Role of Probiotic in GI Disorders

Role of Probiotic in GI Disorders รองศาสตราจารย์นายแพทย์ สมชาย ลีลากุศลวงศ์ รองศาสตราจารย์แพทย์หญิง บุษบา วิวัฒน์เวคิน ศาสตราจารย์คลินิกนายแพทย์ อุดม คชินทร TS6®

2005 U.S. probiotic sales est. $764 million • 2010 expected to be $1.1 billion Yogurts, kefirs & cultured drinks 65.2% Nov.2006… • 2,810,000 Google web hits • 4,447 papers in 5 science databases  345 relate to probiotic safety 

Where “man meets microbe”a dynamic interplay • 400 sq meter surface area - Surface area of a tennis court • > 2 million genes in the bacterial genome vs 35,000 in the human - 100 trillion living bacteria in the human intestine - Over 500 species in human colon • Significant cross-talk” between bacteria and host - One bacteria species can turn on > 100 genes - Toll receptors on dendritic cells / macrophages - Gut contains complex neuroendocrine system

Predominant Flora: Stomach Stomach (0-103 cfu/ml): Gram+ aerobes, Lactobacillus & Streptococcus

Predominant Flora: Intestines Small intestine: Proximal ileum (103-104 cfu/ml) aerobic Gram+Distal ileum (1011-1012 cfu/ml) Gram- anaerobes Colon (1011-1012 cfu/ml): Bacteroides, Eubacteria, Peptostreptococci, E. coli, Bifidobacterium, Fusobacteria

Functions of Normal Flora • Digestion • Production of vitamins • Mucosal maturation • Stimulate Immune System • Attachment • Intestinal transit • Colonization resistance

Probiotics Terms: • Probiotic–Probiotics are live microorganisms (bacteria or yeasts) which, when administered in adequate amounts, confer a health benefit on the host • Prebiotic - nutritional supplement taken to increase the amounts of beneficial bacterial in the gut or vagina. Example “FOS” (fructose oligosaccharides) • Biotherapeutic agent- microorganism used for specific therapeutic activity in humans • Nutriceutical - food products with beneficial effects in preventing or treating diseases

Lactobacillus sp. reuteri casei ramnosus acidophilus Streptococcus sp. Bifidobacterium sp. infantis lactis longum breve bifidum Probiotics • A bacterial strain that: • -Human origin • -Survives the stomach acid and bile • -Adheres to intestinal lining • -Grows and establishes temporary • residence in the intestines • -Clinically demonstrated benefit • -Imparts health benefits • -Safe R Fuller. Probiotics: The Scientific Basis. London: Chapman and Halls. 1992

Select 6 Probiotic Strains TS6® Lactobacillus acidophilus Lactobacillus casei subsps ● Certificate of Analysis Bifidobacterium longum Bifidobacterium bifidus Bifidobacterium infantis Lactococcus lactis

PB PB PB Optimal mucosal barrier function Normal functional immune system Normal intestinal motility Balanced intestinal Flora, optimal host- microbe interaction • Insult • Acute pancreatitis • Major surgery • Trauma • Burns Disturbance of mucosal barrier function Disturbed immune system Disturbed intestinal motility Vicious circle Bacterial overgrowth Disturbed mucosal barrier function increase in bacterial translocation Infectious complications

Probiotics: Mechanisms of Action • Improve epithelial and mucosal barrier function - Produce SCFA - Enhance barrier - Enhance HSP - Helps maintain normal motility patients - Enhance mucosal blood flow - Enhances mucosal growth • Alter host immune response - Induce IL-10, TGF-b, - Stimulate sIgA production - Decrease TNF, IFN-λ, IL-8, p38 MAPK,IL-1 expression, NFkB (in cytosol and activation of PPAR-Y) - Active in regulation of T cells - Activates MALT - Enhance macrophage p y , g) function (cell free extracts and intact bacteria) • Inhibit growth of pathogenic enteric bacteria - Decrease luminal pH - Secrete bactericidal proteins - Stimulate defensin production - Occupy ecological niche • Block epithelial attachment or invasion by pathogens - Block epithelial binding by inducing MUC-2 - Stimulate mucous production to alter biofilm - Inhibit epithelial invasion, Rho dep and indep pathways • Elimination of pathogenic toxins - Several mechanisms (pH, proteolytic, binding) Adapted from Sartor: Curr Opin in Gastro 2005 Yan: Curr Opin in Gastro 2004

Probiotics: Exploring the MutuallyBeneficial Effects of Bacteria and TheirSubstrates in the Human Host Regulate local and systemic immune function Prevent infections (systemic and GI) Metabolic pathway nutrients: glycemic control, cholesterol, amino acids Regulate Inflammation, local and systemic Probiotics Support mucosal barrier Regulate appetite (leptin, ghrelin) Enhance nutrient utilization Regulate bowel motility Prevent neoplastic changes

