Eamonn M MQuigley, Francisco Guarner, Marianne Fraher On behalf of Discussion Group 5 ISAPP 2012 Cork, Ireland

Transcription

1 Eamonn M MQuigley, Francisco Guarner, Marianne Fraher On behalf of Discussion Group 5 ISAPP 2012 Cork, Ireland

2 Eamonn Quigley (Chair) Ireland Francisco Guarner (Co chair) Spain Marianne Fraher (SFA) Ireland Adam Baker Denmark Janine Barlow UK Ted Dinan Ireland Emilie Fargier France Flavia Indrio Italy Philippe Langella France Melanie Lalonde Canada Irene Lenoir Wijnkoop France Elaine Petrof Canada Phoukham Phothirath h h Switzerland Yehuda Ringel USA Fergus Shanahan Ireland Christina Surawicz USA Helen Whelton Ireland

3 Eamonn Quigley Francisco Guarner Fergus Shanahan Ted Dinan Christina Surawicz Elaine Petrof Philippe Langella Helen Whelton Yehuda Ringel Flavia Indrio TOPICS FOR DISCUSSION Probiotics in disease prevention; is this a possibility? What can we learn from from MetaHIT? Pharmabiotics for IBD; is there a future? Use of probiotics for disorders of mood, behavior and cognition Is there a defined optimal microbial profile for faecal transplantation? Synthetic stool preparation Faecalibacterium prausnitzii; therapeutic potential? Probiotics and prebiotics for oral Health Probiotics for functional gut problems Probiotics for infant colicky pain

4 Can studies of the microbiota help us to develop better probiotics and prebiotics? Three strategies Screen organisms for properties and use in disease Study the microbiota in disease and replace what s missing Study an clinically beneficial outcome (e.g. faecal transplant) and reverse engineer

5 Metagenomics of the Human Intestinal Tract Francisco Guarner Zoetendal et al, Gut 2008

6 Most abundant genera in the human gut microbiota Arumugam et al, Nature 2011

7 Most abundant genera in the human gut microbiota Arumugam et al, Nature 2011

8 F. prausnitzii: a bacterium involved in several dysbiosis In Crohn s disease: Philippe Langella Fecal flora In other intestinal diseases Bacteroides Peptostreptococci Coprococci Clostridium Escherichia coli Bifidobacterium Lactobacillus Faecalibacterium prausnitzii Swidsinski et al., 2002; Manichanh et al., 2006; Seksik et al., 2006; Sokol et al., 2009 Irritable bowel syndrome Rajilic Stojanovic M. et al., 2011 F. prausnitzii Colorectal cancer Balamurugan R. et al., 2008 Ulcerative colitis McLaughlin SD. et al., 2010 F. prausnitzii could be considered as a sensor of intestinal health

9 20 patients with active ileal CD requiring an ileo caecal resection M0 Surgical resection Biopsies analysis by FISH M6 colonoscospy Remission or Endoscopic recurrence Eub338(Eubacteria) Bac303 (Bacteroides Prevotella) Ent1458 (Enterobacteria) Erec482 (Clostridium coccoides) Lab158 (Lactobacillus Enterococcus) Bif164(Bifidobacterium) Fprau645 (F. prausnitzii) E t 8 (E t b t i ) F. prausnitzii at M0 3,3%±3,4 Remission at M6 vs 0,3%±0,5 Recurrence at M6 (p=0.03) Cork, ISAPP, October 2, 2012

10 Translational applications of F. prausnitzii strategy Correlation between human microbiota composition and clinical i l data using FISH and qpcr Identification of F. prausnitzii ii Use of prebiotics and probiotics Use of F. prausnitzii (Novel food dossier) Secreted molecule(s) FprauX (Drug dossier) Recent advances; 12 novel strains potential ti candidate molecules l active in high and low grade inflammation models (IBD and IBS models) one genomic library monoxenic and dixenic models Cork, ISAPP, October 2, 2012

11 Unique Microbial Genes in Human Gut Francisco Guarner The gene set is almost complete! The gene set is almost complete! Qin et al, Nature 2010

