Probiotics may play a role in inflammatory bowel disease (IBD). In ulcerative colitis, probiotics like VSL#3 have been shown to induce remission in mild-to-moderate disease, maintain remission, and treat pouchitis. Certain probiotic strains are more effective than others. In Crohn's disease, VSL#3 and S. boulardii have demonstrated benefits like maintaining remission and improving intestinal permeability when used as an adjunct to standard therapies. Well-designed studies provide evidence for the therapeutic potential of specific probiotic strains in both ulcerative colitis and Crohn's disease.

1. Probiotics in Inflammatory Bowel Disorder
(IBD)
Dr. Neelam Mohan
DNB(Pediatrics), FPGH(UK),FIMSA,FACG(USA), FIAP
Director - 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 India
Secretary – 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

2. My Presentation
2
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

3. 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.
3

4. 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., 2013
Stephani J et al. Arch Immunol Ther Exp (Warsz) 2011; 59: 161-177

5. Fact
5
Gut Microbiota
Common
to all
Individualised

6. Role of Microbiome in the pathogenesis of IBD
6

7. 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: 577-594
D’Haens GR et al Gastroenterology 1998; 114: 262-267

8. 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.
8
Harper PH et al Gut 1985; 26: 279-284
de Silva HJ et al Gut 1991; 32: 1166-1169
Taurog JD et al. J Exp Med 1994; 180:2359-2364

9. Intestinal Microbiota in Pathogenesis of
IBD
• 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.
9

10. Intestinal Microbiota in Pathogenesis of
IBD
• 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.
10

11. Intestinal Microbiota in Pathogenesis of
IBD
• Interaction between Intestinal Microbes and mucosa of
susceptible individuals Triggers a cascade of reactions.
11
+ Th1 / Th2
Mucosal damage

12. Machanism of Action of Probiotics
12
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

13. Role of Probiotics in Ulcerative Colitis
13

14. Probiotics in Ulcerative Colitis
Probiotics in treatment of Active Inflammation
in Ulcerative Colitis

15. Randomized Trails of Probiotics as therapy of Active UC
15
Participants /
Treated (Yr
of Study)
Trial
Design
Probiotic (Strains) Trial
Length
(weeks )
Results
20 (10)
(2004)
EBRPC Blend Probiotic (Yakult™)
+ 5ASA
Placebo + 5ASA
12
Pr - 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.

16. Probiotics in Ulcerative Colitis (Mod. to Sev. ) in Children
16
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%)
Remission
4/15 (36.4%)
P < 0.001
Miele E et al. Am J Gastroenterol. 2009;104:437–443.

17. 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
17
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 (P0.01)
were documented only in the L. reuteri group.
Oliva S. et al . Aliment Pharmacol Ther. 2012; 35(3):p. 327–34.

18. Probiotics / Prebiotics / Both in Active UC
18
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)

19. 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.
19
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

20. Probiotics in Ulcerative Colitis
Maintenance of Remission

21. Probiotics in Maintenance of Remission
UC
21
J Clin Gastroenterol. Volume 45, supp.3, Nov./ Dec. 2011
DB, double-blind;

22. Probiotics in Maintenance of Remission
UC
22
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.

23. Probiotics in Ulcerative Colitis
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.

24. Probiotics in Pouchitis
24
J Clin Gastroenterol. Volume 45, supp.3, Nov./ Dec. 2011

25. Summary of Probiotics in UC
25
• 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.

26. 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
26

27. Role of Probiotics in Crohn’s Disease (CD)
27

28. Maintenance of Remission – Adults
28
J Clin Gastroenterol. Volume 45, supp.3, Nov./ Dec. 2011

29. 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,
Azathioprine
Prednisone,
metronidazol/
thalidomide
Improved permeability
(P=0.0005) and
maintenance 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 not
statistically different
29

30. Probiotics in CD in Children
30

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

32. Probiotic Lactobacillus GG in Pediatric CD
32
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

33. 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.
33

34. CAPGAN 2015 : 2 -4 Oct. Online Registration Open
Conference Secretariat:-
Dr. Neelam Mohan
Director
Department of Pediatric Gastroenterology, Hepatology
& Liver Transplantation
Medanta-The Medicity Hospital, Gurgaon – India
Email – info@capgan2015.com
Dr. Neelam Mohan
Organising Secretary
www.capgan2015.co
m

35. 35

39. • 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).

40. 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.