1、Probiotics: A “New” Approach to Gastrointestinal Health and Disease,Douglas A. Jacobstein, MD Division of GI & Nutrition The Sinai Hospital of Baltimore,Yahoo! My Yahoo! Mail Welcome, Guest Sign InSearch Home Help,WebImagesVideoDirectoryLocalNewsShopping My Web BETA | Search Services | Advanced Sear
2、ch | Preferences Search Results Results 1 - 10 of about 2,350,000 for probiotics - 0.03 sec. (About this page) Also try: benefits of probiotics, best probiotics, natren probiotics More. SPONSOR RESULTS Essential Blend Probiotics 25 billion active bacteria. Compare-no dirt-no FOS. Costs less to take
3、than others. Primal Defense Probiotics: 30% Off Primal Defense is a probiotic blend of HSOs that optimizes digestive health. See the book “Restoring Your Digestive Health“ for treatment info. Free shipping and free book. Probiotics-Save 40 to 80% Improve digestion with Acidophilus. 40-80% off majo
4、r brands of vitamins and supplements. S&H only $4.95. Free shipping on orders of $75 or more. 24/7 customer service. No sales tax. ,Objectives,Introduce the concept of probiotics, prebiotics, and synbiotics Give a brief history of probiotics List some of the potential uses Infectious diarrhea Antibi
5、otic associated diarrhea Inflammatory bowel disease Give some insight to the practical considerations when using them,Probiotics Definition,Nutritional supplement Contains 1 or more cultures of living organisms Typically bacteria or yeast Modify the endogenous microflora Have a positive effect on th
6、e host,Prebiotics Definition,Nondigestible food ingredients Fructo-oligosaccharides (chicory, inulin) Lactulose Positively affect the endogenous flora Stimulate the growth of one or a limited number of bacterial species FOSBifidobacteria LactuloseLactobacilli,Synbiotics Definition,A probiotic organi
7、sm in combination with its prebiotic food Providing both the organism and substrate at the time of ingestion may offer improved chance of survival in GI tract,Intestinal Flora,1012 viable bacteria/gram of large bowel content More than total cells in the human body More than total humans who have eve
8、r lived At least 17 families At least 50 genera 400-500 species in any single person 80-90% unculturable,Probiotics 19th Century,Pasteur (1877) Observed antagonistic interaction between bacterial strains Suggested that non-pathogenic bacteria should be used to control pathogenic bacteria,Probiotics
9、Early 20th Century,Metchnikoff (1907) Observed that lactic fermentation of milk arrested putrefaction Suggested that consumption of fermented products would offer the same benefit to humans Felt that longevity in Bulgarian peasants was due to ingestion of “soured milks”,Probiotics Mid to late 20th C
10、entury,1950s, Ferdinand Vergin publishes article discussing effects of antibiotics on beneficial intestinal bacteria1980s Fuller establishes first definition of probiotics,Probiotics Candidates,Lactobacillus acidophilus, reuteri, casei, planatarum, rhamnosus “GG” Bifidobacteria bifidum, breve, infan
11、tis, longum Streptococcus thermophilus Saccharomyces Several combinations on the market,Probiotics Potential Mechanisms of Action,Inhibition of adhesion Immunomodulation Production of antimicrobial substances Modification of toxins or toxin receptors Competition for nutrients Reduction in bacterial
12、translocation Anti-inflammatory signaling within the epithelium,Probiotics Many Potential Uses,Infectious diarrhea and day care related illness Antibiotic Associated Diarrhea Clostridium difficile Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome,Probio
13、tics Many Potential Uses,Infectious diarrhea and day care related illness Antibiotic Associated Diarrhea Clostridium difficile Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome,U.S. Daycare Statistics,National Household Surveys Education Program (NHES),
14、 U.S. Department of Education, 2002,Day Care and Childhood Infection,It has long been suspected that early exposure to other children increases the risk of communicable diseases I Diehl, “The prevalence of colds in nursery school children and non-nursery school children.” J Pediatr 34:52-61, 1949,Im
15、pact of Day Care Center Illness,Children in day care 4.5 times more likely to be hospitalized1 Cost of $2307 (1998 dollars) per diarrhea-associated hospitalization2 Child illness accounts for up to 40% of adult absenteeism from work1 0.52 days lost per month for day care vs. 0.37 days for children i
16、n other childcare1DM Bell, et al. Am J Public Health 79:479-84, 1989 2CM Zimmerman, et al. Pediatr Infect Dis J 20(1):14-9, 2001,Day Care Means Increased Risk of Gastrointestinal Infections,Estimated crude incidence density of diarrhea among children in home care, family day care, and DCCs. From: Lo
17、uhiala. J Pediatr 131(3):476-9, 1997,Potential Methods to Reduce Day Care Center Morbidities,Prevention of infections Respiratory and gastrointestinal Treatment of infections Reduce transmission of disease Probiotics may positively influence each of these methods Stimulating the immune system Reduci
18、ng viral shedding,Prevention of Diarrheal Illness,18 Week Therapy in French Children (6-24 months) in Day Care,CA Pedone, et al. Int J Clin Pract 54(9):568-71, 2000,Prevention of Diarrheal Illness,12 Week Therapy in Israeli Infants (4-10 months) in Day Care,Z Weizman, et al. Pediatrics 115:5-9, 2005
