scholarly journals Altered Stool Microbiota of Infants with Cystic Fibrosis Shows Reduction in Genera Associated with Immune Programming

2018 ◽  
Author(s):  
Katherine M. Antosca ◽  
Diana A. Chernikova ◽  
Kathryn L. Ruoff ◽  
Kewei Li ◽  
Margaret F. Guill ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
General Population ◽  
Microbial Communities ◽  
Systemic Inflammation ◽  
Young Patients ◽  
Airway Disease ◽  
In Vitro Studies ◽  
Gastrointestinal Microbiota ◽  
Stool Microbiota

AbstractPrevious work from our group indicated a connection between the gastrointestinal microbiota of infants and children with cystic fibrosis (CF) and airway disease in this population. Here we examine the stool microbiota of infants with CF and from the general population who did not have CF over the first year of life. CF children had reduced gastrointestinal Bacteroides and Bifidobacterium beginning in infancy, even after adjusting for antibiotic treatment. We also identify several metabolic pathways that are enriched or under represented among the microbial communities in the stool of these young patients with CF as compared to children without CF. In vitro studies demonstrated that exposure of the apical face of a polarized Intestinal cell line to Bacteroides thetaiotaomicron significantly reduced production of IL-8 secreted from both the apical and basolateral face of these cells, suggesting a mechanism whereby changes in the intestinal microflora could impact systemic inflammation. This work further establishes a link between gastrointestinal microbiota, systemic inflammation and airway disease, and presents the opportunity for therapeutic probiotic interventions.Significance statementThere is a surprising link between gastrointestinal microbial communities and airway disease progression in CF. Here we show that infants with CF ≤1 year of age show a distinct stool microbiota compared with children of a comparable age from a general population cohort. We detect associations between stool microbes and airway exacerbation events in the cohort of infants with CF, and in vitro studies provide a possible mechanism for this observation. These data argue that current therapeutics do not establish a healthy-like gastrointestinal microbiota in young patients with CF, and we suggest that interventions that direct the gastrointestinal microbiota closer to a healthy state may provide benefit to these patients.

scholarly journals Altered Stool Microbiota of Infants with Cystic Fibrosis Shows a Reduction in Genera Associated with Immune Programming from Birth

2019 ◽  
Vol 201 (16) ◽  
Author(s):  
Katherine M. Antosca ◽  
Diana A. Chernikova ◽  
Courtney E. Price ◽  
Kathryn L. Ruoff ◽  
Kewei Li ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Alpha Diversity ◽  
Airway Disease ◽  
Intestinal Cell ◽  
First Year ◽  
Gastrointestinal Microbiota ◽  
Immune Programming ◽  
First Year Of Life ◽  
Stool Microbiota

ABSTRACT Previous work from our group indicated an association between the gastrointestinal microbiota of infants with cystic fibrosis (CF) and airway disease in this population. Here we report that stool microbiota of infants with CF demonstrates an altered but largely unchanging within-individual bacterial diversity (alpha diversity) over the first year of life, in contrast to the infants without CF (control cohort), which showed the expected increase in alpha diversity over the first year. The beta diversity, or between-sample diversity, of these two cohorts was significantly different over the first year of life and was statistically significantly associated with airway exacerbations, confirming our earlier findings. Compared with control infants, infants with CF had reduced levels of Bacteroides, a bacterial genus associated with immune modulation, as early as 6 weeks of life, and this significant reduction of Bacteroides spp. in the cohort with CF persisted over the entire first year of life. Only two other genera were significantly different across the first year of life: Roseburia was significantly reduced and Veillonella was significantly increased. Other genera showed differences between the two cohorts but only at selected time points. In vitro studies demonstrated that exposure of the apical face of polarized intestinal cell lines to Bacteroides species supernatants significantly reduced production of interleukin 8 (IL-8), suggesting a mechanism whereby changes in the intestinal microbiota could impact inflammation in CF. This work further establishes an association between gastrointestinal microbiota, inflammation, and airway disease in infants with CF and presents a potential opportunity for therapeutic interventions beginning in early life. IMPORTANCE There is growing evidence for a link between gastrointestinal bacterial communities and airway disease progression in CF. We demonstrate that infants with CF ≤1 year of age show a distinct stool microbiota versus that of control infants of a comparable age. We detected associations between the gut microbiome and airway exacerbation events in the cohort of infants with CF, and in vitro studies provided one possible mechanism for this observation. These data clarify that current therapeutics do not establish in infants with CF a gastrointestinal microbiota like that in healthy infants, and we suggest that interventions that direct the gastrointestinal microbiota closer to a healthy state may provide systemic benefits to these patients during a critical window of immune programming that might have implications for lifelong health.

