Transcript Investigations of the Bacterial Pathogenesis of the

Probiotics
and
Pouchitis
What it all about?
Dr. Matt. Johnson
History of the IAPouch
• 1944 Proctocolectomy + Ileostomy
(Strauss + Strauss)
• 1969 Intra-Abdominal Ileal Reservoir
(Kock)
• 1978 Restorative Proctocolectomy
– (Parks + Nicholls)
• 1987 J-Pouch Modification
– (Nicholls)
• A Normal Pouch
Pathological changes within a
normal Healthy Pouch
• 6/52
– plasma cell infiltration
– Later = lymphocyte infiltration
• 6/12
– Villous atrophy
• >6/12
– “Normal adaptation” to “colonic type mucosa”
– Tendency to colonic metaplasia
Pouch Flora
• Flora (10x as much bacteria as cells in the body)
• 55% of stool = bacteria
• Bacteria feed on undigested food by a process of
fermentation
–
–
–
–
Prox jejunum
Ileum
Pouch
Caecum
103
(cfu/g of dry weight stool)
105-8
107-10
1011-12
Pouch Flora
• The proportion of anaerobes increases distally
– Ileum =
– Caecum =
1:1
(Anaerobe : aerobe)
1000:1
– Ileal Pouch = 100:1
• Colonic type flora (bacterioides, bifidobacteria)
Pouchitis Symptoms
•
•
•
•
A) Post Op Stool Frequency
B) Rectal Bleeding
C) Faecal Urgency* +/- Cramps
D) Fever (unusual)
• * usually due to inflammation at the distal/efferent limb
of the pouch
• There is often poor correlation between symptoms and
either the endoscopic or histology appearance
• Pouchitis
Aetiology of Pouchitis
• Bacterial profiles are genetically determined and remain
•
•
•
stable lifelong
Response to Antibiotics suggests a pathogenic role for
bacteria
Diverting ileostomy is therapeutic in CD (recurs 6/12
post re-anastamosis)
Pouchitis =
–
–
–
–
no difference in number of bacteria (qualitative stool studies)
no difference in type of bacteria (quantitative stool studies)
hightened immunogenicity in UC patients (EGIM of IBD)
loss of tolerance to normal bacteria
• No longer able to distinguish between normal and pathogenic organisms
Clinical Pattern
• After 6/12 patients fall into 3 catagories;
• 1) No pouchitis (45%)
• 2) Relapsing + Remiting Pouchitis (42%)
• 3) Chronic Pouchitis (13%)
– > 4/52
– Recurrent courses of antibiotics needed
Therapy for Pouchitis
• There appears to be a bacterial precipitant
• These bacteria appear to be Metronidazole sensitive G- anaerobes
• Antibiotics (Metronidazole or Ciprofloxacin)
• Probiotics VSL 3 (Gionchetti 1994)
–
–
–
–
4x
3x
1x
1x
lactobacilli
bifidobacteria
Strep Salivarius
S. thermaphiles
• Remission can be maintained in 92.5% at 9/12 Vs 0% in the
placebo group
Probiotic Therapeutic Mechanisms
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•
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•
Increasing the acidity (increases SCFAs)
Altering the hosts immune response at the GI mucosa
Produce antibiotic like substances (bacteriocins)
Increased IgA + IL 10 (anti-inflammatory)
Decreases IFNg and TNFa (pro-inflammatory)
Induces T cell shift towards Th2 (anti-inflammatory)
May competitively inhibit adherence of potentially
pathogenic bacteria
• Increase intestinal mucosa production
• Produce SCFAs and vitamins
Bowel Flora and IBD
• Crohn’s
–
–
–
Low bifidobacteria
Low lactobacilli
High E.coli (in active)
–
Low lactobacilli (in active)
–
High bacteriodes/toxins and E.coli (in active)
1
• UC
2
• IBD
1.
2.
3.
3
Giaffer M.H. et al. The assessment of faecal flora in patients with inflammatory bowel disease
by a simplified bacteriological technique. Journal of Medical Microbiology 35: 5224-5231
Fabia R. et al. Impairment of bacterial flora in human UC and expeimental colitis in the rat.
Digestion 54: 248-243
Swidsinski A. et al. Mucosal flora in inflammatory bowel disease. Gastroenterology 122: 44-54
Animal Studies of Probiotics in IBD
• Prevention
– Lactobacillus reuteri (acetic acid mice)1
– VSL 3 (IL10 deficient mice)2
• Treatment
– Lactobacilli x2 (methotrexate mice)3
– Better with oat fibre
1.
2.
3.
Fabia, R et al. The effects of exogenous administration o Lactobacillus reuteri R2LC and oat fibre on acetic
acid induced colitis in the rat. Scandinavian Journal of Gastroenterology 28: 155-162
Madsen, K.L et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function.
Gastroenterology 121580-591
Mao Y.S et al. The effects of Lacto bacillus strains and oat fibre on methotrexate induced enterocoliis in rats.
Gastroenterology 111: 334-344
Human Studies of Probiotics in UC
• UC Treament
– E.coli Nissle 1917 Vs Mesalazine for 1y
• Remission = 68% Vs 73%
• Relapses = 67% Vs 73%
– E.coli Nissle 1917 Vs Mesalazine for 1y
• n= 222
• Relapses = 36% Vs 33%
1.
2.
1
2
Rembacken B.J. et al. Non-pathogenic E.coli verses mesalazine for the treatment of UC, a randomised trial. Lancet 354: 635-639
Kruis W. et al. Maintainance of remission in UC is equally effective with E.coli Nissle 1917 as with standard mesalazine.