Probiotics inhibits the growth of pathogens viaorganic acids and bacteriocins Bacteria • Escherichia coli (pathogenic) • Salmonella typhimurium • Shigella spp. • Campylobacter jejuni • Streptococcus mutans • Bacillus subtilis • Clostridium perfringens • Helicobacter pylori • Staphylococcus aureus • Listeria monocytogenes • Pseudomonas fluorescens Yeasts and fungi • Candida albicans • Fusarium samiaciens • Aspergillus flavus

After Reuteri intake Probiotics stimulate the immune system inthe small intestine of healthy subjects Before Reuteri intake Resting CD4+ T-helper cells Activated CD4+ T-helper cells • Valeur et al., Appl Environ Microbiol 2004

Does data support probiotic usein the clinical setting ? Clearly Yes but several factors are known to influence this benefit 1) Timing of probiotic delivery Prophylactic, empiric or therapeutic 2) Specific strain of bacteria Various secreted components can modulate activity (peptides, SCFA, NO, Bacteriocins, DNA) 3) Presence of fermentable substrate Prebiotics 4) Quantity of bacteria 5) Method of administration 6) Host factors

Probiotics can prevent, mitigate or treatmany of the current health crisis facing the world • Cancer - Multiple mechanisms • Heart disease - Metabolic syndrome - atherosclerosis • Depression • Hepatic diseases - NASH • Infectious disease • Diarrheal diseases - AAD - Bacterial - C.diff - Viral • Inflammatory diseases - IBD - Allergy - Asthma • Autoimmune diseases • Aging • Obesity • Critical Care - Trauma - Pancreatitis - Transplantation - Sepsis - VAP prevention

Clinical use of probiotic in adults รองศาสตราจารย์นายแพทย์ สมชาย ลีลากุศลวงศ์ • Clinical use of probiotic in pediatrics รองศาสตราจารย์แพทย์หญิง บุษบา วิวัฒน์เวคิน

Probiotics Summary • Living microorganisms with multiple mechanisms of action • Good safety profile • Some applications to prevent and treat infectious diseases • An alternative to antibiotics in some situations • May have other applications, e.g. allergy, cancer, colitis, IBS • Product selection is very important

Good evidence for: Infectious diarrhea Antibx-assoc diarrhea Promising evidence for: Prevention of infectious diarrhea Prevention of atopic conditions other uses? Prescribing Lactobacillus GG best studied to date Combination products not well studied, but may work as well 10 billion organisms/d Keep in fridge Give in cool food/drink 2% risk bloating/gas Take home points… In the future we may be using probiotics as we use antibiotics today: with specific strains used for certain clinical situations guided by controlled studies

Probiotic for Gastrointestinal Disease Somchai Leelakusolvong, M.D. GI Division, Dept of Medicine, Siriraj Medical School Siriraj Endoscopy Center Mahidol University E-mail: srsll@mahidol.ac.th MID-Year GAT Meeting, HUA HIN 25-07-2009

Objective • Definition and role of probiotic: Prof. Udom • Clinical use in pediatric patient: Prof. Budsaba • Clinical use in Adult patient • Gastrointestinal disease • Liver Disease

Role of Probiotics in Clinical Use • Immune • Allergy • Maintenance of Health • Gastrointestinal disease • Diarrhea • Antibiotic associated diarrhea • Inflammatory bowel disease (IBD) • Irritable bowel syndrome (IBS) • Liver disease • Hepatic encephalopathy • NAFLD • Other diseases • Radiation enteritis • H pylori infection • Cancer prevention

Probiotics: Candidates • Lactobacillus • acidophilus, reuteri, casei, plantarum, rhamnosus “GG”, bulgaricus, johnsonii, lactis • Bifidobacteria • bifidum, breve, infantis, longum, lactis, adolescentis • Streptococcus • thermophilus • Saccharomyces • Boulardii • Enterococcus faecalis, Bacillus cereus, Escherichia coli • Several combinations on the market • VSL#3, TS6

Combination Probiotics • TS 6 • Lactobacillus acidophilus • Lactococcus lactis • Lactobacillus casei subsp • Bifidobacterium bifidus • Bifidobacteruim longum • Bifidobacterium infantis

Probiotics and Diarrhea • Nonantibiotic-associated Diarrhea • Majority studies in children • Antibiotic-associated Diarrhea • Not due to Clostridium difficile • Recommended for PREVENTION in ambulatory and hospitalized adult patients • C. difficile-associated Diarrhea (CDAD) • Conflicting opinions on whether probiotics have any role in prevention of CDAD or Rx of initial or severe episode of CDAD

% C diffcile toxin infection % Diarrhea with C difficile ProbioticsClostridium difficile 138 hospitalized adults receiving antibiotics randomized to receive probiotics (Lactobacillus and Bifidobacterium) or placebo Plummer S. Int Microbiol, 2004 Plummer S Int Microbiol, 2004