scholarly journals Cystic Fibrosis Sputum Impairs the Ability of Neutrophils to Kill Staphylococcus aureus

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 703
Author(s):  
Kayla Fantone ◽  
Samantha L. Tucker ◽  
Arthur Miller ◽  
Ruchi Yadav ◽  
Eryn E. Bernardy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Healthy Volunteers ◽  
Airway Disease ◽  
Neutrophil Extracellular Trap ◽  
Lung Function Decline ◽  
Bacterial Killing ◽  
Cystic Fibrosis Sputum ◽  
Microbial Infections

Cystic fibrosis (CF) airway disease is characterized by chronic microbial infections and infiltration of inflammatory polymorphonuclear (PMN) granulocytes. Staphylococcus aureus (S. aureus) is a major lung pathogen in CF that persists despite the presence of PMNs and has been associated with CF lung function decline. While PMNs represent the main mechanism of the immune system to kill S. aureus, it remains largely unknown why PMNs fail to eliminate S. aureus in CF. The goal of this study was to observe how the CF airway environment affects S. aureus killing by PMNs. PMNs were isolated from the blood of healthy volunteers and CF patients. Clinical isolates of S. aureus were obtained from the airways of CF patients. The results show that PMNs from healthy volunteers were able to kill all CF isolates and laboratory strains of S. aureus tested in vitro. The extent of killing varied among strains. When PMNs were pretreated with supernatants of CF sputum, S. aureus killing was significantly inhibited suggesting that the CF airway environment compromises PMN antibacterial functions. CF blood PMNs were capable of killing S. aureus. Although bacterial killing was inhibited with CF sputum, PMN binding and phagocytosis of S. aureus was not diminished. The S. aureus-induced respiratory burst and neutrophil extracellular trap release from PMNs also remained uninhibited by CF sputum. In summary, our data demonstrate that the CF airway environment limits killing of S. aureus by PMNs and provides a new in vitro experimental model to study this phenomenon and its mechanism.

scholarly journals Public good exploitation in natural bacterioplankton communities

2021 ◽  
Vol 7 (31) ◽  
pp. eabi4717
Author(s):  
Shaul Pollak ◽  
Matti Gralka ◽  
Yuya Sato ◽  
Julia Schwartzman ◽  
Lu Lu ◽  
...  
Keyword(s):  
Public Goods ◽  
Public Good ◽  
Microbial Communities ◽  
Genomic Data ◽  
In Vitro Studies ◽  
Genomic Approach ◽  
Ecological Roles ◽  
Extracellular Molecules ◽  
Bacterioplankton Communities

Bacteria often interact with their environment through extracellular molecules that increase access to limiting resources. These secretions can act as public goods, creating incentives for exploiters to invade and “steal” public goods away from producers. This phenomenon has been studied extensively in vitro, but little is known about the occurrence and impact of public good exploiters in the environment. Here, we develop a genomic approach to systematically identify bacteria that can exploit public goods produced during the degradation of polysaccharides. Focusing on chitin, a highly abundant marine biopolymer, we show that public good exploiters are active in natural chitin degrading microbial communities, invading early during colonization, and potentially hindering degradation. In contrast to in vitro studies, we find that exploiters and degraders belong to distant lineages, facilitating their coexistence. Our approach opens novel avenues to use the wealth of genomic data available to infer ecological roles and interactions among microbes.

