Abstract
Ecological networking and in vitro studies predict that anaerobic, mucus-degrading bacteria are keystone species in cystic fibrosis (CF) microbiomes. The metabolic byproducts from these bacteria facilitate the colonization and growth of CF pathogens like Pseudomonas aeruginosa. Here, a multi-omics study informed the control of putative anaerobic keystone species during a transition in antibiotic therapy of a CF patient. A quantitative metagenomics approach combining sequence data with epifluorescence microscopy showed that during periods of rapid lung function loss, the patient’s lung microbiome was dominated by the anaerobic, mucus-degrading bacteria belonging to Streptococcus, Veillonella, and Prevotella genera. Untargeted metabolomics and community cultures identified high rates of fermentation in these sputa, with the accumulation of lactic acid, citric acid, and acetic acid. P. aeruginosa utilized these fermentation products for growth, as indicated by quantitative transcriptomics data. Transcription levels of P. aeruginosa genes for the utilization of fermentation products were proportional to the abundance of anaerobic bacteria. Clindamycin therapy targeting Gram-positive anaerobes rapidly suppressed anaerobic bacteria and the accumulation of fermentation products. Clindamycin also lowered the abundance and transcription of P. aeruginosa, even though this patient’s strain was resistant to this antibiotic. The treatment stabilized the patient’s lung function and improved respiratory health for two months, lengthening by a factor of four the between-hospitalization time for this patient. Killing anaerobes indirectly limited the growth of P. aeruginosa by disrupting the cross-feeding of fermentation products. This case study supports the hypothesis that facultative anaerobes operated as keystone species in this CF microbiome. Personalized multi-omics may become a viable approach for routine clinical diagnostics in the future, providing critical information to inform treatment decisions.
Highlights
Keystone species are members of a community with disproportionately high importance to community stability despite being less abundant than other community members [1]
At Day 0 (First day of cystic fibrosis rapid response (CFRR)), the patient displayed an acute decline in respiratory health characterized by severe cough, dyspnea, and a drop in his percent predicted Forced Expiratory Volume in 1 s to 44%, 9% below the median ppFEV1 (Figure S1)
The gas chromatography–mass spectrometry (GC-MS) metabolomic profiles showed that during the period the patient was off antibiotics, there was an increase in the abundance of fermentation products (Figure 2c)
Summary
Keystone species are members of a community with disproportionately high importance to community stability despite being less abundant than other community members [1]. A combination of multiomics approaches may be a viable (yet still costly) solution for guiding the treatment of polymicrobial diseases characterized by highly individualized microbial communities in cases where standard antibiotic treatment does not improve patient’s health [12,13,14]. One of these approaches is the cystic fibrosis rapid response (CFRR), where metagenomes, metatranscriptomes, metabolomes, and viromes are generated within 48 h from patients undergoing rapid loss in lung function [12]. To date, none of the CFRR studies has timely informed a successful choice of treatment
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