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PROBIOTICS

PROBIOTICS. Ricardo A. Caicedo, M.D. Pediatric Gastroenterology May 2006. Elie Metchnikoff 1845-1916. Bulgaria. Lactobacillus bulgaricus. Definitions. PROBIOTIC

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PROBIOTICS

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  1. PROBIOTICS Ricardo A. Caicedo, M.D. Pediatric Gastroenterology May 2006

  2. Elie Metchnikoff 1845-1916 Bulgaria Lactobacillus bulgaricus

  3. Definitions • PROBIOTIC • Live microorganism (or component such as DNA) which when consumed in adequate amounts, confers a health effect on the host (U.N. Food and Agriculture Organiz. (FAO)) • Prebiotic • Nutrient that promotes the growth of probiotic organisms • ex: oligosaccharides • Postbiotic • Metabolic product of probiotics that benefits host • ex: butyrate, short chain fatty acids • Synbiotic • Having properties of both a probiotic and a prebiotic • ex: human milk

  4. Synbiotics Human milk Prebiotics Probiotics Components of the developing intestinal ecosystem and factors in maintaining homeostasis between them.

  5. Trends • Widely used • Europe: frequently prescribed by physicians • U.S. • OTC • Health food stores • Rarely prescribed • Not well studied • 2005 ACG Meeting: subject of only 1 in > 1000 abstracts Floch, MH et al, J Clin Gastroenterol., 2006

  6. Mechanisms • THE “CROWDED BAR” PHENOMENON • Enhance/replete commensal microflora • Compete with pathogens • For nutrients • For adhesion to intestinal epithelium

  7. Mechanisms • “Crowded bar” • Promote synthesis of bacteriocidins • Strengthen intestinal barrier • Up-regulate tight junction protein synthesis • Increase mucus secretion • Enhance motility • Immunomodulatory • Decrease pro-inflammatory mediators (ex: IL-8) • Synthesis of anti-inflammatory omega-3 fatty acids

  8. Examples of Probiotic Preparations

  9. Not all are created equal… Considerable differences in… • Bioavailability • Dose • Composition • Biological activity • Cost

  10. Infectious diarrhea Community-acquired Nosocomial Antibiotic-associated diarrhea Clostridium difficile disease Inflammatory bowel disease Ulcerative colitis Crohn’s disease Pouchitis Irritable bowel syndrome Necrotizing enterocolitis Helicobacter pylori disease Hepatic encephalopathy Atopic disorders Bacterial vaginosis UTI Radiation enteritis Clinical Trials

  11. Caveats In vitro effects of probiotics may not necessarily correlate with those in vivo Actual number of viable microorganisms in commercial probiotic products may be lower than advertised Most clinical trials of probiotics have involved adult patients

  12. Quality of evidence • Type I: from > 1 properly designed RCT • Type II • II-1: from well-designed cohort or case-controlled trials • II-2: from well-designed cohort or case-control analytic studies, preferably from > 1 center • II-3: from multiple time series with/without the intervention • Type III: from opinions of respected authorities, based on clinical experience or descriptive studies

  13. Clinical Grade ACG Recommendations on Probiotic Use (Floch MH et al, J Clin Gastroenterol 2006; 40:275-8) A Strong positive controlled studies B Suggestive evidence, but some negative studies C Inadequate studies to be certain

  14. Pouchitis • Inflammation of ileal reservoir created after colectomy + ileal pouch anal anastomosis • VSL #3 • Prevention of relapse (15% relapse rate vs. 100% in placebo group) • Maintenance of remission (85% vs. 6%) • Increased bacterial/decreased fungal diversity • LGG ineffective in controlled trial

  15. Pouchitis A Table: Michail S, Fuchs G, Sherman P, Clinical efficacy of probiotics: Review of the evidence with a focus on children: A Nutrition Committee Report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, 2006

  16. Ulcerative Colitis C+ Mild-moderate Low 5-ASA dose: 1500mg/d Prevention of relapse N = 18 N =21 Table: Michail S, Fuchs G, Sherman P, Clinical efficacy of probiotics: Review of the evidence with a focus on children: A Nutrition Committee Report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, 2006

  17. Crohn’s Disease C • LGG may improve stable, mild-mod. CD – based on pilot study • Larger RCT: LGG did not prolong time to relapse Table: Michail S, Fuchs G, Sherman P, Clinical efficacy of probiotics: Review of the evidence with a focus on children: A Nutrition Committee Report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, 2006

  18. Short-term follow-up Some symptomatic improvement IBS C Table: Michail S, Fuchs G, Sherman P, Clinical efficacy of probiotics: Review of the evidence with a focus on children: A Nutrition Committee Report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, 2006

  19. Antibiotic-associated diarrhea A • Reduction by 60% • LGG efficacious in children • S. boulardii in adults • NNT = 10 • LGG not effective in hospitalized adults Meta-analysis D’Souza Al et al, Br Med J. 2002; 324:1361.

  20. Clostridium difficile A- • May help prevent relapse in severe/recurrentC. difficile disease • S. boulardii (1 g/d X 28 d)+ standard abx1 • S. boulardii + high-dose PO vancomycin2 • LGG in small open-label pediatric trial 3 • McFarland LV et al. JAMA 1994; 271:1913-8. • Surawicz CM et al.. Clin Infect Dis. 2000; 31:1012 • Biller JA et al. JPGN 1995; 21:224-6.

  21. Acute Infectious DiarrheaTREATMENT A Huang, JS et al. Dig Dis Sci, 2002; 47:2625-34. In most trials, LGG reduced duration of mild-moderate infectious diarrhea by about 1 day

  22. Community-acquired LGG reduced diarrhea bouts/child/yr1 no sig. difference in no. days with diarrhea 2 Modest reduction of # days absence due to GE and URI Nosocomial LGG RCT3 N=81, age 1-36 m Decreased risk of rotavirus GE NNT = 7 Protective effect not seen in larger RCT (N=220)4 Acute infectious diarrheaPREVENTION B 1. Michail S et al, NASPGHAN 2006. 3. Szajewska H et al.. J Pediatr. 2001; 138:361-5. 2. Hatakka K et al. BMJ 2001; 322:1327. 4. Mastretta E et al. J Pediatr Gastroenterol Nutr. 2002; 35:527-31.

  23. Necrotizing enterocolitis B • Reduced incidence of NEC associated with administration of probiotics in a NICU (Hoyos et al. Int. J. Infectious Dis., 1999) • Decreased NEC and death in RCT of probiotic administration (Lin et al. Pediatrics, 2005) • RCT of daily probiotic suppl. in VLBW neonates: RRR 75%, NNT = 8 (Bin-Nun et al. J. Pediatr., 2005) • Italian multi-center trial (N=565) showed no significant protective effect (Dani et al. Biol. Neonate, 2002)

  24. Summary Grade recommendation A C C C A A- A B B C Table: Michail S, Fuchs G, Sherman P, Clinical efficacy of probiotics: Review of the evidence with a focus on children: A Nutrition Committee Report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, 2006

  25. Safety • Have been used safely in immunocompromised adults (HIV, LTx)1 • Bacteremia/fungemia • Multiple case reports • Indwelling CVL • Preterm infants • Nosocomial spread • Lactic acidosis • Lactobacilli can produce D-lactate, leading to neurological sx2 • Rayes N et al. Am J Transplant 2005; 5:125-30. • Mack DR. Can J Gastroenterol. 2004; 18:671-5.

  26. Future Issues • Multi-center pediatric and neonatal trials • Dose determination • Head-to-head comparison of products • Viable vs. heat or UV-inactivated • Safety

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