Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases Shannon L. Russell, PhD, Matthew J. Gold,

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Presentation transcript:

Perinatal antibiotic-induced shifts in gut microbiota have differential effects on inflammatory lung diseases Shannon L. Russell, PhD, Matthew J. Gold, BSc, Lisa A. Reynolds, PhD, Benjamin P. Willing, PhD, Pedro Dimitriu, PhD, Lisa Thorson, BSc, Stephen A. Redpath, PhD, Georgia Perona-Wright, PhD, Marie-Renée Blanchet, PhD, William W. Mohn, PhD, B. Brett Finlay, PhD, Kelly M. McNagny, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 1, Pages 100-109.e5 (January 2015) DOI: 10.1016/j.jaci.2014.06.027 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Early life streptomycin treatment exacerbates HP. A and B, BAL and differential leukocyte counts of control or antibiotic-treated mice challenged for 3 weeks with SR antigen or PBS and sacrificed on day 20 after initial SR exposure. C, Pathological scores and representative H&E-stained lung sections. Scale bar, 300 μm. Error bars are means ± SEM, representative of at least 3 independent experiments (n = 3-6). Statistics shown are based on comparisons to SR-challenged controls. H&E, Hematoxylin and eosin; ND, none detected; Strep, streptomycin; Vanco, vancomycin. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IFN-γ and IL-17A are upregulated in streptomycin-exacerbated HP. A, Serum SR-specific IgG1 and IgG2a responses after 3 weeks of SR exposure. B and C, Ifng and Il17a mRNA expression and IFN-γ and IL-17A cytokine production in lung homogenates from control and antibiotic-treated mice (means of 3-6 mice per group ± SEM, 1 of at least 2 independent experiments). Data in Fig 2 (C) are pooled from 2 experiments. Statistics shown are based on comparisons to SR-challenged controls. Eosinos, Eosinophils; Lymphos, lymphocytes; Macs, macrophages; ND, none detected; Neutros, neutrophils; Strep, streptomycin; Vanco, vancomycin. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Streptomycin does not alter early innate immune responses in HP. A, Total BAL counts of control or streptomycin-treated mice challenged with SR for 1 (1 × SR) or 3 (3 × SR) consecutive days. B, Frequency of leukocyte subsets in BAL of SR-challenged mice. C, Ifng and Il17a mRNA expression in lung tissue from SR-challenged control and streptomycin-treated mice. D, Intracellular IFN-γ or IL-17A production by innate immune cells (CD45+CD25+lineage−) isolated from lung tissue of SR-challenged mice. Means of 3 to 6 mice per group ± SEM, representative of 2 independent experiments. NS, Not significant; Strep, streptomycin. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Adaptive immunity plays a role in streptomycin-exacerbated HP. A, BAL counts of control or antibiotic-treated, SR-challenged (3 weeks) RAG 1–deficient or wild-type (WT) mice. Total number (B) or frequency (C) of leukocyte subsets in BAL of SR-challenged mice. Data shown are means of 3 to 6 mice per group ± SEM. Statistics shown are based on comparisons to WT controls. Eosinos, Eosinophils; Lymphos, lymphocytes; Macs, macrophages; Neutros, neutrophils; NK, natural killer; Strep, streptomycin; Vanco, vancomycin. *P < .05 and ** P < .01. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Bacteroidetes are enriched in mice treated with streptomycin. Pyrosequencing analysis of 16S rRNA gene amplicons was performed on fecal DNA samples from the indicated mice. A, Relative abundance (%) of OTUs grouped at the family level from the indicated SR-challenged mice. Classification scheme: k, kingdom; p, phylum; c, class; o, order; f, family. Each bar represents an average of 8 mice per group, from 2 independent experiments. Rare taxa were removed from the legend, but still included in the graph. B, Principal coordinate analysis (PCO) of bacterial communities. Each colored circle represents 1 mouse. rRNA, Ribosomal RNA; Strep, streptomycin; Vanco, vancomycin. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Specific bacterial taxa correlate with disease severity in HP. A, Relative abundance (%) of all OTUs classified as Bacteroidetes or Firmicutes was plotted against BAL infiltrates for individual streptomycin-treated mice. B, Heatmap displaying OTUs enriched in either control (C) or streptomycin (S)-treated mice. Samples were hierarchically clustered using the complete linkage method. Colored “cells” represent log-transformed % relative abundances and vary between blue and red. The numbered vertical bar represents Spearman correlations between differentially abundant OTUs and BAL counts in the lungs of control and streptomycin-treated, SR-challenged mice. Correlation coefficient values are represented by colors ranging from brown (negative correlations) to green (positive correlation). Each column represents 1 mouse. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Abundance of immune cell subsets in BAL of SR-challenged antibiotic-treated mice. Frequency (%) of leukocyte subsets relative to total BAL cells from (A) 3-week SR-challenged or (B) 3-week PBS-challenged antibiotic-treated mice, quantified by cytospin or flow cytometry. Means of 3 to 6 mice per group ± SEM, representative of at least 2 independent experiments. Strep, Streptomycin; Vanco, vancomycin. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Streptomycin treatment does not polarize systemic DC or T-cell responses toward TH1/TH17 effector phenotypes. A, IFN-γ and IL-17A secretion by OT-II cells cultured for 3 days with DCs isolated from mesenteric lymph nodes of control or antibiotic-treated naive animals with or without OVA in the presence of LPS or anti-CD3. Supernatant cytokines from cocultures were quantified by cytokine bead array. B, Intracellular IFN-γ and IL-17A cytokine production by splenic CD4+ T cells cultured for 7 days in neutral, TH1-, or TH17-inducing conditions. Means of 3 mice per group ± SEM and representative data from 1 (A) or 2 (B) independent experiments. OVA, Ovalbumin; Strep, streptomycin; Vanco, vancomycin. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Interindividual differences exist between streptomycin-treated and control microbial communities. Family-level phylogenetic classification of 16S rRNA gene frequencies in fecal DNA from SR-challenged control (C) and streptomycin-treated (S) animals. Those indicated with a classification level other than family level (f) could be identified confidently only to the level indicated: k, kingdom; p, phylum; c, class; o, order; f, family. Each bar represents 1 mouse. Rare taxa were removed from the legend, but still included in the graph. rRNA, Ribosomal RNA. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Specific bacterial taxa correlate with disease severity in streptomycin-treated mice. Relative abundance (%) of select bacterial taxa grouped at family level (unless otherwise specified) was plotted against total BAL infiltrates of individual mice treated with streptomycin and challenged for 3 weeks with SR antigen. Significant positive or negative correlation coefficients are indicated beside each corresponding graph. Those with a classification level other than family (f) could be identified confidently only to the level indicated: p, phylum; c, class; o, order; f, family. Each dot on the graph represents abundance/BAL from 1 mouse. Journal of Allergy and Clinical Immunology 2015 135, 100-109.e5DOI: (10.1016/j.jaci.2014.06.027) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions