Probiotics in IBD: why have they been (somewhat) disappointing Probiotics in IBD: why have they been (somewhat) disappointing... until now ? Philippe Marteau, MD, PhD Eco... logic group & Medico-surgical department of Digestive Diseases Lariboisière hospital, Paris

? ? Microbes IBD ? Which micro-organism ? Or microbial component ?

Probiotics and IBD : RCTs in Humans POUCHITIS VSL#3 to prevent pouchitis occurrence or recurrence A situation where antibiotics are clearly effective

Probiotics and IBD : RCTs in Humans CROHN’s 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

RCTs Probiotics in Crohn’s disease Situation Probiotic n Months Relapse probiotic group control group P Reference POR VSL #3 28 12 20 % † 40 %† * Gionchetti et al. abstr CD ECN 30 % 70 % Malchow S. b 6 6.3 % 37.5 % Guslandi et al. L. GG 45 16.6% 10.5% NS Prantera et al. L GG 75 24 31% 17% Bousvaros et al. LA1 98 49% † 64% † Marteau et al. 70 3 27.9% 33% † Van Gossum et al.

RCTs Probiotics in Crohn’s disease Situation Probiotic n Months Relapse probiotic group control group P Reference POR VSL #3 28 12 20 % † 40 %† * Gionchetti et al. abstr CD ECN 30 % 70 % Malchow S. b 6 6.3 % 37.5 % Guslandi et al. L. GG 45 16.6% 10.5% NS Prantera et al. L GG 75 24 31% 17% Bousvaros et al. LA1 98 49% † 64% † Marteau et al. 70 3 27.9% 33% † Van Gossum et al.

RCTs Probiotics in Crohn’s disease Situation Probiotic n Months Relapse probiotic group control group P Reference POR VSL #3 28 12 20 % † 40 %† * Gionchetti et al. abstr CD ECN 30 % 70 % Malchow S. b 6 6.3 % 37.5 % Guslandi et al. L. GG 45 16.6% 10.5% NS Prantera et al. L GG 75 24 31% 17% Bousvaros et al. LA1 98 49% † 64% † Marteau et al. 70 3 27.9% 33% † Van Gossum et al.

RCTs Probiotics in Crohn’s disease Situation Probiotic n Months Relapse probiotic group control group P Reference POR VSL #3 28 12 20 % 40 % * Gionchetti et al. abstr CD ECN 30 % 70 % Malchow S. b 6 6.3 % 37.5 % Guslandi et al. L. GG 45 16.6% 10.5% NS Prantera et al. L GG 75 24 31% 17% Bousvaros et al. LA1 98 49% 64% Marteau et al. 70 3 27.9% 33% Van Gossum et al.

Why did Probiotics fail so far in Crohn’s ? 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 ?

RCTs Probiotics in Crohn’s disease Situation Probiotic n Months Relapse probiotic group control group P Reference POR VSL #3 28 12 20 % 40 % * Gionchetti et al. abstr CD ECN 30 % 70 % Malchow S. b 6 6.3 % 37.5 % Guslandi et al. L. GG 45 16.6% 10.5% NS Prantera et al. L GG 75 24 31% 17% Bousvaros et al. LA1 98 49% 64% Marteau et al. 70 3 27.9% 33% Van Gossum et al. Lactobacillus johnsonii LA1 Dose : no Ineffectiveness End point, population : no Galenics of the tested product ? Statistical power : no Failure of the selection strategy ?

RCTs Probiotics in Crohn’s disease Situation Probiotic n Months Relapse probiotic group control group P Reference POR VSL #3 28 12 20 % 40 % * Gionchetti et al. abstr CD ECN 30 % 70 % Malchow S. b 6 6.3 % 37.5 % Guslandi et al. L. GG 45 16.6% 10.5% NS Prantera et al. L GG 75 24 31% 17% Bousvaros et al. LA1 98 49% 64% Marteau et al. 70 3 27.9% 33% Van Gossum et al. Lactobacillus rhamnosus GG Galenics : no Ineffectiveness End point, population : no Failure of the selection strategy ! Statistical power : no

Lactobacillus GG to prevent atopic eczema Kalliomäki et al. Lancet 2001;357:1076-9 % Eczema. 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 p = 0,038 46% 23% PLACEBO L. GG

Probiotics Microflora Probiotic Health Immune cells

Pharmacological approach of probiotics Micro-organism Active components Targets Specific effects Positive Negative Pharmacokinetics Survival Adhesion / colonisation Fate of active components

Probiotics and IBD : mechanisms ? Competitive exclusion ? Immunomodulation ? …. Production of anti-inflammatory molecules ? What is reaching the targets in the intestine ?

E. coli Nissle 1917 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 to prevent relapse of UC : 3RCT Equivalent to 5-ASA No placebo controlled trial

Inhibition de l’adhésion et de l’invasion de LF82 AIEC E. coli Nissle 1917 L. casei DN-114 001 Intestine-407 CFU invasive LF82/ well x 105 % d’invasion Boudeau et al. APT 2003 Ingrassia et al. AEM 2005

Increased expression of ZO-2 - PK C E. coli Nissle 1917 Tight junctions DEFENSINS Expression of HB D-2 Increased expression of ZO-2 - PK C Zirrek et al. Cell microbiol 2006 Wehkamp et al. Infect immun 2004

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

Pharmacokinetics of probiotics in the small bowel Vesa T, Marteau P Pharmacokinetics of probiotics in the small bowel Vesa T, Marteau P. Alim Pharmacol Ther 2000;14:823-8 L. lactis Marker (spores of bacillus) Pharmacokinetics of L. lactis : a bile sensitive strain

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

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

Where to shoot ? E. coli… Firmicutes +++

Thank you 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 ?