A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis Magali Noval Rivas, PhD, Oliver T. Burton,

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Presentation transcript:

A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis Magali Noval Rivas, PhD, Oliver T. Burton, PhD, Petra Wise, PhD, Yu-qian Zhang, PhD, Suejy A. Hobson, MD, Maria Garcia Lloret, MD, Christel Chehoud, BA, Justin Kuczynski, PhD, Todd DeSantis, MSc, Janet Warrington, PhD, Embriette R. Hyde, BSc, Joseph F. Petrosino, PhD, Georg K. Gerber, MD, PhD, Lynn Bry, MD, PhD, Hans C. Oettgen, MD, PhD, Sarkis K. Mazmanian, PhD, Talal A. Chatila, MD, MSc Journal of Allergy and Clinical Immunology Volume 131, Issue 1, Pages 201-212 (January 2013) DOI: 10.1016/j.jaci.2012.10.026 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Oral sensitization and anaphylaxis in Il4raF709 mice: prevention of oral sensitization by antigen-specific Treg cells. A, Il4raF709 and WT BALB/c control mice were either sham sensitized with PBS or sensitized with OVA (100 μg) or OVA/SEB (100 μg/10 μg) by means of gastric gavage once weekly for 8 weeks. Select groups of mice were administered intravenously at the start of the sensitization protocol (day 0), either 5 × 105 cells of DO11.10+ Treg (TR) cells isolated from DO11.10+Foxp3EGFP mice or PBS. At the end of the sensitization period, mice were challenged with 5 mg of OVA by means of gastric gavage and monitored for rectal temperature changes. B, Total (left) and OVA-specific (right) serum IgE levels measured after OVA challenge. C, Enumeration of mast cell infiltration of small intestinal tissues of sensitized mice. D, Serum mMCP-1 levels in mice after OVA challenge. E, Small intestinal histopathology of sham (PBS)–sensitized, OVA-sensitized, and OVA-sensitized/DO11.10+ Treg cell–treated mice (toluidine blue staining; original magnification ×200). Results represent data on 5 to 10 mice per group derived from 2 independent experiments. *P < .05 and ***P < .001, 2-way ANOVA. Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Effect of allergen sensitization on phylogenetic diversity. A, Relative abundance of the different microbial phyla in fecal samples of WT and Il4raF709 mice that were either sham sensitized with PBS or sensitized with OVA or OVA/SEB. The combined profile of OVA- and OVA/SEB-sensitized Il4raF709 mice is also shown, as is that of OVA-sensitized Il4raF709 mice that have been treated with allergen-specific Treg cells. B, Relative abundance of the Firmicutes Erysipelotrichi/Erysipelotrichales/Erysipelotrichaceae family in the different groups. C, Relative abundance of the Proteobacteria/Gammaproteobacteria/Enterobacteriales/Enterobacteriaceae family in the different groups. Results represent 4 to 6 mice per group. *P < .05, 1-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Allergen sensitization of Il4raF709 mice is associated with a microbiotic signature. A, NMDS based on weighted UniFrac distance between samples of sham-sensitized versus OVA- and OVA/SEB-sensitized mice performed on the 251 taxa the abundance of which was significantly different between groups (sham versus allergen sensitized) by using the KW test. B, Hierarchical clustering (average linkage) based on weighted UniFrac distance between samples given abundance of 251 taxa with significant abundance differences across at least 1 of the categories. C, Nearest shrunken centroid analysis of OTUs that best characterize the difference between the sham- versus allergen-sensitized groups. The direction of the horizontal bars reflects either overrepresentation or underrepresentation of the indicated OTUs (left- and right-sided bars, respectively). The length of the bar represents the magnitude of the effect. D, Representation of the abundance of the OTUs identified by the nearest shrunken centroid analysis using the PAM method. Nine mice were used for the OVA+OVA/SEB group (n = 5 and 4 mice, respectively), and 5 mice were used for the PBS group. Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Phylogenetic tree based on 16S rDNA gene sequences of bacterial families with taxa showing significantly different abundances between the sham- and allergen-sensitized Il4raF709 mice shown in Fig 3. Of the 3422 OTUs found present in at least 1 of the samples, 251 OTUs within 41 families were identified by using the KW test to be differentially abundant between the 2 groups. For each family, 1 OTU with the greatest difference between the 2 group means was selected. For the 4 families that contained OTUs with both higher and lower abundance scores, both OTUs were selected. A representative 16S rDNA gene from each of the 45 OTUs was aligned and used to infer a phylogenetic tree. The rings around the tree comprise a heat map in which the inner ring includes the sham-treated and the outer ring includes the OVA+OVA/SEB-treated samples. The color saturation indicates the degree of difference from the mean value of the sham-treated samples, where dark blue indicates a ratio of 0 (least abundant), white indicates a ratio of 1.0 (equivalent abundance), and dark red indicates a ratio of 59 (most abundant). Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Enforced tolerance with allergen-specific Treg cells resets the microbiota of allergen-sensitized Il4raF709 mice. A, NMDS based on weighted UniFrac distance between samples of OVA- and OVA/SEB-sensitized mice (n = 9) versus those of Treg cell–treated, OVA-sensitized mice (n = 5) based on the 627 taxa with significantly different abundance between groups (sham versus allergen sensitized) by using the KW test. B, Hierarchical clustering (average linkage) based on weighted UniFrac distance between samples given abundance of 627 taxa with significant abundance differences across at least 1 of the categories. C, Nearest shrunken centroid analysis of OTUs that best characterize the difference between allergen-sensitized versus tolerant groups. D, Representation of the abundance of the OTUs identified by the nearest shrunken centroid analysis using the PAM method. Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Phylogenetic tree based on 16S rDNA gene sequences of bacterial families with taxa showing significantly different abundances between allergen (OVA+OVA/SEB)-sensitized Il4raF709 mice and Treg cell-treated OVA-sensitized Il4raF709 mice shown in Fig 5. KW analysis identified 627 OTUs within 78 families that have significantly different abundance between the comparison groups. One OTU with the greatest difference between the 2 group means from each family was selected. For the 8 families that contained OTUs with both higher and lower abundance scores, both OTUs were selected. The rings around the tree comprise a heat map in which the inner rings represent the samples of tolerized mice and the outer rings represent those of allergen-sensitized mice. The color saturation indicates the degree of difference from the mean value of the sham-treated samples, where dark blue indicates a ratio of 0 (least abundant), white indicates a ratio of 1.0 (equivalent abundance), and dark red indicates a ratio of 17 (most abundant). Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 The microbiota signatures of allergen-sensitized Il4raF709 and WT mice are distinct. A, NMDS based on weighted UniFrac distance between samples of OVA/SEB-sensitized WT versus OVA/SEB-sensitized Il4raF709 mice based on the 352 taxa with significantly different abundance between groups by using the KW test. B, Hierarchical clustering based on weighted UniFrac distance between samples. C, Nearest shrunken centroid analysis of OTUs that best characterize the difference between the groups. D, Representation of the abundance of the OTUs identified by using the nearest shrunken centroid analysis with the PAM method. E, Venn diagram showing the abundance levels of different OTUs in relation to the sensitization state of WT and Il4raF709 mice. The labels define the abundance states of sets of OTUs in relation to specific comparison groups, such as F709 OVA/SEB<F709 PBS, which identifies those OTUs that are less abundant in allergen-sensitized (OVA/SEB) Il4raF709 mice compared with sham (PBS)–sensitized mice. The number of OTUs thus identified is indicated in parentheses. Spheres indicate intersections between 2 sets, and the colored webs show which intersection of sets form the spheres. F, Contingency table representation of the results shown in the Venn diagram. P < .0001 by using the χ2 test (excluding the 3036 OTUs that did not change on sensitization in both WT and Il4raF709 mice). Six mice for the WT OVA/SEB group versus 4 mice for the Il4raF709 OVA/SEB group. Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 The gut microbiota of allergen-sensitized Il4raF709 mice promote allergen-specific responses and anaphylaxis. A, Agglomerative clustering of donor and recipient stool samples based on 16S OTUs derived from 16S pyrosequencing data. The y-axis represents Bray-Curtis dissimilarity values computed on the relative abundances of OTUs in each sample. A Bray-Curtis value of 0 indicates identical microbial communities, and a Bray-Curtis value of 1 indicates communities with no overlapping OTUs. Heights of lines on the dendrogram indicate Bray-Curtis values at the 95th percentile. B, Core body temperature changes in flora-reconstituted, OVA/SEB-sensitized WT GF mice challenged with 150 mg of OVA. The mice were reconstituted with flora from OVA/SEB-sensitized Il4raF709 or WT BALB/c mice and then sensitized with OVA/SEB and challenged with OVA. Conventional sham- and OVA/SEB-sensitized Il4raF709 mice were used as control animals. C, Serum mMCP-1 levels in flora-reconstituted mice after OVA challenge. D, Total and OVA-specific IgE antibody responses in flora-reconstituted mice. E, Representative flow cytometric analysis of OVA-specific mesenteric CD4+ T cells of flora-reconstituted GF mice producing IL-4 and IFN-γ. F, Enumeration of the percentages of cytokine-producing T cells shown in Fig 8, E. Results represent data from 6 to 12 flora-reconstituted WT GF mice per group derived from 2 independent experiments. *P < .05, **P < .005, ***P < .001, 1- and 2-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2013 131, 201-212DOI: (10.1016/j.jaci.2012.10.026) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions