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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 <i>Pseudomonas aeruginosa</i>. 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 <i>Streptococcus</i>, <i>Veillonella</i>, and <i>Prevotella</i> 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. <i>P. aeruginosa</i> utilized these fermentation products for growth, as indicated by quantitative transcriptomics data. Transcription levels of <i>P. aeruginosa</i> 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 <i>P. aeruginosa,</i> 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 <i>P. aeruginosa</i> 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.