Probiotics Probiotics and and PouchitisPouchitis

What it all about?What it all about?

Dr. Matt. JohnsonDr. Matt. Johnson

History of the IAPouchHistory of the IAPouch

• 1944 Proctocolectomy + Ileostomy 1944 Proctocolectomy + Ileostomy (Strauss + Strauss)(Strauss + Strauss)

• 1969 Intra-Abdominal Ileal Reservoir 1969 Intra-Abdominal Ileal Reservoir (Kock)(Kock)

• 1978 Restorative Proctocolectomy 1978 Restorative Proctocolectomy – (Parks + Nicholls)(Parks + Nicholls)

• 1987 J-Pouch Modification 1987 J-Pouch Modification – (Nicholls)(Nicholls)

• A Normal PouchA Normal Pouch

Pathological changes within a Pathological changes within a normal Healthy Pouchnormal Healthy Pouch

• 6/526/52– plasma cell infiltrationplasma cell infiltration– Later = lymphocyte infiltrationLater = lymphocyte infiltration

• 6/126/12– Villous atrophyVillous atrophy

• >6/12>6/12– ““Normal adaptation” to “colonic type Normal adaptation” to “colonic type

mucosa”mucosa”– Tendency to colonic metaplasia Tendency to colonic metaplasia

Pouch FloraPouch Flora

• Flora (10x as much bacteria as cells in the body)Flora (10x as much bacteria as cells in the body)• 55% of stool = bacteria55% of stool = bacteria• Bacteria feed on undigested food by a process of Bacteria feed on undigested food by a process of

fermentationfermentation

– Prox jejunum Prox jejunum 10103 3 (cfu/g of dry weight (cfu/g of dry weight stool)stool)

– Ileum Ileum 10105-85-8

– Pouch Pouch 10107-107-10

– Caecum Caecum 101011-12 11-12

Pouch FloraPouch Flora

• The proportion of anaerobes increases distally The proportion of anaerobes increases distally

– Ileum = Ileum = 1:1 1:1 (Anaerobe : aerobe)(Anaerobe : aerobe)– Caecum = Caecum = 1000:1 1000:1

– Ileal Pouch = Ileal Pouch = 100:1100:1•Colonic type flora (bacterioides, Colonic type flora (bacterioides,

bifidobacteria)bifidobacteria)

Pouchitis SymptomsPouchitis Symptoms

• A) Post Op Stool FrequencyA) Post Op Stool Frequency• B) Rectal BleedingB) Rectal Bleeding• C) Faecal Urgency* +/- CrampsC) Faecal Urgency* +/- Cramps• D) Fever (unusual)D) Fever (unusual)

• * usually due to inflammation at the distal/efferent * usually due to inflammation at the distal/efferent limb of the pouchlimb of the pouch

• There is often poor correlation between symptoms There is often poor correlation between symptoms and either the endoscopic or histology appearance and either the endoscopic or histology appearance

• PouchitisPouchitis

Aetiology of PouchitisAetiology of Pouchitis

• Bacterial profiles are genetically determined and Bacterial profiles are genetically determined and remain stable lifelongremain stable lifelong

• Response to Antibiotics suggests a pathogenic role Response to Antibiotics suggests a pathogenic role for bacteriafor bacteria

• Diverting ileostomy is therapeutic in CD (recurs 6/12 Diverting ileostomy is therapeutic in CD (recurs 6/12 post re-anastamosis)post re-anastamosis)

• Pouchitis = Pouchitis = – no difference in number of bacteria (qualitative stool no difference in number of bacteria (qualitative stool

studies)studies)– no difference in type of bacteria (quantitative stool studies)no difference in type of bacteria (quantitative stool studies)– hightened immunogenicity in UC patients (EGIM of IBD)hightened immunogenicity in UC patients (EGIM of IBD)– loss of tolerance to normal bacterialoss of tolerance to normal bacteria

• No longer able to distinguish between normal and pathogenic organismsNo longer able to distinguish between normal and pathogenic organisms

Clinical PatternClinical Pattern

• After 6/12 patients fall into 3 After 6/12 patients fall into 3 catagories;catagories;

• 1) No pouchitis (45%)1) No pouchitis (45%)

• 2) Relapsing + Remiting Pouchitis 2) Relapsing + Remiting Pouchitis (42%)(42%)

• 3) Chronic Pouchitis (13%)3) Chronic Pouchitis (13%)– > 4/52> 4/52– Recurrent courses of antibiotics neededRecurrent courses of antibiotics needed