12 My Experience 34 patients Very successful every pt s C diff has been eradicated 1 recurred with antibiotic Treated with probiotics, resolved Christina Surawicz 2 re transplanted with different donor with success (sons +; daughter ) 1 patient with ih Crohn s C. difficile il gone but still with symptoms (active Crohn s) 2 with enemas alone

13 Standard Frozen Stool Prep 43 patients t RCDI Prescreened donor pool in many (two donors used for 33 patients) t Efficacious 70 92% Some retreated Some gas + irregular BMs transient Frozen stool odorless Hamilton et al, Am J Gastroenterol 2012; 107: (Alex Khoruts)

14 Conclusion FMT is a crude way to treat RCDI But highlights importance of microbiome Important to define friends and foes

15 Ecosystem therapeutics Emerging paradigm in medicine Displacing i a damaged d ecosystem with ih a healthy one (e.g. Fecal transplantation) How do we define a healthy ecosystem? Encodes a full functional repertoire of genes Can exist in a stable equilibrium Colonizes and persists Contrast with traditional probiotics Elaine Petrof which have to be taken continuously to be maintained

16 Challenges of making a therapeutic ecosystem Currently culture each isolate separately and combine to make formulation Difficult to culture some members as pure species Difficult to ensure reproducibility Better way would be to culture as a chemostat community Easier Cheaper More reproducible Doses supplied with a bolus of nutrients to improve seeding efficiency

17 At Week2, in vivo (patient) and in vitro (Robogut) samples share similar features PT D2 W2 Robogut W2 In vivo (in patient) In vitro

18 Preventive use of probiotics An opportunity to reduce healthcare expenditures PUBLICATION COSTING DATA COMMENTS Financial burden of hospital acquired C.difficile infection J Hosp Infect 1996 Additional treatment costs: 4000 ( 5920)/patient 94% of the additional costs associated with C. difficile infection were due to increased duration of stay Health care costs and mortality associated with nosocomial diarrhea due to C.difficile Clin Infect Dis 2002 Additional treatment costs/patient: $ patients prospectively followed A conservative estimate of the cost of CDAD in the US exceeds $1.1 billion/year The emerging infectious challenge of CDAD in Massachusetts hospitals: clinical and economic consequences Infect Control Hosp Epidemiol 2007 $10,212 to $13,675/patient 1034 CDAD cases during 2000 Short and long term attributable costs of CDAD in nonsurgical inpatients Clin Infect Dis 2008 Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial Br Med J 2007 Savings from the * use of a probiotic formula in the prophylaxis of antibiotic associated diarrhea J Medical Economics 2012 The median attributable costs of CDAD in nonsurgical inpatients per admission over a 1 year period were estimated between $1,077,306 and $1,422,360 Estimated costs for: Prevention AAD 50 /case Prevention CDAD 60 /case Mean savings (payer) : $1968 to $2661/patient Methods are conservative and may underestimate the true attributable cost of CDAD no data on outpatient costs n = 135 Good compliance to the probiotic drink Cost consequence analysis based on published data and adjusted for the North American context *A cost effectiveness analysis based on this clinical trial shows the potential of considerable cost savings (unpublished pilot study)

19 What are Psychobiotics? Ted Dinan

20 Lactobacillus strain, GABA receptor expression and bh behaviour Bravo et al (2011), PNAS 108, 16050

21 Effects of Vagotomy

22 Probiotics in FGID patients perspective Who takes probiotics and why? Yehuda Ringel Use of Probiotics in 131 Subjects with Functional Bowel Symptoms Referral for Probiotics Intentionally Tried Probiotics 35% Not Tried Probiotics 65% Only 22% of subjects take probiotics following advice of healthcare provider Ringel Kulka et al DDW 2011

23 Probiotics in FBD how do we move forward? Clinical interventional studies Probiotics Prebiotics Antibiotics Diet Intestinal Microbiota Composition Function Stability/resilience Gastrointestinal Functions Functional GI Symptoms Motility/Transit Sensation Barrier Immune Other

24 10 YEAR RETROSPECTIVE STUDY chldren(1456 male) Age: median 7.9 year (min 3 max 16) Chi2 TEST Flavia Indrio p<0.002 p<0.001 Colics Regurgitation Constipation RAP NORMAL p<0.001

