Current and emerging treatments targeting the microbiota for IBS Peter McLean, PhD Scientific Director GI Drug Discovery Unit Takeda Disclaimer • I’m a former employee of GSK and Nestle • I’m a current employee of Takeda • The views expressed in this presentation are solely mine and are not attributable to my current employer Progress in IBS research: a “road-map” p. 3 Lines of evidence supporting a role of gut microbiota in IBS pathophysiology Antibiotic use risk factor for developing IBS GI infections involved in the onset (post-infective IBS) Villarreal et al., 2012 Lee et al., 2013 Halvorson et al., 2006 Non-absorbable antibiotic rifaximin improves symptoms Increased colonic fermentation Chassard et al., 2012 Ringel et al., 2014 Farmer et al., 2014 Pimentel et al., 2011 Altered stability and composition Mättö et al., 2005 Kassinen et al., 2007 Duboc et al., 2012 Dietary Modulation Low Fodmap Elemental diet Microbiota and IBS Pimentel et al., 2004 Symptoms associated with composition and levels of metabolites Probiotic bacteria improve symptoms Tana et al., 2010 Jeffery et al., 2012 Whorwell et al., 2006 Faecal supernatants increase intestinal pain in conventional mice Risk factor Gecse et al., 2008 Association Intervention targeting microbiota Human-rodent transfer studies Transfer of Symptoms to germ free rodents via microbiota Crouzet et al., 2013 Jun Lu et al., 2012 De Palma et al., submitted Transfer of IBS symptoms via the microbiota to germ-free mice 25 Healthy p< 0.001 D-IBS Intestinal transit score 20 10 Healthy donor Healthy Human microbiota transfer into germ-free mice D-IBS 5 p= 0.001 Total time in light (s) 350 Anxiety-like behavior D-IBS donor 15 300 250 Bright box Dark Darkbox box 2 200 Healthy 150 Jun Lu et al., 2012 // De Palma et al., submitted D-IBS 3 1 Microbiota Pathways in Pathogenesis of IBS Shanahan & Quigley 2014 Treatments targeting the microbiota-gut-brain axis Current Emerging Psychotropic Probiotics Low FODMAP Prebiotics Microbiota and IBS Microbial Ecosystem Therapeutics Faecal microbiota Transplant Probiotics Antibiotics Mechanisms of FODMAPs - short-chain fermentable carbohydrates - increase luminal water and gas production bloating and distension Tuck et al., Expert Rev. Gastroenterol. Hepatol. 2014 The case for FODMAPs in IBS Clinical evidence suggests low FODMAP diet is effective in some IBS patients Gastroenterology 2014;146:67–75 CLINICAL AT Existing evidence should be interpreted with caution: - Limited number of randomised controlled trials - Difficulties with choice and blinding of the control “placebo” group - Controlled feeding does not mimic the real-life restricted diet - NNT~4 suggests that around 1 in 4 IBS patients will respond Potential Issues: - nutrient deficiencies and microbiota effects with long term restriction diet The Case for Prebiotics “selectively fermented ingredients that allow specific changes in the composition and/or activity of microbiota that confers health benefits” Whelan, K. Proc. Nutrition Soc (2013) Clinical data is mixed - 2 studies showing improvement in IBS associated with increased bifidobacteria. High doses worsen symptoms, consistent with a FODMAP mechanism. Key will be to identify patients likely to respond to prebiotics The Case for Probiotics “probiotics are effective treatments for IBS (NNT=7), although which individual strains are the most beneficial remains unclear” L. plantarum 299v L. rhamnosus, L. plantarum, L. acidophilus, E. faecium Am J Gastroenterol. 2014 B. infantis 35624 Next generation probiotics: modulation of behavior B. longum 999 normalized anxiety-like behavior induced intestinal inflammation Latency to step down (anxiety) Dependent on neuronal (vagal) communication between gut and brain Control (-) Mice model (Low dose DSS-induced anxiety) DSS alone DSS + LPR DSS + BL999 DSS + BL999 Vagotomy Not associated with an antiinflammatory effect Bercik et al., 2010 Dpm x mm2 1400 Accompanied by a normalization of BDNF expression in the CNS 800 200 C (-) C (+) LPR BL999 PROBIO'STICK® L. helveticus R0052 and B. longum R0175 Probio'Stick® significantly reduced stress-related intestinal symptoms (abdominal pain, nausea and vomiting) and psychological distress in healthy volunteers Stress-related intestinal symptoms Diop et al., 2008 Psychological distress Messaoudi et al., 2011 Remains to determined if effective in IBS patients but could be considered for patients with stresssensitivity or psychological symptoms. The Case for Antibiotics NNT=10 Pimentel et al., 2011 Is efficacy due to SIBO eradication or suppression of fermenting bacteria? How to predict response to treatment? Lactulose breath test, cecal pH? Exclusive elemental diet Hypothesis: starves microbiota of nutrients suppressing of microbiota Lactulose breath tests in IBS patients with SIBO before and after 14 days of elemental diet Before subjects with normalized breath test improved bowel symptoms Day 15 Pimentel et al., 2004 Issues  Requires confirmation in RCT in IBS without SIBO  Tolerability of exclusive elemental diet  Dietary advice for after elemental diet phase The case for faecal microbiota transplant in IBS 3 published case studies of FMT in FGIDs – showing improvement in 50-90% of cases - improvements in pain, bloating and bowel habits. Aroniadis & Brandt 2014 Issues  Identification of suitable donors and standardized preparation procedures  Safety risk “FMT may prove more beneficial than probiotics, as donated feces, in a sense, are the ultimate human probiotic”. Aroniadis & Brandt 2014 What is the ultimate human probiotic? Next generation microbial ecosystem therapeutics based on growing knowledge of microbial aetiology Spectrum of microbiota-targeted modulators Proteases Gases Bile acids ecosystem-level Single targets Olle B, 2013 Summary Current treatment options targeting microbiota include: - low FODMAP diet - probiotics/prebiotics - antibiotics Future directions: - psychtropic probiotics - faecal microbiota transplants - microbial ecosystem therapeutics Key to success will be identification of microbial signatures to stratify patients most likely to respond to microbiota-directed therapies Jeffery et al., 2012 Acknowledgements Nestle Research Gaby Bergonzelli Bernard Berger Enea Rezzonico McMaster University Elena Verdu Premek Bercik Steve Collins Maria Ines Pinto Sanchez Paul Moyeddi Common food sources of FODMAPs Short-chain fermentable carbohydrates Gibson & Shepherd, Am J Gastroenterol 2012