Probiotics and AAD Relative risk of antibiotic-associated diarrhea in patients treated with Saccharomyces boulardii compared withplacebo NNT= 10 Szajewska H, et al. APT 2005;22:365-72

ProbioticsFor Prevention of AAD • Meta-analysis from 2810 patients, 25 RCT • 13 RCT (52%) demonstrated significant →  incidence of AAD vs placebo •  44% on adults group •  67% on pediatric group • Combined relative risk for AAD = 0.43 (95% CI 0.31-0.58) → significant protective effect of probiotics against AAD • Mainly use two probiotics • LGG • S. boulardii McFarland LV. Am J Gastro 2006;101:812-822

Diarrhea related chemotherapy of colorectal cancerL. rhamnosus GG for 24 wks with 5-FU based chemotherapy Osterlund P, et al. Br J of Cancer 2007;97:1028-1034

Probiotics: Inflammatory Bowel Diseases (IBD)For INDUCTION OF REMISSION in UC Mallon PT, et al. Cochrane Database of Systematic Reviews 2007, Issue 4.CD005573

Probiotics: Inflammatory Bowel Diseases (IBD)For INDUCTION OF REMISSION in CD Butterworth AD, et al. Cochrane Database of Systematic Reviews 2008, Issue 3,

Probiotics: Inflammatory Bowel Diseases (IBD) • For UC • Induction of remission= recommendation C • Trials limited open-label studies • Accumulating evidence suggestive it may be useful (E. coli Nissile and VSL#3) • Maintenance of remission= recommendation C • 2 large RCT using E. coli Nissle • E. coli Nissle similar efficacy to mesalamine • For CD • Reccommendation C for both induction and maintenance of remission • Small studies , open label • E. coli Nissle, S. boulardii, and LGG Fedorak RN, et al. J Clin Gastro 2008;42:S97-103

Probiotics: Inflammatory Bowel Diseases (IBD) • For Pouchitis • Induction of remission= recommendation C • High dose VSL#3 • Maintenance of remission= recommendation A • Pouchitis in ileal-pouch-anal anastomosis • Using VSL#3 Fedorak RN, et al. J Clin Gastro 2008;42:S97-103

Probiotics and IBSFecal flora in IBS sub group Malinen et al. Am J Gastro 2005;100:373-382

Probiotics and IBSEffect of VSL#3 on colonic transit time with significant bloating IBS VSL#3 significant retarded colonic transit time with normal stool form and consistency Kim HJ, et al. Neurogastro Motility 2005;17:687

Probiotics and IBS Weekly scores of flatulence and bloating run-in and in response to placebo or VSL#3 Kim HJ, et al. Neurogastroenterol Motil 2005;17:687

Probiotics and IBSRCT in IBS since 2000 Recommendation B (B infantis) or C Quigley EM, et al. J Clin Gastro 2008;42:S85-90

Probiotics: Immune response and Allergy • Immune response • Recommendation A • Definitely accepted in the treatment of childhood allergy and eczema • LGG and B. lactis Isolauri E, et al. J Clin Gastro 2008;42:S91-96

Probiotics: Other diseases • Necrotizing Enterocolitis • Radiation enteritis • Recommendation C • Limited studies • Vaginitis and Vaginosis • Recommendation C • LGG, L. reuteri and L. acidophilus • Helicobacter pylori gastritis Isolauri E, et al. J Clin Gastro 2008;42:S91-96

Probiotics and vaginitis Falagas ME, et al J Antimicrob Chemother 2006;58:266

Probiotics: Other diseases • Necrotizing Enterocolitis • Radiation enteritis • Recommendation C • Limited studies • Vaginitis and Vaginosis • Recommendation C • LGG, L. reuteri and L. acidophilus • Helicobacter pylori gastritis Isolauri E, et al. J Clin Gastro 2008;42:S91-96

Probiotics and H pyloriusing L. gasseri, assessing H pylori by UBT eradication rate = 87% vs 80% placebo with triple Rx Sakamoto I, et al. J Antimicrob Chemother. 2001;57:709-10

Probiotics and H pyloriImproved tolerance during H pylori eradication (triple Rx) Symptom score Probiotics Probiotics Myllyluoma E, et al. APT. 2005;21:1263

Probiotics and Liver disease • Prevention of infections • Reducing postorthotopic liver transplantation (OLT) infection (2 studies) • L.plantarum 299 • Synbiotic 2000 • Hepatic encephalopathy (4 studies) • Using E. faecium SF68 vs lactulose 4 wks •  serum ammonia and improvement in neurocognitive tests Loguercio C, et al. J Hepatol 1995;23:39 • Minimal improvement HE by using Synbiotic 2000 Liu Q, et al. Hepatology 2004;39:1441 • MHE 60 cirrhosis with fructo-oligosaccharide vs placebo Malaguarnera M, et al. DDS 2007;52:3259 Sheth AA, et al. J Clin Gastro 2008;42:S80-84

Role of Probiotic in GI Disorders