25 Prevention of the FGD in neonates by Lactobacillus Reuteri Supplementation Anthropometric assessment Number of minutes crying each day Number of regurgitations Number of bowel movements The patients received the probiotics or placebo every day for 28 days and on the 29th day all assessments repeated

26 Prevention of the FGD in neonates by Lactobacillus Reuteri Supplementation U O B U.O. B. Trambusti Trambusti, Policlinico di Bari Ospedale SS. Annunziata - Taranto Ospedale Civile Crotone Policlinico S. Matteo - Pavia O Ospedale d l di S Sesto t S S. Gi Giovannii (MI) Policlinico S.Orsola Malpighi (BO) Arcispedale S.Anna (FE) Ospedale "Frà Frà Castoro Castoro - San Bonifacio (VR) 9. Ospedale "Orlandi" - Bussolengo (VR) 10. Ospedale "Sacro Cuore - Negrar (VR) ENROLLED 468

27 Results at one month 80 Mins of crying time/day L.reuteri Placebo 3,7 p <0.05 Number of daily bm s 4,3 4,2 4,1 4 3,9 3,8 3,6 3,5 3,4 3,3 L. reuteri Placebo p <0.05

28 Inflammatory Bowel Disease Biological basis for modulation of the microbiota Heterogeneity of IBD Fergus Shanahan Crohn s and UC are different Still at an early phase in describing the phenotypes within these disorders and tailoring therapy accordingly Modest effects of probiotics; expectations too great But safe New approaches Precise targeting of microbes e.g. thuracin GMO s

29 Probiotics for Oral Health Potential Helen Whelton 79 Billion Spent on oral care annually in EU More than all cancer treatment combined Oral diseases impacted by a shift in the microbial balance Favourable shifts; Potential ti to improve oral health and QoL potential to generate huge savings

30 Summary of potential for oral probiotic therapy Disease or Condition i Eid Evidence for probioticuse i Dental caries Periodontal Disease Oral yeast infections Halitosis (bad breath) Oral mucosal diseases and manifestations of systemic disease Xerostomia Burning mouth syndrome Experimental and clinical evidence show positive effect Very weak evidence Very weak experimental and clinical evidence Some clinical evidence (3 studies) No evidence No evidence* No evidence *one study suggested improvement Adapted from Jukka H Meurman / Probiotics and Oral Health

31 Summary of potential for oral probiotic therapy Disease or Condition i Eid Evidence for probioticuse i Dental caries Lactobacillus rhamnosus GG Lactobacillus reuteri Bifidobacterium lactis Streptococcus thermophilus Lactococcus lactis Lactobacillus casei Lactobacillus bulgaricus Periodontal Disease Oral yeast infections Halitosis (bad breath) Lactobacillus reuteri L. rhamnosus GG, L rhamnosus LC705 and Propionibacterium freudenreichii ssp. shermanii JS. Weissella cibaria

32 Probiotics in Prevention Potential Populations Healthy population At risk ik groups About to get antibiotics Relatives of diseased dindividuals d Eamonn Quigley Environmental e.g. day care, PI IBS, ICU, Pouch Disease recurrence CDAD IBD IBS

33 Potential Indications General health Digestive health Resp infections (coughs, colds, flu s) Enteric infections Rotavirus etc CDAD IBD Primary Secondary Oral health Urogenital

34 Potential Indications Obesity Primary Secondary prevention of complications IBS and common digestive complaints Allergy and related disorders Pre natal Post natal Cancer Colorectal l Primary Secondary

35 Endpoints Disease Occurrence Activity/recurrence Socio economic QOL Days lost from work Impact Intermediate markers Polyps for cancer Metabolites Inflammatory markers

36 Problems Disease/symptom prevalence Study population p size Timing Infancy/childhood vs adulthood Time course e.g. cancer What is meaningful? Product? Characterized? Optimized? Evidenced? Extrapolation from animal studies The Pivotal Window

37 Regulation may have the last word! Food vs Drug Health vs Disease Who will do/pay for the trials? GMO s will the public accept?