scholarly journals Polymicrobial Interactions in the Cystic Fibrosis Airway Microbiome Impact the Antimicrobial Susceptibility of Pseudomonas aeruginosa

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 827
Author(s):  
Emma Reece ◽  
Pedro H. de Almeida Bettio ◽  
Julie Renwick
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Airway Disease ◽  
Chronic Infections ◽  
Sensitivity Testing ◽  
Antimicrobial Sensitivity ◽  
Cystic Fibrosis Airway ◽  
Airway Microbiome ◽  
Diverse Community

Pseudomonas aeruginosa is one of the most dominant pathogens in cystic fibrosis (CF) airway disease and contributes to significant inflammation, airway damage, and poorer disease outcomes. The CF airway is now known to be host to a complex community of microorganisms, and polymicrobial interactions have been shown to play an important role in shaping P. aeruginosa pathogenicity and resistance. P. aeruginosa can cause chronic infections that once established are almost impossible to eradicate with antibiotics. CF patients that develop chronic P. aeruginosa infection have poorer lung function, higher morbidity, and a reduced life expectancy. P. aeruginosa adapts to the CF airway and quickly develops resistance to several antibiotics. A perplexing phenomenon is the disparity between in vitro antimicrobial sensitivity testing and clinical response. Considering the CF airway is host to a diverse community of microorganisms or ‘microbiome’ and that these microorganisms are known to interact, the antimicrobial resistance and progression of P. aeruginosa infection is likely influenced by these microbial relationships. This review combines the literature to date on interactions between P. aeruginosa and other airway microorganisms and the influence of these interactions on P. aeruginosa tolerance to antimicrobials.

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

2016 ◽  
Author(s):  
Jeffrey M. Flynn ◽  
David Niccum ◽  
Jordan M. Dunitz ◽  
Ryan C. Hunter
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Airway Disease ◽  
Short Chain Fatty Acids ◽  
Oral Bacteria ◽  
Nutrient Sources ◽  
Bacterial Fermentation ◽  
Persistent Inflammation

Chronic respiratory infections are composed of complex microbial communities that incite persistent inflammation and airway damage. Despite the high density of bacteria that colonize the airways, nutrient sources that sustain bacterial growth in vivo are unknown. Here we examine the role of respiratory mucins in the ecological dynamics of the cystic fibrosis lung microbiota. While P. aeruginosa was unable to efficiently utilize mucins, saliva-derived anaerobes stimulated the growth of opportunistic pathogens when provided mucins as the sole carbon source. The fermentative metabolisms of these oral anaerobes generated amino acids and short chain fatty acids (propionate and acetate) during mucin enrichment in vitro, which were also found within expectorated sputum from CF patients. The significance of these findings was supported by in vivo P. aeruginosa gene expression, which revealed a heightened response to propionate. Given that propionate is exclusively derived from bacterial fermentation, these data support a central role for mucin fermentation in the carbon flux of the lower airways. More specifically, commensal oral bacteria may contribute to airway disease by degrading mucins, in turn providing nutrients for pathogens otherwise unable to obtain carbon in the lung.

