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

2. Lactobacillus bulgaricus
Elie Metchnikoff
Bulgaria
After much research, he was convinced that he had discovered why so many Bulgarians lived noticeably longer than other people. This phenomenon, he theorized, was due to their consumption of large quantities of cultured foods, especially yogurt, which he believed, help maintain the benign ("friendly") bacteria that live in the gastrointestinal tract.
Dr. Metchnikoff was among the first to recognize the relationship between disease and what he called the "poisons" produced in the bowel. He demonstrated how friendly living bacteria normalize bowel habits and fight disease-carrying bacteria, thereby extending the normal life span. His book persuaded many that living longer is the happy result of an intestinal tract that maintains a healthy daily supply of the cultured bacteria found in yogurt. It was Dr. Metchnikoff who named the primary yogurt-culturing bacteria Lactobacillus bulgaricus , in honor of the yogurt-loving Bulgarians.
Lactobacillus bulgaricus

3. Definitions PROBIOTIC Prebiotic Postbiotic Synbiotic
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 Not well studied
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
NAME
COMMENT
Bifidobacteria
brevis, longum, lactis, infantis
E. coli Nissle 1917
Nonpathogenic strain
Lactobacillus
acidophilus, bulgaricus, casei, plantarum, rhamnosus, LGG
Saccharomyces boulardii
yeast
VSL #3
Combination of 8 different probiotic bacteria

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

10. Clinical Trials Infectious diarrhea Antibiotic-associated 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

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: 1500 mg/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. IBS C Short-term follow-up Some symptomatic improvement
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
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 difficileA-
May help prevent relapse in severe/recurrent C. 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:
Surawicz CM et al.. Clin Infect Dis. 2000; 31:1012
Biller JA et al. JPGN 1995; 21:224-6.

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

22. Acute infectious diarrhea PREVENTIONB
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
1. Michail S et al, NASPGHAN Szajewska H et al.. J Pediatr. 2001; 138:361-5.
2. Hatakka K et al. BMJ 2001; 322: Mastretta E et al. J Pediatr Gastroenterol Nutr. 2002; 35:

23. Necrotizing enterocolitisB
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. A C C C A A- A B B C Summary Grade recommendation
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:
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