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Probiotics in IBD: why have they been (somewhat) disappointing... until now ? Philippe Marteau, MD, PhD Eco... logic group & Medico-surgical department of Digestive Diseases Lariboisire hospital, Paris Slide 2 MicrobesIBD ? ? Which micro-organism ? Or microbial component ? ? Slide 3 Probiotics and IBD : RCTs in Humans POUCHITIS VSL#3 to prevent pouchitis occurrence or recurrence A situation where antibiotics are clearly effective Slide 4 Probiotics and IBD : RCTs in Humans CROHNs DISEASE Prevention of postoperative recurrence (POR) Prevention of relapse of medically treated CD E. coli Nissle 1917 Saccharomyces boulardii VSL #3 (abstract from 2000) Lactobacillus rhamnosus GG Lactobacillus johnsonii LA1 Small open trial with genetically modified Lactococcus lactis secretingIL-10 Slide 5 RCTs Probiotics in Crohns disease SituationProbioticnMonths Relapse probiotic group Relapse control group PReference PORVSL #3281220 % 40 %*Gionchetti et al. abstr CDECN281230 %70 %*Malchow CDS. b2866.3 %37.5 %*Guslandi et al. PORL. GG451216.6%10.5%NSPrantera et al. CDL GG752431%17%NSBousvaros et al. PORLA198649% 64% NSMarteau et al. PORLA170327.9%33% NSVan Gossum et al. Slide 6 RCTs Probiotics in Crohns disease SituationProbioticnMonths Relapse probiotic group Relapse control group PReference PORVSL #3281220 % 40 %*Gionchetti et al. abstr CDECN281230 %70 %*Malchow CDS. b2866.3 %37.5 %*Guslandi et al. PORL. GG451216.6%10.5%NSPrantera et al. CDL GG752431%17%NSBousvaros et al. PORLA198649% 64% NSMarteau et al. PORLA170327.9%33% NSVan Gossum et al. Slide 7 RCTs Probiotics in Crohns disease SituationProbioticnMonths Relapse probiotic group Relapse control group PReference PORVSL #3281220 % 40 %*Gionchetti et al. abstr CDECN281230 %70 %*Malchow CDS. b2866.3 %37.5 %*Guslandi et al. PORL. GG451216.6%10.5%NSPrantera et al. CDL GG752431%17%NSBousvaros et al. PORLA198649% 64% NSMarteau et al. PORLA170327.9%33% NSVan Gossum et al. Slide 8 RCTs Probiotics in Crohns disease SituationProbioticnMonths Relapse probiotic group Relapse control group PReference PORVSL #3281220 %40 %*Gionchetti et al. abstr CDECN281230 %70 %*Malchow CDS. b2866.3 %37.5 %*Guslandi et al. PORL. GG451216.6%10.5%NSPrantera et al. CDL GG752431%17%NSBousvaros et al. PORLA198649%64%NSMarteau et al. PORLA170327.9%33%NSVan Gossum et al. Slide 9 Why did Probiotics fail so far in Crohns ? Ineffectiveness ?... And then failure of the selection procedure or model or strategy (rationale on which the trial was decided) ? Dose ? Galenics of the tested product ? End point ? and population treated ? Statistical power of the trial ? Slide 10 RCTs Probiotics in Crohns disease SituationProbioticnMonths Relapse probiotic group Relapse control group PReference PORVSL #3281220 %40 %*Gionchetti et al. abstr CDECN281230 %70 %*Malchow CDS. b2866.3 %37.5 %*Guslandi et al. PORL. GG451216.6%10.5%NSPrantera et al. CDL GG752431%17%NSBousvaros et al. PORLA198649%64%NSMarteau et al. PORLA170327.9%33%NSVan Gossum et al. Dose : no Ineffectiveness End point, population : no Galenics of the tested product ? Statistical power : noFailure of the selection strategy ? Lactobacillus johnsonii LA1 Slide 11 RCTs Probiotics in Crohns disease SituationProbioticnMonths Relapse probiotic group Relapse control group PReference PORVSL #3281220 %40 %*Gionchetti et al. abstr CDECN281230 %70 %*Malchow CDS. b2866.3 %37.5 %*Guslandi et al. PORL. GG451216.6%10.5%NSPrantera et al. CDL GG752431%17%NSBousvaros et al. PORLA198649%64%NSMarteau et al. PORLA170327.9%33%NSVan Gossum et al. Galenics : no Ineffectiveness End point, population : no Failure of the selection strategy ! Statistical power : no Lactobacillus rhamnosus GG Slide 12 % Eczema. p = 0,038 PLACEBO L. GG Lactobacillus GG to prevent atopic eczema Kalliomki et al. Lancet 2001;357:1076-9 Double blind RCT 132 new borns at risk to develop atopy L. GG in the mother then baby vs placebo 6 months follow up 2 years and 4 years 46% 23% Slide 13 Probiotics Probiotic Health Immune cells Microflora Slide 14 Pharmacological approach of probiotics Micro-organism Active components Targets Specific effects Positive Negative Pharmacokinetics Survival Adhesion / colonisation Fate of active components Slide 15 Competitive exclusion ? . Immunomodulation ? . Production of anti-inflammatory molecules ? What is reaching the targets in the intestine ? Probiotics and IBD : mechanisms ? Slide 16 Escherichia coli serotype O6,K5,H1 (non pathogenic) Mutaflor, Germany Survive in the GIT can inhibit the growth of other E. coli or enteric bacteria E. coli Nissle 1917 Slide 17 E. coli Nissle 1917 to prevent relapse of UC : 3RCT Equivalent to 5-ASA No placebo controlled trial Slide 18 Intestine-407 CFU invasive LF82/ well x 10 5 % dinvasion L. casei DN-114 001 Inhibition de ladhsion et de linvasion de LF82 AIEC E. coli Nissle 1917 Boudeau et al. APT 2003 Ingrassia et al. AEM 2005 Slide 19 E. coli Nissle 1917 Increased expression of ZO-2 - PK C Expression of HB D-2 Zirrek et al. Cell microbiol 2006 Wehkamp et al. Infect immun 2004 Tight junctions DEFENSINS Slide 20 Lactococcus lactis to deliver active molecules in the gastrointestinal tract during (experimental) IBD Genetically modified L. lactis secreting IL-10 or trefoil peptides --> reduction of experimental colitidies in mice Steidler L Science 2000 Vandenbroucke et al. Gastroenterology 2004 Human trial ongoing Slide 21 Pharmacokinetics of probiotics in the small bowel Pharmacokinetics of probiotics in the small bowel Vesa T, Marteau P. Alim Pharmacol Ther 2000;14:823-8 Pharmacokinetics of L. lactis : a bile sensitive strain L. lactis Marker (spores of bacillus) Slide 22 CONCLUSIONS... concept = using ingested living micro-organisms to produce and transport molecules of potential therapeutic interest to targets in the intestine Original pharmacological approach : potential for in vivo production of active molecules, targeting immune cells, presenting immunogenic molecules in a microbial context... Proven therapeutic effects in specific situations Extrapolation of effects between products is not possible and one should avoid excessive enthusiasm or scepticism Slide 23 PROGRES Proof of concept... Probiotics do work in IBD Clinical usefulness ? Yes for ECN in UC More rational development in... IBD... should involve knowledge on the pharmacology i.e. galenics, kinetics, mechanisms of action and target the best patho-physiologic hypothesis Slide 24 Where to shoot ? E. coli Firmicutes +++ Slide 25 Unanswered Questions Unanswered Questions How do probiotics work and how can we select new strains ? Do probiotics work better after antibiotics ? Do combinations of strains work better ?