Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures

Madan, Juliette C.; Koestler, Devin C.; Stanton, Bruce A.; Davidson, Lisa; Moulton, Lisa A.; Housman, Molly L.; Moore, Jason H.; Guill, Margaret F.; Morrison, Hilary G.; Sogin, Mitchell L.; Hampton, Thomas H.; Karagas, Margaret R.; Palumbo, Paul; Foster, James A.; Hibberd, Patricia L.; O’Toole, George A.

doi:10.1128/mbio.00251-12

Cited by 315 publications

(326 citation statements)

References 54 publications

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“…Their increased residence time allows anaerobes to degrade respiratory mucins and condition the lung environment into a niche that is suitable for pathogens to thrive (Fig 8C). Several lines of clinical evidence exist in support of our proposed model: (i) pediatric patients often have asymptomatic primary colonization by oral anaerobes [45,46] prior to the establishment of chronic P. aeruginosa infections, (ii) routine administration of broad-spectrum antibiotics in the absence of respiratory infection symptoms is an effective therapy to delay the onset of colonization by P. aeruginosa and reduce the frequency of acute exacerbations [47,48], and (iii) the in vitro antibiotic susceptibility of lung pathogens does not always correlate with clinical outcomes [49]. In the latter instance, we propose that antibiotics do not solely target the pathogen, but rather disrupt the complex metabolic interactions that supply them with substrates for growth and stimulate their pathogenicity.…”

Section: Discussionmentioning

confidence: 93%

Evidence and role for bacterial mucin degradation in cystic fibrosis airway disease

Flynn

Niccum

Dunitz

et al. 2016

Preprint

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Chronic lung infections in cystic fibrosis (CF) patients are composed of complex microbial communities that incite persistent inflammation and airway damage. Despite the high density of bacteria that colonize the lower airways, nutrient sources that sustain bacterial growth in vivo, and how those nutrients are derived, are not well characterized. In this study, we examined the possibility that mucins serve as an important carbon reservoir for the CF lung microbiota. While Pseudomonas aeruginosa was unable to efficiently utilize mucins in isolation, we found that anaerobic, mucin-fermenting bacteria could stimulate the robust growth of CF pathogens when provided intact mucins as a sole carbon source. 16S rRNA sequencing and enrichment culturing of sputum also identified that mucin-degrading anaerobes are ubiquitous in the airways of CF patients. The collective fermentative metabolism of these mucin-degrading communities in vitro generated amino acids and short chain fatty acids (propionate and acetate) during growth on mucin, and the same metabolites were also found in abundance within expectorated sputum. The significance of these findings was supported by in vivo P. aeruginosa gene expression, which revealed a heightened expression of genes required for the catabolism of propionate. Given that propionate is exclusively derived from bacterial fermentation, these data provide evidence for an important role of mucin fermenting bacteria in the carbon flux of the lower airways. More specifically, microorganisms typically defined as commensals may contribute to airway disease by degrading mucins, in turn providing nutrients for pathogens otherwise unable to efficiently obtain carbon in the lung. Author SummaryPersistent CF lung infections are composed of hundreds of microbial taxa whose interactions contribute to respiratory failure. Despite their importance, the complex interplay between the lung microbiota and host environment is poorly understood. For example, the nutrients that sustain bacterial growth in vivo, and how those nutrients are derived, are not well characterized. We reveal that a subset of CF microbiota is capable of fermenting mucins for carbon and energy which, in-turn, can support the carbon demands of other PLOS Pathogens |

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Section: Discussionmentioning

confidence: 93%

Evidence and role for bacterial mucin degradation in cystic fibrosis airway disease

Flynn

Niccum

Dunitz

et al. 2016

Preprint

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“…Limited studies of children with CF indicate that bacterial community diversity (a measure of both the number and relative abundances of the species present) increases with age (14,26). In contrast, several cross-sectional and longitudinal studies of adults have shown that diversity decreases with age and declining lung function (14,18,22,23).…”

Section: The Lung Microbiome In Cfmentioning

confidence: 99%

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

et al. 2014

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Despite significant advances in treatment strategies targeting the underlying defect in cystic fibrosis (CF), airway infection remains an important cause of lung disease. In this two-part series, we review recent evidence related to the complexity of CF airway infection, explore data suggesting the relevance of individual microbial species, and discuss current and future treatment options. In Part I, the evidence with respect to the spectrum of bacteria present in the CF airway, known as the lung microbiome is discussed. Subsequently, the current approach to treat methicillin-resistant Staphylococcus aureus, gram-negative bacteria, as well as multiple coinfections is reviewed. Newer molecular techniques have demonstrated that the airway microbiome consists of a large number of microbes, and the balance between microbes, rather than the mere presence of a single species, may be relevant for disease pathophysiology. A better understanding of this complex environment could help define optimal treatment regimens that target pathogens without affecting others. Although relevance of these organisms is unclear, the pathologic consequences of methicillin-resistant S. aureus infection in patients with CF have been recently determined. New strategies for eradication and treatment of both acute and chronic infections are discussed. Pseudomonas aeruginosa plays a prominent role in CF lung disease, but many other nonfermenting gram-negative bacteria are also found in the CF airway. Many new inhaled antibiotics specifically targeting P. aeruginosa have become available with the hope that they will improve the quality of life for patients. Part I concludes with a discussion of how best to treat patients with multiple coinfections.

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“…The low bacterial diversity found in CF has been associated with higher inflammation, more advanced disease stage, and worse prognosis (83,84). Dietary manipulations could restore microbial diversity in the airways in CF (85). Furthermore, low microbiota diversity also precedes the development of an exacerbation (86).…”

Section: Lessons Learned From the Study Of Airway Microbiota In Lungmentioning

confidence: 99%

Lung Microbiome for Clinicians. New Discoveries about Bugs in Healthy and Diseased Lungs

2014

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Microbes are readily cultured from epithelial surfaces of the skin, mouth, and colon. In the last 10 years, culture-independent DNAbased techniques demonstrated that much more complex microbial communities reside on most epithelial surfaces; this includes the lower airways, where bacterial culture had failed to reliably demonstrate resident bacteria. Exposure to a diverse bacterial environment is important for adequate immunological development. The most common microbes found in the lower airways are also found in the upper airways. Increasing abundance of oral characteristic taxa is associated with increased inflammatory cells and exhaled nitric oxide, suggesting that the airway microbiome induces an immunological response in the lung. Furthermore, rhinovirus infection leads to outgrowth of Haemophilus in patients with chronic obstructive pulmonary disease, and human immunodeficiency virus-infected subjects have more Tropheryma whipplei in the lower airway, suggesting a bidirectional interaction in which the host immune defenses also influence the microbial niche. Quantitative and/or qualitative changes in the lung microbiome may be relevant for disease progression and exacerbations in a number of pulmonary diseases. Future investigations with longitudinal follow-up to understand the dynamics of the lung microbiome may lead to the development of new therapeutic targets.

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Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures

Cited by 315 publications

References 54 publications

Evidence and role for bacterial mucin degradation in cystic fibrosis airway disease

Evidence and role for bacterial mucin degradation in cystic fibrosis airway disease

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

Lung Microbiome for Clinicians. New Discoveries about Bugs in Healthy and Diseased Lungs

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