Gastroenterology 120 Suppl. 1:A127 (Abstr. 680)
Human Studies of Probiotics in CD
• E.coli Nissle 1917 1
• Reduced relapse rate
• allowed decrease/cessation in steroids
• Mesalazine + yeast Sacchromyces boulardii 2
• for 6/12
• 1/16 relapsed Vs 6/16 on mesalazine
alone
1.
2.
Malchow, Helmut A., 1997 Crohn’s disease and E.coli. Journal of Clinical Gastroenterology 25: 653-658
Guslandi M. et al. Saccharomyces boulardii in maintainance treatment of Crohn’s. Digestive Diseases and
Sciences 45: 1462-1464
Probiotic Trials in Acute Pouchitis
High dose of probiotics is effective in the treatment of mild pouchitis. A pilot study.
Amanidini C, Gionchetti P et al. Digestive and Liver Disease 2002; 34 (Suppl. 1):A96
• Abstract
• Positive results
• NB = Not written up into a paper ?why
Probiotic Trials in Chronic Pouchitis
Oral bacteriotherapy as maintainance therapy in patients wih chronic pouchitis: a double blind placebo
controlled trial. Giochetti P, et al. Gastroenterology 2000; 119:305-309
40 Patients
Placebo
6g VSL 3
n = 20
n = 20
n = 20
Relapse
n=0
Remission
after 9/12
n=3
n = 17
Trials of Probiotics as Prophylaxis
Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo controlled trial.
Giochetti P, et al. Gastroenterology 2000; 124: 1202-1209
40 Patients
Placebo
6g VSL 3
n = 20
n = 20
n=8
Pouchitis
40%
n=2
10%
n = 12
Remission
n = 18
60%
after 12/12
90%
Probiotics as od Maintainance
Once daily high high dose probiotic therapy maintaining remission in recurrent/refractory pouchitis.
Mimura T, et al. GUT 2004; 124: 108-114
36 Patients
Placebo
6g VSL 3
n = 16
n = 20
n = 15
Pouchitis
93%
n = 2, +1
15%
n=1
Remission
n = 17
7%
after 12/12
85%
What’s on Offer
Name
Strain
Implant Uses
Saccaromyces
boulardii
Yes
Actimel
L.casei strain
Yes
Stoneyfield
Yogurt
L.reiteri
Yes
Arla
L.acidophilus
Yes
L.rhamnosus
Yes
PrimaLiv
L.rhamnosus
Yes
Yakult
L.casei strain
Yes
Culturelle
L.casei GG
Yes
CDT
Pro Viva
L.plantarum
Yes
IBS
DN-114001
NCFB 1748
VTT E-97800
271
Shirota
299v
Diarrhoea
Prevention + Rx
Diarrhoea Rx
Where’s the Future Heading
• Pre-biotics
– “Non-Digestible Food (NDF) ingredients that
beneficially effect he host by selectively
stimulating the growth and/or activity of one
or a limited number of bacteria in the colon,
that can improve host health” 1 {Gibson G.
1995}
Prebiotics
NDOs = Non-Digestible Oligosaccharides 8-15g / d
– Average American diet = 5g / d
Such CHO – soluble fibre
• A) Encourages growth of beneficial (saccharolytic) bacteria
• B) Attract harmful (proteolytic) bacteria away from mucosa (gut
wall) by saturating the adhesin-CHO binding sites
Best NDO = Oligosaccharides eg in breast milk
Oligofructose increases bifido’s x10 1
• particularly if low to start (Crohn’s + UC)
1.
2.
2
Bouhnik Y. et al. Effects of fructo-oligosaccharide indigestion on faecal bifidobacteria and
selected metabolic indexes of colon carcinogenesis in healthy humans. Nutrition and Cancer 26:
21-29
Van Loo J. et al. Functional food properties of non-digestible oligosaccharide: a consensus
report from the ENDO project. British Journal of Nutrition 81: 121-132
Prebiotics Side Effects
• Flatulence + Bloating
• Rx = Gradually increase fibre with time
– Gradual increase in Bifidobacterium
– Decrease freely available NDF
– Decreases gas formed by other bacteria
Prebiotics and the Pouch
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•
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IBD
Lactosucrose 8.5g a day for 14/7
– Increase Bifidobacteria in 7/7 with IBD
Lactulose 1 12
– Increased lactobacilli
– Decreased colitis in mice
Pouchitis
Inulin 24g a day for 21/7 (crossover trial) 2 12
– Decreased inflammation in 19/19 pouches
1.
2.
Madsen L. et al. Lactobacillus species prevent colitis in IL10 gene-deficient mice.
Gastroenterology 116: 1107-1114
Welters C. et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa
in patients with ileal pouch anal anastamosis. Diseases of the colon and rectum 45: 621627
Natural Prebiotics
• Nutraceuticals = “functional foods”
• Inulin / Fructo-oligosaccharides / Lactulose
Transgalacto-oilgosaccharides
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Chicory (boiled root = 90% inulin)
Jerusalem artichoke
Onion
Leek
Garlic
Asparagus
Banana
(cereals eg. Oatmeal)
Natural Prebiotics
•
•
•
•
1)
2)
3)
4)
Isomalto-oligosaccharides (ISO) = Starch
Soyo-oligosaccharides (SOS) = Soya Beans
Xylo-oligosaccharides (XOS) = corn cobs
Lactosucrose (LS) = artificial sweeteners