Effects of sodium concentration on human neutrophil bactericidal functions

1995 ◽  
Vol 269 (3) ◽  
pp. L388-L393 ◽  
Author(s):  
J. P. Mizgerd ◽  
L. Kobzik ◽  
A. E. Warner ◽  
J. D. Brain
Keyword(s):  
Cystic Fibrosis ◽  
Blood Cells ◽  
White Blood Cells ◽  
Airway Disease ◽  
Sodium Concentration ◽  
Coated Particles ◽  
Airway Infections ◽  
Pmn Functions ◽  
Peripheral White Blood Cells

What are the ionic requirements for neutrophil (PMN) function and how might altered electrolyte concentrations contribute to airway disease? The in vitro killing of Pseudomonas aeruginosa by human peripheral white blood cells (WBCs) was progressively compromised Na+ concentration was lowered from 124 to 62 mM; at 62 mM Na+, bactericidal activity was 28.8 +/- 7.4% (SE) of normal. In contrast, Cl- concentration affected killing only when lowered to 8 mM. We examined phagocytosis and oxidative metabolism in response to P. aeruginosa or particles opsonized with either immunoglobulin G (IgG) or complement (C'). Phagocytosis of P. aeruginosa and of IgG-coated particles was Na(+)-dependent (31.2 +/- 3.1 and 58.6 +/- 14.2% of normal, respectively, at 62 mM Na+). However, no effect on uptake of C'-coated particles was observed, and the respiratory burst at 70 mM Na+ was normal regardless of stimuli. Thus low Na+ concentration compromises select PMN functions. These results may help explain why airways of cystic fibrosis (CF) patients become colonized with bacteria such as P. aeruginosa. Perhaps the low concentration of Na+ reported for some CF respiratory secretions inhibits bactericidal functions of PMNs, predisposing these patients to airway infections.

Neutrophil elastase and elastase-rich cystic fibrosis sputum degranulate human eosinophils in vitro

1999 ◽  
Vol 276 (1) ◽  
pp. L28-L34 ◽  
Author(s):  
Hong Liu ◽  
Stephen C. Lazarus ◽  
George H. Caughey ◽  
John V. Fahy
Keyword(s):  
Cystic Fibrosis ◽  
Neutrophil Elastase ◽  
Eosinophil Cationic Protein ◽  
Airway Disease ◽  
Cathepsin G ◽  
Cationic Protein ◽  
The Mean ◽  
Buffer Control ◽  
Positive Controls

Neutrophils, eosinophils, and their proinflammatory constituents are important mediators of airway disease, and high levels of neutrophil proteases and eosinophil cationic protein (ECP) are found in sputum from patients with cystic fibrosis (CF). To investigate whether neutrophil proteases or CF sputum causes eosinophil degranulation, purified eosinophils from atopic asthmatic subjects were incubated for 2 h with neutrophil elastase, cathepsin G, and CF sputum, and the release of ECP was measured. We found that the percent release of ECP was higher after incubation with neutrophil elastase (10−5 M) than with a buffer control [6.1 ± 0.8 (SE) vs. 1.7 ± 0.1%; P < 0.003] and represented >50% of the release caused by positive controls [Ca2+ ionophore A-23187 (5 × 10−6 M) or serum-coated Sephadex beads]. The release of ECP after incubation with cathepsin G (2.3 ± 0.2%) and CF sputum (6.2 ± 2.0%) was also significantly higher than that with a buffer control ( P < 0.05). Neutralization of free elastase activity with α1-proteinase inhibitor reduced the mean percent degranulation of eosinophils by neutrophil elastase by 50% ( P = 0.0004) and by CF sputum by 75% ( P = 0.02). Preincubation of eosinophils with cytochalasin B (10 mg/ml) and depletion of the incubation medium of Ca2+ also significantly attenuated degranulation of eosinophils incubated with purified free neutrophil elastase or CF sputum ( P < 0.05). We conclude that neutrophil proteases, especially neutrophil elastase, and elastase-rich CF sputum cause degranulation of eosinophils in a mechanism partially dependent on Ca2+ and actin filaments.

scholarly journals Activity of Antibiotics against Staphylococcus aureus in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture Medium

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Yvan Diaz Iglesias ◽  
Tobias Wilms ◽  
Rita Vanbever ◽  
Françoise Van Bambeke
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Metabolic Activity ◽  
Culture Medium ◽  
Young Patients ◽  
Major Influence ◽  
Strain Atcc ◽  
Content Type ◽  
Drug Concentrations

