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 103 (cfu/g of dry weight stool) Ileum 105-8 Pouch 107-10 Caecum 1011-12

Pouch Flora The proportion of anaerobes increases distally Ileum = 1:1 (Anaerobe : aerobe) Caecum = 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 lactobacilli 3x bifidobacteria 1x Strep Salivarius 1x S. thermaphiles Remission can be maintained in 92.5% at 9/12 Vs 0% in the placebo group

Probiotic Therapeutic Mechanisms 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 UC IBD Low bifidobacteria Low lactobacilli High E.coli (in active) 1 UC Low lactobacilli (in active) 2 IBD High bacteriodes/toxins and E.coli (in active) 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 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 1 Remission = 68% Vs 73% Relapses = 67% Vs 73% E.coli Nissle 1917 Vs Mesalazine for 1y 2 n= 222 Relapses = 36% Vs 33% 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 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 n = 20 6g VSL 3 n = 20 n = 20 Relapse n = 3 n = 0 Remission after 9/12 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 n = 20 6g VSL 3 n = 20 n = 8 40% Pouchitis n = 2 10% n = 12 60% Remission after 12/12 n = 18 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 n = 16 6g VSL 3 n = 20 n = 15 93% Pouchitis n = 2, +1 15% n = 1 7% Remission after 12/12 n = 17 85%

What’s on Offer Name Strain Implant Uses Saccaromyces boulardii Yes Diarrhoea Prevention + Rx Actimel L.casei strain DN-114001 Stoneyfield Yogurt L.reiteri Diarrhoea Rx Arla L.acidophilus NCFB 1748 L.rhamnosus VTT E-97800 PrimaLiv L.rhamnosus 271 Yakult L.casei strain Shirota Culturelle L.casei GG CDT Pro Viva L.plantarum 299v IBS

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) 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 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 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: 621-627

Natural Prebiotics Nutraceuticals = “functional foods” Inulin / Fructo-oligosaccharides / Lactulose Transgalacto-oilgosaccharides Chicory (boiled root = 90% inulin) Jerusalem artichoke Onion Leek Garlic Asparagus Banana (cereals eg. Oatmeal)

Natural Prebiotics 1) Isomalto-oligosaccharides (ISO) = Starch 2) Soyo-oligosaccharides (SOS) = Soya Beans 3) Xylo-oligosaccharides (XOS) = corn cobs 4) Lactosucrose (LS) = artificial sweeteners