences in diversity (Fisher’s alpha) were shown to be significant in NTM culture-positive and NTM culture-negative samples (A); however, there was little impact beyond this when the different NTM groups were considered (B). The asterisk indicates a statistically significant Tukey’s honestly significant difference result, where * and ** represent P values of <0.05 and 0.01, respectively.

Fig 2

The effect of modulators on microbiome diversity. Significant changes in microbiome diversity (Fisher’s alpha) were observed for pwCF during modulator treatment, where diversity levels increase with modulators (A), with an accompanying decrease in how dominated (Berger-Parker) the communities were (B). The asterisk indicates a statistically significant Tukey’s honestly significant difference result, where ** represents P values of <0.01.

Fig 3

Interactions of NTM culture status (positive/negative) and modulator therapy (modulator/none) on microbiome diversity. Samples from pwCF who were NTM culture negative and on CFTR modulator therapy had significantly more diverse microbiomes than any of the other combinations of NTM culture status and CFTR modulator therapy. The asterisk indicates a statistically significant Tukey’s honestly significant difference result, where * and *** represent P values of <0.05 and 0.001, respectively.

Fig 4

Graphical representation of community dissimilarity in ordinal space using non-metric multidimensional scaling. Dissimilarities between the communities were measured using the Bray-Curtis dissimilarity index and plotted in ordinal space where points closest together are highly similar, whereas points far apart are highly dissimilar. Significant clusters were observed between samples that were NTM culture positive (dotted line, red circular points) and those that were negative (continuous line, square points), with subclusters (gray lines) indicating the NTM groups; MABSC (orange), MAC (green), and other (blue). Ellipses represent the standard deviation around the mean centroid for the cluster. Gray lines converge at the centroid for that cluster. NMDS, non-metric multidimensional scaling.

Fig 5

Microbiome composition is significantly influenced by modulator therapy. Plotted in ordinal space using non-metric multidimensional scaling, there are significant differences between microbiomes with (filled points, dotted line) and without (open points, continuous line) CFTR modulator therapy. NTM groups are denoted as follows: MABSC (orange), MAC (green), and other (blue). Ellipses represent the standard deviation around the mean centroid for the cluster.