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1.
Am J Respir Crit Care Med ; 203(9): 1099-1111, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33166473

RESUMEN

Rationale: Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with an increased T-helper cell type 17 (Th17) inflammatory phenotype.Objectives: In this study, we evaluated the microbial and host immune-response dynamics after aspiration with oral commensals using a preclinical mouse model.Methods: Aspiration with a mixture of human oral commensals (MOC; Prevotella melaninogenica, Veillonella parvula, and Streptococcus mitis) was modeled in mice followed by variable time of killing. The genetic backgrounds of mice included wild-type, MyD88-knockout, and STAT3C backgrounds.Measurements and Main Results: 16S-rRNA gene sequencing characterized changes in microbiota. Flow cytometry, cytokine measurement via Luminex and RNA host-transcriptome sequencing was used to characterize the host immune phenotype. Although MOC aspiration correlated with lower-airway dysbiosis that resolved within 5 days, it induced an extended inflammatory response associated with IL-17-producing T cells lasting at least 14 days. MyD88 expression was required for the IL-17 response to MOC aspiration, but not for T-cell activation or IFN-γ expression. MOC aspiration before a respiratory challenge with S. pneumoniae led to a decrease in hosts' susceptibility to this pathogen.Conclusions: Thus, in otherwise healthy mice, a single aspiration event with oral commensals is rapidly cleared from the lower airways but induces a prolonged Th17 response that secondarily decreases susceptibility to S. pneumoniae. Translationally, these data implicate an immunoprotective role of episodic microaspiration of oral microbes in the regulation of the lung immune phenotype and mitigation of host susceptibility to infection with lower-airway pathogens.


Asunto(s)
Infecciones Neumocócicas/prevención & control , Streptococcus pneumoniae , Células Th17/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/fisiología , Infecciones Neumocócicas/etiología , Prevotella melaninogenica , Streptococcus mitis , Veillonella
2.
Am J Respir Crit Care Med ; 202(12): 1678-1688, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-32673495

RESUMEN

Rationale: Workers' exposure to metalworking fluid (MWF) has been associated with respiratory disease.Objectives: As part of a public health investigation of a manufacturing facility, we performed a cross-sectional study using paired environmental and human sampling to evaluate the cross-pollination of microbes between the environment and the host and possible effects on lung pathology present among workers.Methods: Workplace environmental microbiota were evaluated in air and MWF samples. Human microbiota were evaluated in lung tissue samples from workers with respiratory symptoms found to have lymphocytic bronchiolitis and alveolar ductitis with B-cell follicles and emphysema, in lung tissue samples from control subjects, and in skin, nasal, and oral samples from 302 workers from different areas of the facility. In vitro effects of MWF exposure on murine B cells were assessed.Measurements and Main Results: An increased similarity of microbial composition was found between MWF samples and lung tissue samples of case workers compared with control subjects. Among workers in different locations within the facility, those that worked in the machine shop area had skin, nasal, and oral microbiota more closely related to the microbiota present in the MWF samples. Lung samples from four index cases and skin and nasal samples from workers in the machine shop area were enriched with Pseudomonas, the dominant taxa in MWF. Exposure to used MWF stimulated murine B-cell proliferation in vitro, a hallmark cell subtype found in the pathology of index cases.Conclusions: Evaluation of a manufacturing facility with a cluster of workers with respiratory disease supports cross-pollination of microbes from MWF to humans and suggests the potential for exposure to these microbes to be a health hazard.


Asunto(s)
Aerosoles/efectos adversos , Contaminantes Ocupacionales del Aire/efectos adversos , Instalaciones Industriales y de Fabricación , Microbiota , Pseudomonas pseudoalcaligenes , Trastornos Respiratorios/fisiopatología , Adulto , Microbiología del Aire , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Respiratorios/etiología , Estados Unidos
3.
Am J Respir Crit Care Med ; 199(1): 99-109, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29969291

RESUMEN

RATIONALE: Obstructive sleep apnea (OSA) is associated with recurrent obstruction, subepithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. OBJECTIVES: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. METHODS: Two large cohorts were used: 1) a discovery cohort of 472 subjects from the WTCSNORE (Seated, Supine and Post-Decongestion Nasal Resistance in World Trade Center Rescue and Recovery Workers) cohort, and 2) a validation cohort of 93 subjects rom the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing), and 2) biomarkers for inflammation (inflammatory cells, IL-8, and IL-6). Longitudinal 3-month samples were obtained in the validation cohort, including after continuous positive airway pressure treatment when indicated. MEASUREMENTS AND MAIN RESULTS: In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; and 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of cooccurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea-hypopnea index. Three months of treatment with continuous positive airway pressure did not change the composition of the nasal microbiota. CONCLUSIONS: We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed.


