Dr. neelam mohan

Probiotics in Inflammatory Bowel Disorder (IBD)

Dr. Neelam MohanDNB(Pediatrics), FPGH(UK),FIMSA,FACG(USA), FIAPDirector - Department of Pediatric Gastroenterology, Hepatology and Liver Transplantation Medanta Medicity – Gurgaon ( Delhi NCR)

Pioneer in liver transplant program in India & heads the busiest Pediatric Liver Transplant Centre.Pioneer in Endoscopy in neonates. Set up first IAP fellowship program in Pediatric Gastroenterology & Hepatology in India. National Coordinator of diarrhea module 2012 – in IndiaSecretary – Indian Society of Gastroenterology, Hepatology & Nutrition (ISPGHAN)Honored with “Zee swasth Bharat Samman” Award by the health Minister of India & “DMA Centenary Award - 2014” by Hon’ble Health Minister Harsh Vardhan & Hon’ble Finance Minister Arun Jaitley.

Probiotics from Bench to Community ; 7-8 March 2015, The Grand , New Delhi

My Presentation

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Role of Microbiome in the pathogenesis of IBD

Role of Probiotics in Ulcerative Coltitis• Acute inflammation • Maintenance treatment• Pouchitis

Role of Probiotics in Crohn’s disease

Adults & children

Charaka Samhita (supposed to be written in 1000 BC), a treatise on Ayurveda medicine “Jataragni” (fire in stomach) – Beneficial

microbial flora of GI tract &“Takra” i.e., fermented milk, as “Amrita” or

elixir.

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Interesting facts

• The human gut normally hosts roughly 1014 bacterial organisms of up to 1000 different species; this bacterial community can add up to 1-2 kg.

• In total, the number of intestinal bacteria is approximately ten times the number of cells constituting the human body

• The collective bacterial genome, also referred to as the microbiome, contains 100-fold more genes than the entire human genome.

4Wehkamp J et al. Germany: Falk Foundation e.V., 2013Stephani J et al. Arch Immunol Ther Exp (Warsz) 2011; 59: 161-177

Fact

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Gut Microbiota

Common to all

Individualised

Role of Microbiome in the pathogenesis of IBD

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Intestinal Microbiota & IBD

• There is plenty of evidence supporting the hypothesis of the involvement of intestinal microbiota in IBD pathogenesis.

• Crohn’s disease (CD) and ulcerative colitis (UC) tend to occur in the colon and distal ileum, which contain the highest intestinal bacterial concentrations.

• A pathogenic role of luminal constituents is suggested by the prevention and treatment of Crohn’s disease by the diversion of fecal stream and reactivation of inflammation within one week following reinfusion of ileostomy contents.

Sartor RB et al. Gastroenterology 2008; 134: 577-594D’Haens GR et al Gastroenterology 1998; 114: 262-267

Intestinal Microbiota in Pathogenesis of IBD

• Similarly, Ulcerative Colitis patients who undergo ileal pouch-anastomosis surgery develop mucosal inflammation after bacterial colonization of the pouch.

• Furthermore, there are many studies on animal models supporting the role of gut microbiota in the development of IBD.

• In experimental animal models of IBD, genetically- engineered animals developed spontaneous colitis under standard laboratory conditions, but remained colitis-free when they were raised in a sterile, germ-free environment, thus indicating that bacterial exposure and colonization are essential for the development of colitis.

8Harper PH et al Gut 1985; 26: 279-284

de Silva HJ et al Gut 1991; 32: 1166-1169Taurog JD et al. J Exp Med 1994; 180:2359-2364


• The majority of genes found to be associated with an increased risk for the development of IBD are those encoding proteins that act to preserve the mucosal barrier and/or regulate the host immune system.

• A major breakthrough in understanding the linkage between genetic predisposition and IBD development was the discovery of the NOD2/CARD15 gene, which encodes a protein responsible for microbial recognition, induction of antimicrobial genes, and control of the host adaptive immune response.

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• Patients with CD have increased intestinal permeability, which could reflect mucosal barrier defects that promote bacterial translocation through the intestinal mucosa.

• The intestinal mucus barrier is significantly altered in UC patients, particularly in terms of mucus composition and phospholipid concentration.

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• Interaction between Intestinal Microbes and mucosa of susceptible individuals Triggers a cascade of reactions.

