DISCUSSION GROUP #5 ISAPP 2014 THE MICROBIOME AND HEALTH: PROMISING ENDPOINTS FOR INTERVENTIONS. Friday, June 20, 2014

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1 DISCUSSION GROUP #5 ISAPP 2014 THE MICROBIOME AND HEALTH: PROMISING ENDPOINTS FOR INTERVENTIONS Friday, June 20, 2014 Chairs: George Fahey, Jens Walter 1

2 What do we want to achieve? Treatment of disease Maintenance of remission Prevent disease Improve quality of life? Importance of gut microbiota in human disease Heart disease Colon Cancer Diabetes Obesity IBD Allergies Autoimmune diseases 2

3 Despite major advances in gut microbiome research showing its impact on disease, there is still a lot to be done to realize its full potential Functional Studies in Animal Models Association Studies in Humans Nielsen et al, Nature Biotechnol 2014 Dysbiosis of the intestinal microbiota 3

4 There is often no consensus on the disybiotic patterns of the microbiome Even where there is a consensus, cause and effect relationships have not been established Individual variation in the microbiome complicate determination of such associations After long discussion, the consensus in Group 5 was therefore: Microbiome features, at the current point, are not well enough established to serve as bonafide primary endpoints in clinical studies However, information on dysbiosis can be used to identify targets for interventions, and a characterization of the microbiome should be included in studies. What endpoints should we measure Primary endpoints have to be established and accepted enough to provide the evidence to support a health claim Metabolic disease Hypertension Dyslipidemia Glucose disregulation CRP/IL-6? CVD Hypertension LDL/HDL CRP Adiposity Prevention of secondary myocardia infarction TMAO? Colon Cancer Polyps Blood in feces 4

5 Outcomes Disease Oriented Evidence (DOE): outcomes include intermediate, histopathologic, physiologic, or surrogate results (e.g., blood sugar, blood pressure, flow rate, coronary plaque thickness) that may or may not reflect improvement in patient outcomes Patient Oriented Outcomes: outcomes that matter to patients and help them live longer or better lives, including reduced morbidity, reduced mortality, symptom improvement, improved quality of life, or lower cost Generally are RCT and meta analysis but don t have to be Important to be very specific with question Specify if primary outcome is incidence, prevention, duration or prevalence In probiotic literature sometimes they state what their primary outcome is but in abstract and discussion report something different Sample size should be based on primary endpoint 5

6 There was a major consensus that microbiome characterization should be a major component of clinical trials Compositional and functional (metabolism) analysis Confirm dysbiotic shifts Test if dysbiotic shifts can be redressed Has the potential to give some mechanistic insight Such research might result in microbiome endpoints in the future Despite major advances in gut microbiome research showing its impact on disease, there is still a lot to be done to realize its full potential Functional Studies in Animal Models Association Studies in Humans Functional Studies in Humans Therapeutic Advances in the Treatment of Disease Is there a plausible mechanism of action based on genomics and/or metabolomics of the consortium relative to the host? Can a study be designed to demonstrate proof-ofconcept. What are measurable pharmacokinetic parameters of the consortium (structure and/or product production) and quantifiable pharmacodynamic responses of the host? To promote a health claim in the prevention of disease, can an intermediate biomarker be identified (i.e. the gut microbiota, TMAO, and ASCVD?) 6

7 Diet, the Gut Microbiome, and its Metabolome Holmes et al. Cell Met. 2012;16:559 Wang et al. Nature. 2011;472:57-63 Regulatory Issues When choosing outcomes need to consider local regulatory issues In US if you diagnosis, cure, mitigate, treat, or prevent a disease you are a drug For example, endpoint may need to be colonic transit time not constipation 7

8 Stool characteristics Gut microbiota Fecal metabolites Biomarkers Microbiome and health in animals Dogs/Cats Inflammation Immune function Gut permeability Tremaroli and Backhed, 2012 Prebiotics and Probiotics for Equids Probiotics Yeast (SC) Digestibility fibre diges bility 1 VFA produc on 2 ra o of acetate+butyrate: propionate 3 Microflora celluloly c bacteria 4 lactate u lising bacteria (s mulatory pep des as in ruminants?) 3 lactate producing bacteria 3 effect of environmental changes on LI (e.g transpor ng) 4 Clinical applications Effects on pathogens and infectious diarrhoea not been looked at in horses 1 Julliand (2006); 2 Medina et al. (2002); 3 Jouany et al. (2009); 4 Julliand & Zeyner (2008) 8

9 Central Role of the Gastrointestinal Tract in Maintaining Aquatic Animal Health The gastrointestinal tract (GIT) has profound effects on aquatic animal health because: Its integrity is vital for normal nutrient absorption It modulates many aspects of innate and adaptive immunity due to the presence of signifbers and types of immune cells It may guard against pathogen entrance into the body 9