Asunto(s)
Microbiota , Cavidad Nasal/microbiología , Apnea Obstructiva del Sueño/microbiología , Adulto , Biomarcadores/análisis , Femenino , Humanos , Interleucina-6/análisis , Interleucina-8/análisis , Masculino , Microbiota/genética , Persona de Mediana Edad , Líquido del Lavado Nasal/química , ARN Ribosómico 16S/genética , Índice de Severidad de la Enfermedad
4.
Issue Brief (Commonw Fund) ; 2018: 1-11, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29320140

RESUMEN

Issue: Our health care and social services delivery systems are not well-equipped to effectively manage patients with multiple chronic diseases and complex social needs such as food, housing, or substance abuse services. Community-level efforts have emerged across the nation to integrate the activities of disparate social service organizations with local health care delivery systems. Evidence on the experiences and outcomes of these programs is emerging, and there is much to learn about their approaches and challenges. Goal: Profile and classify burgeoning initiatives, understand common challenges, and surface solutions to address those challenges. Methods: Mixed-methods approach, including literature search, surveys, semistructured interviews with program leaders, and consultation with expert panels. Findings and Conclusions: We categorized cross-sector community partnerships in four dimensions. We also identified five common challenges: inadequate strategies to sustain cost-savings, improvement, and funding; lack of accurate and timely measurement of return on investment; lack of mechanisms to share potential savings between health care and social services providers; lack of expertise to integrate multiple data sources during health care or social services provision; and lack of a cross-sector workflow evidence base.


Asunto(s)
Servicios de Salud Comunitaria , Relaciones Comunidad-Institución , Prestación Integrada de Atención de Salud , Afecciones Crónicas Múltiples/terapia , Apoyo Social , Redes Comunitarias , Necesidades y Demandas de Servicios de Salud , Humanos
5.
Pediatr Pulmonol ; 53(9): 1288-1298, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29984544

RESUMEN

In pediatric patients with chronic cough, respiratory culture techniques commonly yield negative results. Studies using culture-independent methods have found a high relative abundance of oral microbes in the lower airways, suggesting that the topographical continuity, and dynamics of the intraluminal contents of the aerodigestive system likely influence the lower airway microbiota. We hypothesize that in subjects with chronic cough, clinical diagnosis will correlate with distinct microbial signatures detected using culture-independent methods. STUDY DESIGN AND METHODS: We enrolled 36 pediatric subjects with chronic cough in a cross-sectional study. Subjects were categorized into four clinical groups: asthma, bacterial bronchitis, neurologically impaired-orally fed, and neurologically impaired enterally fed. Samples from the aerodigestive tract were obtained through bronchoscopy and upper endoscopy. 16S rRNA gene sequencing compared the microbiota from bronchoalveolar lavage (BAL), tracheal, supraglottic, esophageal, gastric, and duodenal samples. RESULTS: We observed that the lower airway microbiota of asthma subjects had higher α diversity as compared with the other groups. ß diversity analysis of BAL samples revealed significant differences between the groups. Among the taxonomic differences found, most differentially enriched taxa were upper airway organisms such as Rothia, Gemellaceae (u.g. or uncharacterized genus), and Granulicatella in asthma, Prevotella in bacterial bronchitis, and Veillonella in neurologically impaired orally fed subjects. Greater dissimilarity between the upper airway and lower airway microbiota was associated with increased neutrophilic airway inflammation. CONCLUSIONS: Distinct dysbiotic signatures can be identified in the lower airway microbiota of pediatric subjects with chronic cough that relates to the degree and type of inflammation.


Asunto(s)
Líquido del Lavado Bronquioalveolar/microbiología , Tos/complicaciones , Tos/diagnóstico , Disbiosis/complicaciones , Disbiosis/diagnóstico , Asma/complicaciones , Asma/microbiología , Infecciones Bacterianas/microbiología , Bronquitis/complicaciones , Bronquitis/microbiología , Lavado Broncoalveolar , Broncoscopía , Niño , Preescolar , Enfermedad Crónica , Estudios Transversales , Nutrición Enteral/efectos adversos , Femenino , Humanos , Inflamación , Masculino , Microbiota , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/microbiología , Estudios Prospectivos , ARN Ribosómico 16S/genética , Sistema Respiratorio/microbiología
6.
ERJ Open Res ; 3(3)2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28717640

RESUMEN

Therapies targeting inflammation reveal inconsistent results in idiopathic pulmonary fibrosis (IPF). Aerosolised interferon (IFN)-γ has been proposed as a novel therapy. Changes in the host airway microbiome are associated with the inflammatory milieu and may be associated with disease progression. Here, we evaluate whether treatment with aerosolised IFN-γ in IPF impacts either the lower airway microbiome or the host immune phenotype. Patients with IPF who enrolled in an aerosolised IFN-γ trial underwent bronchoscopy at baseline and after 6 months. 16S rRNA sequencing of bronchoalveolar lavage fluid (BALF) was used to evaluate the lung microbiome. Biomarkers were measured by Luminex assay in plasma, BALF and BAL cell supernatant. The compPLS framework was used to evaluate associations between taxa and biomarkers. IFN-γ treatment did not change α or ß diversity of the lung microbiome and few taxonomic changes occurred. While none of the biomarkers changed in plasma, there was an increase in IFN-γ and a decrease in Fit-3 ligand, IFN-α2 and interleukin-5 in BAL cell supernatant, and a decrease in tumour necrosis factor-ß in BALF. Multiple correlations between microbial taxa common to the oral mucosa and host inflammatory biomarkers were found. These data suggest that the lung microbiome is independently associated with the host immune tone and may have a potential mechanistic role in IPF.

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