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+ Th1 / Th2

Mucosal damage

Machanism of Action of Probiotics

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Pathogens Probiotics

Produce antimicrobial

substance

Stimulation of immunity

Compete for nutrients

Competition for receptors

Receptors on intestinal walls where pathogens attached

Degradation of toxin pathogen receptors

Mucin secretion

Block receptors

Role of Probiotics in Ulcerative Colitis

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Probiotics in Ulcerative Colitis

Probiotics in treatment of Active Inflammation

in Ulcerative Colitis

Randomized Trails of Probiotics as therapy of Active UC

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Participants / Treated (Yr of Study)

Trial Design

Probiotic (Strains) Trial Length (weeks )

Results

20 (10) (2004)

EBRPC Blend Probiotic (Yakult™) + 5ASA

Placebo + 5ASA

12Pr - 40%, Placebo 30%, [OR 0.64 (95% CI 0.10 to 4.10)]

90 (30) (2004)

R Blend Probiotic (VSL#3™) + Balasalazide

Placebo + Balasalazide

8 Pr - 80% Placebo 70%, [OR 0.58 (95% CI 0.18 to 1.91)]

102 (52) (1999)

DBRDD Single strain (E. coli Nissle) + Steriods Mesalazine + steroids

12 Pr- 68.4%, mesalazine 74.6%, OR 1.35 (95% CI 0.6 to 3.04).

EBRPC: Endoscopy blinded, randomized, placebo-controlled; R: Randomized; DBRDD: Double-blind, randomized, double-dummy.

Dosing (CFU/day) 1 × 1010

9 × 1011

1 × 1011

Mallon et al. concluded that addition of a probiotic to conventional therapy did not improve overall remission rates in patients with mild to moderate ulcerative colitis but the addition of probiotics may reduce disease activity.

Probiotics in Ulcerative Colitis (Mod. to Sev. ) in Children

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Corticosteroid dose (1 mg/kg/day to a maximum of 40 mg/day) and Mesalamine (50 mg/kg/day) dose (n=14)

+ +

Probiotic VSL#3 Placebo

Remission 13/14 (92.8%)

Remission4/15 (36.4%)

P < 0.001

Miele E et al. Am J Gastroenterol. 2009;104:437–443.

Probiotics in Ulcerative Colitis (UC) in Children – Recent Trial

• 31 children with mild to moderate ulcerative proctitis / proctosigmoiditis with mild to moderate disease activity

• Study duration 8 weeks

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Mesalazine + Enema solution with L. reuteri ATCC 55730.

Mesalazine + Placebo

• Clinical and endoscopic improvements better in the probiotic group. • Histological score significantly decreased in the L. reuteri group (P<0.01). • A significant increase in the mucosal expression levels of IL-10 and a significant decrease in the levels of IL-1b, TNFa, and IL-8 mucosal expression levels (P\0.01) were documented only in the L. reuteri group.

Oliva S. et al . Aliment Pharmacol Ther. 2012; 35(3):p. 327–34.

Probiotics / Prebiotics / Both in Active UC

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Fujimori, S. et al. Nutrition 2009, 25, 520–525

Patients on stable doses of aminosalicylates and/or prednisolone for at least 4 weeks in remission or had mildly active UC

Prebiotics Probiotics B longum

Prebiotics + Probiotics B longum

Only those patients taking a combination of a Prebiotic and B. longum had an improvement (p = 0.03)

Probiotic in Adults UC in India

• Multicenter, randomized, double blind, placebo-controlled trial from India.

• VSL#3 in adults with mild-to- moderate UC. • Dose - 3.6 × 1012 CFU VSL#3 (N = 77) or placebo (n = 70) twice

daily for 12 weeks.

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Sood et al. Clin. Gastroenterol. Hepatol. 2009, 7, 1202–1209

Probiotic Placebo p Value

Primary end point (50% decrease in *UCDAI ) at 6 weeks

32.5% 10% 0.001

Secondary end points - 12 weeks 42.9% 15.7% 0.001

*UC disease activity index


Maintenance of Remission

Probiotics in Maintenance of Remission UC

21J Clin Gastroenterol. Volume 45, supp.3, Nov./ Dec. 2011

DB, double-blind;

Probiotics in Maintenance of Remission UC

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J Clin Gastroenterol. Volume 45, supp.3, Nov./ Dec. 2011

Children

• It is not the probiotic and the dose alone but also the specific strain of probiotic that matters.