Therapy for PouchitisTherapy for Pouchitis

• There appears to be a bacterial precipitantThere appears to be a bacterial precipitant• These bacteria appear to be Metronidazole sensitive G- These bacteria appear to be Metronidazole sensitive G-

anaerobes anaerobes

• Antibiotics (Metronidazole or Ciprofloxacin)Antibiotics (Metronidazole or Ciprofloxacin)

• Probiotics VSL 3 (Gionchetti 1994)Probiotics VSL 3 (Gionchetti 1994)– 4x lactobacilli4x lactobacilli– 3x bifidobacteria3x bifidobacteria– 1x Strep Salivarius1x Strep Salivarius– 1x S. thermaphiles1x S. thermaphiles

• Remission can be maintained in 92.5% at 9/12 Vs 0% in Remission can be maintained in 92.5% at 9/12 Vs 0% in the placebo groupthe placebo group

Probiotic Therapeutic Probiotic Therapeutic MechanismsMechanisms• Increasing the acidity (increases SCFAs)Increasing the acidity (increases SCFAs)• Altering the hosts immune response at the GI Altering the hosts immune response at the GI

mucosamucosa• Produce antibiotic like substances (bacteriocins)Produce antibiotic like substances (bacteriocins)• Increased IgA + IL 10 (anti-inflammatory)Increased IgA + IL 10 (anti-inflammatory)• Decreases IFNg and TNFa (pro-inflammatory)Decreases IFNg and TNFa (pro-inflammatory)• Induces T cell shift towards Th2 (anti-inflammatory)Induces T cell shift towards Th2 (anti-inflammatory)• May competitively inhibit adherence of potentially May competitively inhibit adherence of potentially

pathogenic bacteriapathogenic bacteria• Increase intestinal mucosa productionIncrease intestinal mucosa production• Produce SCFAs and vitamins Produce SCFAs and vitamins

Bowel Flora and IBDBowel Flora and IBD

• Crohn’sCrohn’s– Low bifidobacteriaLow bifidobacteria– Low lactobacilliLow lactobacilli– High E.coli (in active) High E.coli (in active) 11

• UCUC– Low lactobacilli (in active) Low lactobacilli (in active) 22

• IBDIBD– High bacteriodes/toxins and E.coli (in active) High bacteriodes/toxins and E.coli (in active) 33

1.1. Giaffer M.H. et al. The assessment of faecal flora in patients with inflammatory bowel disease by a 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: 5224-5231simplified bacteriological technique. Journal of Medical Microbiology 35: 5224-5231

2.2. Fabia R. et al. Impairment of bacterial flora in human UC and expeimental colitis in the rat. Fabia R. et al. Impairment of bacterial flora in human UC and expeimental colitis in the rat. Digestion 54: 248-243Digestion 54: 248-243

3.3. Swidsinski A. et al. Mucosal flora in inflammatory bowel disease. Gastroenterology 122: 44-54 Swidsinski A. et al. Mucosal flora in inflammatory bowel disease. Gastroenterology 122: 44-54

Animal Studies of Probiotics in Animal Studies of Probiotics in IBDIBD

• Prevention Prevention – Lactobacillus reuteri (acetic acid mice)Lactobacillus reuteri (acetic acid mice)11

– VSL 3 (IL10 deficient mice)VSL 3 (IL10 deficient mice)22

• Treatment Treatment – Lactobacilli x2 (methotrexate mice)Lactobacilli x2 (methotrexate mice)33

– Better with oat fibreBetter with oat fibre

1.1. Fabia, R et al. The effects of exogenous administration o Lactobacillus reuteri R2LC and oat fibre 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: 155-162on acetic acid induced colitis in the rat. Scandinavian Journal of Gastroenterology 28: 155-162

2.2. Madsen, K.L et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier Madsen, K.L et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121580-591function. Gastroenterology 121580-591

3.3. Mao Y.S et al. The effects of Lacto bacillus strains and oat fibre on methotrexate induced Mao Y.S et al. The effects of Lacto bacillus strains and oat fibre on methotrexate induced enterocoliis in rats. Gastroenterology 111: 334-344enterocoliis in rats. Gastroenterology 111: 334-344

Human Studies of Probiotics in Human Studies of Probiotics in UCUC• UC Treament UC Treament

– E.coli Nissle 1917 Vs Mesalazine for 1y E.coli Nissle 1917 Vs Mesalazine for 1y 11

• Remission = 68% Vs 73%Remission = 68% Vs 73%• Relapses = 67% Vs 73%Relapses = 67% Vs 73%

– E.coli Nissle 1917 Vs Mesalazine for 1y E.coli Nissle 1917 Vs Mesalazine for 1y 22