ABSTRACT Staphylococcus aureus is a highly prevalent pathogen in the respiratory tract of young patients with cystic fibrosis (CF) and causes biofilm-related infections. Here, we set up an in vitro model of a biofilm grown in Trypticase soy broth supplemented with glucose and NaCl (TGN) or in artificial sputum medium (ASM) and used it to evaluate on a pharmacodynamic basis the activity of antibiotics used in CF patients and active on staphylococci (meropenem, vancomycin, azithromycin, linezolid, rifampin, ciprofloxacin, tobramycin). Rheological studies showed that ASM was more elastic than viscous, as was also observed for sputa from CF patients, with elastic and viscous moduli being, respectively, similar to and slightly lower than those of CF sputa. Biofilms formed by methicillin-sensitive S. aureus strain ATCC 25923 and methicillin-resistant S. aureus strain ATCC 33591 reached maturity after 24 h, with biomass (measured by crystal violet staining) and metabolic activity (assessed by following resazurin metabolization) being lower in ASM than in TGN and viability (assessed by bacterial counts) being similar in both media. Full concentration-response curves of antibiotics obtained after 24 h of incubation of biofilms showed that all antibiotics were drastically less potent and less efficient in ASM than in TGN toward viability, metabolic activity, and biomass. Tobramycin selected for small-colony variants, specifically in biofilms grown in ASM; the auxotrophism of these variants could not be established. These data highlight the major influence exerted by the culture medium on S. aureus responsiveness to antibiotics in biofilms. The use of ASM may help to determine effective drug concentrations or to evaluate new therapeutic options against biofilms in CF patients.

Hyperabsorption of Na+ and raised Ca(2+)-mediated Cl- secretion in nasal epithelia of CF mice

1994 ◽  
Vol 266 (5) ◽  
pp. C1478-C1483 ◽  
Author(s):  
B. R. Grubb ◽  
R. N. Vick ◽  
R. C. Boucher
Keyword(s):  
Cystic Fibrosis ◽  
Secretory Pathway ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Airway Disease ◽  
Na Channel ◽  
Cl Secretion ◽  
Regulatory Link

We investigated the effect of homozygous genetic disruption of the murine cystic fibrosis transmembrane regulator (CFTR) gene on regulation of the rates of Na+ absorption and Cl- secretion by nasal epithelia in cystic fibrosis (CF) mice. The basal in vivo nasal potential difference (PD; -28.8 +/- 1.8 mV, n = 10) and amiloride-sensitive PD (delta 13.8 +/- 1.0 mV, n = 10) were raised in CF mice compared with controls [-7.8 +/- 0.8 mV, n = 14 (basal); delta 4.5 +/- 0.7 mV, n = 14 (amiloride)], consistent with raised Na+ transport. In vitro studies of freshly excised nasal epithelia confirmed that CF epithelia exhibited a greater basal equivalent short-circuit current (Ieq; 63.5 +/- 12 microA/cm2, n = 15) vs. control (30.2 +/- 7.2 microA/cm2, n = 16) and amiloride-sensitive Ieq (delta 46.2 +/- 12.5 microA/cm2) vs. control (delta 11.3 +/- 4.5 microA/cm2). Tissue from normal mice failed to secrete Cl- in response to ionomycin (delta Ieq: -1.2 +/- 1.9 microA/cm2, n = 18), whereas CF murine tissue responded with a large rise in Ieq (delta 55.1 +/- 19.1 microA/cm2, n = 13). We conclude that CF murine nasal epithelia exhibit Na+ hyperabsorption, providing strong evidence for a regulatory link between CFTR and Na+ channel activity in airway epithelia. We speculate that upregulation of the Ca(2+)-mediated Cl- secretory pathway buffers the severity of airway disease in the CF mouse.

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