D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease Inge Kepert, PhD, Juliano Fonseca, PhD, Constanze Müller,

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Presentation transcript:

D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease Inge Kepert, PhD, Juliano Fonseca, PhD, Constanze Müller, PhD, Katrin Milger, MD, Kerstin Hochwind, PhD, Matea Kostric, MSc, Maria Fedoseeva, MSc, Caspar Ohnmacht, PhD, Stefan Dehmel, PhD, Petra Nathan, PhD, Sabine Bartel, PhD, Oliver Eickelberg, MD, Michael Schloter, PhD, Anton Hartmann, PhD, Philippe Schmitt-Kopplin, PhD, Susanne Krauss-Etschmann, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1525-1535 (May 2017) DOI: 10.1016/j.jaci.2016.09.003 Copyright © 2016 Terms and Conditions

Fig 1 Screening of supernatants from different probiotic strains for immune activity on human cells. A, Dose-dependent capacity of bacterial supernatants from LGG (fx1), Bifidobacterium BB-420 (fx2), and Lactobacillus casei W56 (fx3) to lower CCL17 secretion of human Hodgkin lymphoma KM-H2 cells. The negative control was nonprobiotic Lactobacillus rhamnosus DSM-20021 (fx4). Three independent experiments in duplicates are shown (mean ± SD percentages relative to CCL17 secretion of untreated KM-H2 cells). LGG: **P < .005 and ***P < .0005, L casei W56: ##P < .005, ###P < .0005, BB-420: §§P < .005, §§§P < .0005, Student t test. B, Capacity of supernatants from LGG, Bifidobacterium BB-420, Lactobacillus casei W56, or nonprobiotic Lactobacillus rhamnosus DSM-20021 to prevent full upregulation of costimulatory molecules and HLA-DR on LPS-stimulated human monocyte-derived DCs. +/-, With/without bacterial supernatant. Five independent experiments are shown (mean ± SD percentages relative to LPS alone). **P < .01 and ***P < .001, Dunn multiple comparison test. Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig 2 Overview on the ability of bacterial supernatants from all 37 strains to decrease CCL17 secretion of KM-H2 cells. Shaded bars, Nonprobiotic Lactobacillus rhamnosus DSM-20021 (negative control); LGG was included as a positive control in all experiments with strains other than lactobacilli. Open bars, Untreated KM-H2 cells and medium control cells. Three independent experiments in duplicates are shown (mean + SD percentages relative to CCL17 secretion of untreated KM-H2 cells). **P < .005 and ***P < .0005, Student t test. Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig 3 Capacity of subfractions of probiotic supernatants to decrease CCL17 secretion in KM-H2 cells. Subfractions with different polarity (MeOH/H2O gradient chromatography) from supernatants of LGG (top) or Lactobacillus casei W56 (middle). Negative controls were nonprobiotic DSM-20021 and blank CDM1 medium (bottom). Three independent experiments in duplicates are shown (mean ± SD percentages relative to constitutive CCL17 secretion of untreated KM-H2 cells). **P < .005 and ***P < .0005, Student t test. Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig 4 Effect of tryptophan L- and D-isomers on CCL17 secretion by KM-H2 cells. KM-H2 cells were stimulated with different concentrations of synthetic L- and D-isomers of tryptophan followed by CCL17 quantification in KM-H2 culture medium after 24 hours. Circles, D-tryptophan; diamonds, L-tryptophan. Three independent experiments in duplicates are shown (mean ± SD percentages relative to constitutive CCL17 secretion of untreated KM-H2 cells). *P < .05, **P < .005, and ***P < .0005, Student t test. Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig 5 Oral D-tryptophan reduces allergic airway inflammation. A, Serum D-tryptophan in mice receiving D-tryptophan (50 mmol/L) in drinking water or water only (ultraperformance liquid chromatography mass spectrometry peak areas). Note the different scales for D-tryptophan (solid bars) and L-tryptophan (shaded bars). **P = .006 and ***P = .004, Welch Test, mean ± SD. B, Total number of cells in bronchoalveolar lavage fluid (BAL). C, Differential cell count. D, Measurement of airway resistance to increasing doses of methacholine (2-way ANOVA with the Bonferroni posttest). E, Geometric mean (fold change) of Ifn-g and Il-4 in lung-derived CD3+CD4+ lymphocytes. F, Il-4 levels in bronchoalveolar lavage of mice, as assessed by using a Cytometric Bead Array. G, Helios-positive Treg cells of lung-derived CD3+CD4+Foxp3+ lymphocytes. Student t test: *P < .05, **P < .01, and ***P < .001. Fig 5, B, C, E and F, n = 8 mice per group, Mann-Whitney U test, median ± SD, *P < .05, ***P < .001, and Fig 5, D and G, n = 6 to 12 mice per group. Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig 6 D-tryptophan (DTrp) influences in vitro primary T-cell differentiation. Primary murine splenocytes were differentiated toward TH1 (A), TH2 (B), and Treg (C) cells with respective cytokine mixes in the presence of 0, 10, or 50 μmol/L D-tryptophan (dissolved in water). Differentiation was assessed by means of flow cytometry, quantitative RT-PCR, and the Cytometric Bead Array for Il-13 and Il-5 protein levels from culture supernatants. Graphs depict fold changes to differentiated cells not treated with D-tryptophan. *P < .05, n = 3 to 4 independent experiments, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig 7 Oral D-tryptophan (DTrp) supplementation increased gut Treg cell numbers and the intestinal bacterial community in mice with AAI. A, Percentage of Foxp3+ cells within CD3+CD4+ T cells in the lamina propria of the colon. ****P < .0001, n = 6 to 12 mice per group, Student t test. B, α-Diversity of bacterial communities. Shannon diversity index was used to estimate bacterial diversity for each treatment (Wilcoxon rank sum test). Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions

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Fig E9 Journal of Allergy and Clinical Immunology 2017 139, 1525-1535DOI: (10.1016/j.jaci.2016.09.003) Copyright © 2016 Terms and Conditions