• n= 222n= 222• Relapses = 36% Vs 33%Relapses = 36% Vs 33%

1.1. Rembacken B.J. et al. Non-pathogenic E.coli verses mesalazine for the treatment of UC, a randomised trial. Lancet Rembacken B.J. et al. Non-pathogenic E.coli verses mesalazine for the treatment of UC, a randomised trial. Lancet 354: 635-639354: 635-639

2.2. Kruis W. et al. Maintainance of remission in UC is equally effective with E.coli Nissle 1917 as with standard 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)mesalazine. Gastroenterology 120 Suppl. 1:A127 (Abstr. 680)

Human Studies of Probiotics in Human Studies of Probiotics in CDCD• E.coli Nissle 1917 E.coli Nissle 1917 11

• Reduced relapse rateReduced relapse rate• allowed decrease/cessation in steroidsallowed decrease/cessation in steroids

• Mesalazine + yeast Sacchromyces boulardii Mesalazine + yeast Sacchromyces boulardii 22

• for 6/12for 6/12• 1/16 relapsed Vs 6/16 on mesalazine 1/16 relapsed Vs 6/16 on mesalazine

alonealone

1.1. Malchow, Helmut A., 1997 Crohn’s disease and E.coli. Journal of Clinical Gastroenterology 25: 653-658Malchow, Helmut A., 1997 Crohn’s disease and E.coli. Journal of Clinical Gastroenterology 25: 653-6582.2. Guslandi M. et al. Saccharomyces boulardii in maintainance treatment of Crohn’s. Digestive Diseases Guslandi M. et al. Saccharomyces boulardii in maintainance treatment of Crohn’s. Digestive Diseases

and Sciences 45: 1462-1464and Sciences 45: 1462-1464

Probiotic Trials in Acute Probiotic Trials in Acute PouchitisPouchitisHigh dose of probiotics is effective in the treatment of mild pouchitis. A pilot study.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):A96Amanidini C, Gionchetti P et al. Digestive and Liver Disease 2002; 34 (Suppl. 1):A96

• Abstract Abstract

• Positive resultsPositive results

• NB = Not written up into a paper ?NB = Not written up into a paper ?whywhy

Probiotic Trials in Chronic Probiotic Trials in Chronic PouchitisPouchitis

Oral bacteriotherapy as maintainance therapy in patients wih chronic pouchitis: a double 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 blind placebo controlled trial. Giochetti P, et al. Gastroenterology 2000; 119:305-309

Placebo

n = 20

6g VSL 3

n = 20

40 Patients

n = 20

n = 0

n = 3

n = 17

Relapse

Remission

after 9/12

Trials of Probiotics as Trials of Probiotics as ProphylaxisProphylaxis

Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo controlled Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo controlled trial. trial.

Giochetti P, et al. Gastroenterology 2000; 124: 1202-1209 Giochetti P, et al. Gastroenterology 2000; 124: 1202-1209

Placebo

n = 20

6g VSL 3

n = 20

40 Patients

n = 8

40%

n = 12

60%

n = 2

10%

n = 18

90%

Pouchitis

Remission

after 12/12

Probiotics as od MaintainanceProbiotics as od MaintainanceOnce daily high high dose probiotic therapy maintaining remission in recurrent/refractory Once daily high high dose probiotic therapy maintaining remission in recurrent/refractory

pouchitis. pouchitis. Mimura T, et al. GUT 2004; 124: 108-114 Mimura T, et al. GUT 2004; 124: 108-114

Placebo

n = 16

6g VSL 3

n = 20

36 Patients

n = 15

93%

n = 1

7%

n = 2, +1

15%

n = 17

85%

Pouchitis

Remission

after 12/12

What’s on OfferWhat’s on OfferNameName StrainStrain ImplanImplan

ttUsesUses

Saccaromyces Saccaromyces boulardiiboulardii

YesYes DiarrhoeaDiarrhoea

Prevention + Prevention + RxRx

ActimelActimel L.casei strainL.casei strain DN-114001DN-114001

YesYes

Stoneyfield Stoneyfield YogurtYogurt

L.reiteriL.reiteri YesYes Diarrhoea RxDiarrhoea Rx

ArlaArla L.acidophilusL.acidophilus NCFB 1748NCFB 1748

YesYes

L.rhamnosusL.rhamnosus VTT E-97800VTT E-97800

YesYes

PrimaLivPrimaLiv L.rhamnosusL.rhamnosus 271271

YesYes

YakultYakult L.caseiL.casei strain strain Shirota Shirota

YesYes

CulturelleCulturelle L.caseiL.casei GG GG YesYes CDTCDT

Pro VivaPro Viva L.plantarumL.plantarum 299v299v

YesYes IBSIBS

Where’s the Future HeadingWhere’s the Future Heading

• Pre-bioticsPre-biotics– ““Non-Digestible Food (NDF) ingredients Non-Digestible Food (NDF) ingredients

that beneficially effect he host by that beneficially effect he host by selectively stimulating the growth selectively stimulating the growth and/or activity of one or a limited and/or activity of one or a limited number of bacteria in the colon, that number of bacteria in the colon, that can improve host health” can improve host health” 11 {Gibson G. {Gibson G. 1995}1995}

PrebioticsPrebiotics

NDOs = Non-Digestible Oligosaccharides 8-15g / dNDOs = Non-Digestible Oligosaccharides 8-15g / d– Average American diet = 5g / dAverage American diet = 5g / d

Such CHO – soluble fibreSuch CHO – soluble fibre• A) Encourages growth of beneficial (saccharolytic) bacteriaA) Encourages growth of beneficial (saccharolytic) bacteria• B) Attract harmful (proteolytic) bacteria away from mucosa (gut B) Attract harmful (proteolytic) bacteria away from mucosa (gut

wall) by saturating the adhesin-CHO binding siteswall) by saturating the adhesin-CHO binding sites

Best NDO = Oligosaccharides eg in breast milk Best NDO = Oligosaccharides eg in breast milk Oligofructose increases bifido’s x10 Oligofructose increases bifido’s x10 1 1

• particularly if low to start (Crohn’s + UC) particularly if low to start (Crohn’s + UC) 22

1.1. Bouhnik Y. et al. Effects of fructo-oligosaccharide indigestion on faecal bifidobacteria and 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 selected metabolic indexes of colon carcinogenesis in healthy humans. Nutrition and Cancer 26: 21-2926: 21-29

2.2. Van Loo J. et al. Functional food properties of non-digestible oligosaccharide: a consensus Van Loo J. et al. Functional food properties of non-digestible oligosaccharide: a consensus report from the ENDO project. British Journal of Nutrition 81: 121-132report from the ENDO project. British Journal of Nutrition 81: 121-132

Prebiotics Side EffectsPrebiotics Side Effects

• Flatulence + BloatingFlatulence + Bloating

• Rx = Gradually increase fibre with Rx = Gradually increase fibre with time time – Gradual increase in Bifidobacterium Gradual increase in Bifidobacterium – Decrease freely available NDFDecrease freely available NDF– Decreases gas formed by other bacteria Decreases gas formed by other bacteria

Prebiotics and the PouchPrebiotics and the Pouch

• IBDIBD• Lactosucrose 8.5g a day for 14/7Lactosucrose 8.5g a day for 14/7

– Increase Bifidobacteria in 7/7 with IBDIncrease Bifidobacteria in 7/7 with IBD• Lactulose 1 12Lactulose 1 12

– Increased lactobacilliIncreased lactobacilli– Decreased colitis in miceDecreased colitis in mice

• Pouchitis Pouchitis • Inulin 24g a day for 21/7 (crossover trial) 2 12Inulin 24g a day for 21/7 (crossover trial) 2 12

– Decreased inflammation in 19/19 pouchesDecreased inflammation in 19/19 pouches

1.1. Madsen L. et al. Lactobacillus species prevent colitis in IL10 gene-deficient mice. Madsen L. et al. Lactobacillus species prevent colitis in IL10 gene-deficient mice. Gastroenterology 116: 1107-1114Gastroenterology 116: 1107-1114

2.2. Welters C. et al. Effect of dietary inulin supplementation on inflammation of pouch 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 mucosa in patients with ileal pouch anal anastamosis. Diseases of the colon and rectum 45: 621-627 45: 621-627

Natural PrebioticsNatural Prebiotics

• Nutraceuticals = “functional foods” Nutraceuticals = “functional foods” • Inulin / Fructo-oligosaccharides / Lactulose Inulin / Fructo-oligosaccharides / Lactulose

Transgalacto-oilgosaccharidesTransgalacto-oilgosaccharides

• Chicory (boiled root = 90% inulin)Chicory (boiled root = 90% inulin)• Jerusalem artichokeJerusalem artichoke• Onion Onion • LeekLeek• GarlicGarlic• AsparagusAsparagus• BananaBanana• (cereals eg. Oatmeal)(cereals eg. Oatmeal)

Natural PrebioticsNatural Prebiotics

• 1) Isomalto-oligosaccharides (ISO) = 1) Isomalto-oligosaccharides (ISO) = StarchStarch

• 2) Soyo-oligosaccharides (SOS) = Soya 2) Soyo-oligosaccharides (SOS) = Soya BeansBeans

• 3) Xylo-oligosaccharides (XOS) = corn 3) Xylo-oligosaccharides (XOS) = corn cobs cobs

• 4) Lactosucrose (LS) = artificial 4) Lactosucrose (LS) = artificial sweetenerssweeteners