Treatment of Pouchitis

Proctocolectomy with ileal pouch-anal anastomosis may be required in some UC patients because their disease was medically intractable or they developed secondary dysplasia or cancer. Pouchitis or inflammation of the ileal reservoir created during the procedure may develop in between 15 and 50% in patients. It is the most common complication of the surgery and although the exact etiology is not clear host genetic factors, local pouch issues and the microbiota contained within the pouch are thought to be involved.

Probiotics in Pouchitis


Summary of Probiotics in UC

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• Over the past 3 years we have seen a more robust efficacy of probiotics, such as VSL#3, to induce remission in mild-to-moderately active UC

• The efficacy of probiotics as an “ADJUNCT” therapy for patients who fail standard therapy and who otherwise have to step up to steroids and/or immunosuppressives is an important contribution to the clinical field.

• This beneficial effect was also reported in children with UC, a group in which we would like to avoid the use of steroids that could lead to further growth retardation.

Summary of Probiotics in UC

Probiotics Strains Evidence

Inductions of Remission VSL#3 Level A

Maintenance of Remission VSL#3

E coli Nissle 1917

Level A

Level B

Pouchitis VSL#3 Level A

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Role of Probiotics in Crohn’s Disease (CD)

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Maintenance of Remission – Adults


Probiotic - S. Boulardii in CD – Adults

First Author Date

Design duration

Probiotic Concomitant Therapy

Results

Vilela et al ;

Scand J Gastroenterol.2008

DB, R, C 3mo S. Boulardii (4108 CFU) n=15

Mesalamine,AzathioprinePrednisone, metronidazol/thalidomide

Improved permeability(P=0.0005) andmaintenance of remission

Bourreille A, et al

Clin Gastroenterol Hepatol. 2013

RCT, 1 yr S. Boulardii Frequency of relapses -Saccharomyces boulardii group - (47.5 %)Placebo - (53.2 %)

Time to relapse was also notstatistically different

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Probiotics in CD in Children

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Gupta P et al. J Pediatr Gastroenterol Nutr 2000;31:453Y7.

Probiotic Lactobacillus GG in Pediatric CD

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Multi centric , USA, n=75 children (5-21 yrs)

Groups

LGG (n=39) Placebo (n=36)

• No difference in adverse events in the 2 groups. • Median time to relapse was same in 2 groups

Summary Probiotics in CD

• There is no evidence of efficacy for any used strain in pediatric / adult CD unlike UC.

• The pathogenesis of UC and CD, especially the role of microbes-host interaction, is different between these 2 disease entities .

• Given the array of genotype & phenotype of CD, we need to identify the specific Probiotic that may be beneficial.

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CAPGAN 2015 : 2 -4 Oct. Online Registration Open

Conference Secretariat:-Dr. Neelam Mohan

DirectorDepartment of Pediatric Gastroenterology, Hepatology

& Liver TransplantationMedanta-The Medicity Hospital, Gurgaon – India

Email – [email protected]

Dr. Neelam MohanOrganising Secretary

www.capgan2015.com

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• Probiotics (Yakult™) + 5-ASA had similar effectiveness to placebo + 5-ASA for induction of remission [28]: probiotic 40%, placebo 30%, OR 0.64 (95% CI 0.10 to 4.10).

• Probiotics (VSL#3™) + balsalazide had similar effectiveness to placebo + balsalazide for induction of remission [30]: probiotic 80%, placebo 70%, OR 0.58 (95% CI 0.18 to 1.91).

• Probiotics (E. coli Nissle 1917) + steroids had similar effectiveness to mesalazine + steroids for induction of remission [31]: probiotic 68.4%, mesalazine 74.6%, OR 1.35 (95% CI 0.6 to 3.04).

Blend Probiotic (VSL#3). Dose-1 × 1011/kg

• N=29 (14), DBRPC

• In a trial in children with moderate-to-severe disease VSL#3™ or placebo was administered along with corticosteroids and mesalamine.

• The corticosteroid dose (1 mg/kg/day to a maximum of 40 mg/day) and mesalamine (50 mg/kg/day) dose were those commonly used.

• The corticosteroids were tapered after a month if subjects were in remission.

• In this study, remission was achieved in 13 of 14 participants (92.8%) treated with VSL#3™ and IBD therapy and in 4 of 15 patients (36.4%) treated with placebo and IBD therapy (p < 0.001).

• This result must be taken in context the response rate to corticosteroids and mesalamine in the placebo treated group.

Miele, E et al. Am. J. Gastroenterol. 2009, 104, 437–443.

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Dr. neelam mohan