Asthma. In Europe ~30 million children and adults under 45 have asthma. On average 3 people a day die from asthma in the UK

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1 Dr Neil Williams Nottingham Trent University College of Science and Technology Department of Sport Science 1

2 Asthma In Europe ~30 million children and adults under 45 have asthma On average 3 people a day die from asthma in the UK Increased prevalence of asthma linked to: Pharmacological management o Adverse side effects o 50% patients poorly controlled o Poor adherence 2

3 Exercise Induced Asthma (EIA) Transient narrowing of the airways during or on cessation of exercise Symptoms of wheezing, coughing, tightness in the chest, and mucus production Up to 90% of asthma sufferers can experience EIA Asthma and EIA is the most commonly reported medical condition amongst Olympic and Paralympic athletes Underdiagnosed in elite athletes Poor medication adherence / ineffective 3

4 Disordered gut microbiota in asthma Infants who develop asthma show gut dysbiosis in first 100 days of life (Arrieta et al 2015) Gut Dysbiosis Allergic asthma patients display lower levels of Bifidobacterium adolescentis (Hevia et al 2016) Dietary galacto-oligosaccharides prevent airway eosinophilia and hyperresponsiveness in a murine house dust mite-induced asthma model (Verheijden et al 2015) Beneficial microbes synbionts Pathogenic microbes pathobionts Asthma and airway inflammation Could the gut microbiota be a therapeutic target for athletes with exercise induced asthma? 4

5 Gut Microbiota - a therapeutic target? Diet Gut lung axis Exercise Prebiotics Asthma Airway inflammation Lung microbiota 5

6 Prebiotic Supplementation and EIA 10 diagnosed asthma sufferers with exercise induced asthma and 8 non-asthmatic non-eia controls Double-blind, randomised, placebo controlled study Participants entered the study on their normal diet and then received a daily dose for 21 days of either: Prebiotic (B-GOS) 5.5 g d -1 (48% wt:wt of Bimuno-galactooligosaccharide) Placebo Maltodextrin (Clasado, Milton Keynes, UK) Measures of pulmonary function and airway inflammation pre and post a hyperventilation challenge 6

7 Prebiotic Supplementation and EIA Eucpanic voluntary hyperpnoea o Mimics breathing rates associated with exercise Lung function Blood serum markers Day 0 Day 0 Prebiotic Placebo 2 week washout Day 21 Day 21 7

8 Peak Fall in FEV 1 (%) Prebiotic Supplementation and EIA Lung function: 0-10 Placebo Day 0 Placebo Day 21 B-GOS Day 0 Asthma B-GOS Day 21 Controls 40% improvement in lung function -20 Placebo Day 0 World 1 st * Placebo Day 21 B-GOS Day 0 B-GOS Day 21 Patient perceivable difference -50 *B-GOS Day 0 vs. B-GOS Day 21 (P = 0.004) Williams et al (2016) Br J Nutr. 8

9 Serum TNF-a concentration (pg ml -1 ) Prebiotic Supplementation and EIA Airway Inflammation: HIB B-GOS (DAY 0) HIB B-GOS (DAY 21) HIB Placebo (DAY 0) HIB Placebo (DAY 21) Suppression of TNF-α 5 4 * ** Reduced airway inflammation Pre-EVH h Williams et al (2016) Br J Nutr Significant difference: B-GOS Day 0 vs. B-GOS Day 21 (*P = 0.04; **P = 0.002) 9

10 CRP (mg.l -1 ) CCL17 concentration (pg.ml -1 ) Prebiotic Supplementation and EIA Airway Inflammation: *** Placebo Day 0 Placebo Day 21 B-GOS Day 0 B-GOS Day 21 Reduced serum chemokine CCL Placebo Day 0 Placebo AsthmaB-GOS Day 21 Day 0 B-GOS Day 21 Control 6 5 *** P = * P = 0.05 ** P = Reduced CRP Reduced systemic inflammation ** * Williams et al (2016) Br J Nutr 0 Placebo Day 0 Placebo B-GOS Asthma Day 21 Day 0 B-GOS Day 21 Control 10

11 Prebiotic Supplementation and EIA How might this work? Beneficial microbial colonization Prebiotic Metabolite production Microbes Dendritic cell polarization T cell differentiation Local (airway) immune modulation Systemic translocation Airway translocation Suppressed airway inflammation Local (gut) immune modulation 11

12 Prebiotic Supplementation and EIA How might this work? 1. Increased dendritic cell sampling of probiotic bacteria Alterations in naïve T cell differentiation Pre/probiotics increases IL-10 and Foxp3 transcriptions in murine lung tissue (Sagar et al., 2014a; Sagar et al., 2014b) Augmented Foxp3 expression in murine blood CD4 + CD25 + Foxp3 + T cells (Sagar et al., 2014a) 2. Metabolite production Increase in SCFA production prevents development of murine allergic airway disease (Thorburn et al., 2015) Dietary acetate increases Foxp3 expression in murine lung tissue and Treg cell counts in peripheral lymph nodes 3. Alterations in the gut interface and permeability Improved intestinal barrier function Reduced microbial translocation and reductions in LPS 12

13 Prebiotic Supplementation and EIA Future research direction Could the gut microbiota be a therapeutic target for adults with severe asthma - larger scale trials needed Comparative analysis of the gut and lung microbiota between adults with asthma and controls Gut and lung microbiota responses to prebiotic interventions in human adults with asthma Mechanistic explorations in human studies - short chain fatty acid and cell and immune marker responses to prebiotic interventions 13

14 Thank you for listening Dr Neil Williams Nottingham Trent University College of Science and Technology Department of Sport Science 14