Dynamics of the nasal microbiota in infancy: A prospective cohort study.

BACKGROUND Understanding the composition and dynamics of the upper respiratory tract microbiota in healthy infants is a prerequisite to investigate the role of the microbiota in patients with respiratory diseases. This is especially true in early life, when the immune system is in development. OBJECTIVE We sought to describe the dynamics of the upper respiratory tract microbiota in healthy infants within the first year of life. METHODS After exclusion of low-quality samples, microbiota characterization was performed by using 16S rDNA pyrosequencing of 872 nasal swabs collected biweekly from 47 unselected infants. RESULTS Bacterial density increased and diversity decreased within the first year of life (R(2) = 0.95 and 0.73, respectively). A distinct profile for the first 3 months of life was found with increased relative abundances of Staphlyococcaceae and Corynebacteriaceae (exponential decay: R(2) = 0.94 and 0.96, respectively). In addition, relative bacterial abundance and composition differed significantly from summer to winter months. The individual composition of the microbiota changed with increasing time intervals between samples and was best modeled by an exponential function (R(2) = 0.97). Within-subject dissimilarity in a 2-week time interval was consistently lower than that between subjects, indicating a personalized microbiota. CONCLUSION This study reveals age and seasonality as major factors driving the composition of the nasal microbiota within the first year of life. A subject's microbiota is personalized but dynamic throughout the first year. These data are indispensable to interpretation of cross-sectional studies and investigation of the role of the microbiota in both healthy subjects and patients with respiratory diseases. They might also serve as a baseline for future intervention studies.

Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.

BACKGROUND Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. OBJECTIVE We sought to test the immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. METHODS Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis-like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and T(H)2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid. RESULTS Sensitization to food allergens through an atopic dermatitis-like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific T(H)2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease. CONCLUSION Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.

Influence of inspiration to expiration ratio on cyclic recruitment and derecruitment of atelectasis in a saline lavage model of acute respiratory distress syndrome*

OBJECTIVE Cyclic recruitment and derecruitment of atelectasis can occur during mechanical ventilation, especially in injured lungs. Experimentally, cyclic recruitment and derecruitment can be quantified by respiration-dependent changes in PaO2 (ΔPaO2), reflecting the varying intrapulmonary shunt fraction within the respiratory cycle. This study investigated the effect of inspiration to expiration ratio upon ΔPaO2 and Horowitz index. DESIGN Prospective randomized study. SETTING Laboratory investigation. SUBJECTS Piglets, average weight 30 ± 2 kg. INTERVENTIONS At respiratory rate 6 breaths/min, end-inspiratory pressure (Pendinsp) 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and FIO2 1.0, measurements were performed at randomly set inspiration to expiration ratios during baseline healthy and mild surfactant depletion injury. Lung damage was titrated by repetitive surfactant washout to induce maximal cyclic recruitment and derecruitment as measured by multifrequency phase fluorimetry. Regional ventilation distribution was evaluated by electrical impedance tomography. Step changes in airway pressure from 5 to 40 cm H2O and vice versa were performed after lavage to calculate PO2-based recruitment and derecruitment time constants (TAU). MEASUREMENTS AND MAIN RESULTS In baseline healthy, cyclic recruitment and derecruitment could not be provoked, whereas in model acute respiratory distress syndrome, the highest ΔPaO2 were routinely detected at an inspiration to expiration ratio of 1:4 (range, 52-277 torr [6.9-36.9 kPa]). Shorter expiration time reduced cyclic recruitment and derecruitment significantly (158 ± 85 torr [21.1 ± 11.3 kPa] [inspiration to expiration ratio, 1:4]; 25 ± 12 torr [3.3 ± 1.6 kPa] [inspiration to expiration ratio, 4:1]; p < 0.0001), whereas the PaO2/FIO2 ratio increased (267 ± 50 [inspiration to expiration ratio, 1:4]; 424 ± 53 [inspiration to expiration ratio, 4:1]; p < 0.0001). Correspondingly, regional ventilation redistributed toward dependent lung regions (p < 0.0001). Recruitment was much faster (TAU: fast 1.6 s [78%]; slow 9.2 s) than derecruitment (TAU: fast 3.1 s [87%]; slow 17.7 s) (p = 0.0078). CONCLUSIONS Inverse ratio ventilation minimizes cyclic recruitment and derecruitment of atelectasis in an experimental model of surfactant-depleted pigs. Time constants for recruitment and derecruitment, and regional ventilation distribution, reflect these findings and highlight the time dependency of cyclic recruitment and derecruitment.

Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis.

Reactive oxygen species (ROS) have been implemented in the etiology of pulmonary fibrosis (PF) in systemic sclerosis. In the bleomycin model, we evaluated the role of acquired mutations in mitochondrial DNA (mtDNA) and respiratory chain defects as a trigger of ROS formation and fibrogenesis. Adult male Wistar rats received a single intratracheal instillation of bleomycin and their lungs were examined at different time points. Ashcroft scores, collagen and TGFβ1 levels documented a delayed onset of PF by day 14. In contrast, increased malon dialdehyde as a marker of ROS formation was detectable as early as 24 hours after bleomycin instillation and continued to increase. At day 7, lung tissue acquired significant amounts of mtDNA deletions, translating into a significant dysfunction of mtDNA-encoded, but not nucleus-encoded respiratory chain subunits. mtDNA deletions and markers of mtDNA-encoded respiratory chain dysfunction significantly correlated with pulmonary TGFβ1 concentrations and predicted PF in a multivariate model.