19、,Treatment of Acute Diarrhea,5 Day Therapy in Danish Children (9 to 44 months) in Day Care with Acute Diarrhea,V Rosenfeldt, et al. Pediatr Infect Dis J 21:417-9, 2002,Whole Study Group,Treatment of Acute Diarrhea,5 Day Therapy in Danish Children (9 to 44 months) in Day Care with Acute Diarrhea,V Ro
20、senfeldt, et al. Pediatr Infect Dis J 21:417-9, 2002,Early Intervention (60 hours),Rotavirus Diarrhea,Affects 70% of children up to age 51 Approximately 50,000 hospitalizations annually in the U.S. in children under 5 years of age1 Most common cause of infectious diarrhea in community settings2 High
21、est proportion in children 12 to 36 months Symptoms typically last 3-8 days3 Viral shedding up to 21 days after onset of symptoms1AW Tucker, et al. JAMA 279(17): 1371-6, 1998 2V Waters, et al. Pediatr Infect Dis J 19(9): 843-8, 2000 3LK Pickering, ed. Red Book, 26th ed.: 534-6, 2003,Probiotics Infec
22、tious Diarrhea,Children up to 2 years of age in chronic care facility Randomized to receive B. bifidum and S. thermophilus or placebo Statistically less diarrhea (7% vs 31%) Statistically less rotavirus shedding (10% vs 39%),Saavedra et al, Lancet 1994,Probiotics Antibiotic Associated Diarrhea,Commo
23、n side effect of antibiotic therapy Up to 40% of children receiving broad spectrum antibiotic therapy Mechanism Likely due to altered microbial flora Leads to altered metabolism of osmotically active substances,Probiotics Antibiotic Associated Diarrhea,188 children 6 months to 10 years of age random
24、ized to receive Lactobacillus GG versus placebo while receiving oral antibiotics Significant differences in patients who had diarrhea were seen (26% placebo vs 8% probiotic),Vanderhoof J et al, J Pediatr, 1999,Vanderhoof J et al, J Pediatr, 1999,Vanderhoof J et al, J Pediatr, 1999,Prevention of Diar
25、rheal Illness (After Antibiotics for Respiratory Illness),2 Week Therapy in Finnish Children (2 weeks to 12 years),T Arvola, et al. Pediatrics 104(5), 1999,Probiotics Antibiotic Associated Diarrhea,S. boulardii Reduced rate of diarrhea in 116 patients versus placebo Lactobacillus GG Decreased diarrh
26、ea in people treated with triple therapy for H. pylori Found to reduce days of diarrhea and side effects when coadministered with erythromycin in healthy volunteers,Probiotics Clostridium difficile,Second most common cause of bacterial diarrhea (25% of cases) Commonly precipitated by antibiotic use
27、or disruption of endogenous flora Positive response to LGG in patients with recurrent infection Successful prevention of recurrence with S. boulardii,Probiotics Clostridium difficile,138 hospitalized adults receiving antibiotics randomized to receive probiotics (Lactobacillus and Bifidobacterium) or
28、 placebo Patients receiving probiotics were less likely to have C. difficile toxin (46% vs 78%) Patients who developed diarrhea were less likely to have C. difficile toxin (2.9% vs 7.25%),Plummer S Int Microbiol, 2004,Probiotics Many Potential Uses,Infectious diarrhea and day care related illness An
29、tibiotic Associated Diarrhea Clostridium difficile Inflammatory bowel disease Travelers diarrhea Prevention of NEC Allergy Irritable Bowel Syndrome,Chronic Inflammation: Imbalance Between Mediators,Pro-inflammatory,Anti-inflammatory,TNFa,IL-1b,IL-8,IL-12,IFNg,TGFb,IL-10,IL-1Ra,IL-4/IL-13,The Develop
30、ment of Inflammatory Bowel Disease,Initiating Event,Damage,Abnormal Immune Response,Ongoing Inflammation,What is the “initiating event?”,Bacteria in IBD,Normal intestinal bacteria may cause inflammation to start In people without IBD, the body turns off the inflammation In people with IBD, the body
31、cannot turn off the inflammation The process continues until something stops it,Bacteria and IBD The Evidence,Special mice bred to develop IBD Stay healthy in sterile (bacteria-free) conditions Get sick when given “normal” intestinal bacteria,Bacteria and IBD The Evidence,Diversion (ostomy) Healing
32、occurs when stool is diverted Inflammation returns when bowel is put back together Antibiotics Certain antibiotics that work against the intestinal bacteria help improve IBD The newly discovered IBD gene (Nod2) Involved in the bodys response to bacteria,From Fedorak RN and Madsen KL Inflamm Bowel Di
33、s, 2004,Probiotics in IBD: Pouchitis,J Pouch,Probiotics in IBD: Pouchitis,People with a history of “pouchitis” after colectomy 20 people given VSL3 20 people given placeboAfter 9 months: 3 out of 20 on VSL3 had a flare of pouchitis 20 out of 20 who received placebo had a flare,Ginochetti et al, Gast
34、roenterology, 2000,P 0.001,Probiotics in IBD: Pouchitis,Remission of pouchitis with antibiotics 36 patients randomized to receive VSL#3 or placebo Followed for 12 months 85% of probiotic group in remission at 1 year versus 6% of placebo group (p 0.001),Mimura et al, Suppl to Gastroenterology, 2002,P
35、robiotics in IBD Preliminary Studies,Ulcerative colitis patients All given steroids 59 given mesalamine (Pentasa, Asacol) 57 given a probiotic Remission rates similar (75% vs. 68%) Relapse rates similar (73% vs. 67%) Length of remission similar (206 days vs. 221 days),Rembacken et al Lancet, 1999,Pr
36、obiotics in IBD Preliminary Studies,4 pediatric patients with active Crohns disease Given Lactobacillus GG for 6 months Patients had improvement in disease activity Patients had improvement in intestinal permeability,Gupta et al, J Pediatr Gastroenterol Nutr, 2000,Probiotics in IBD Preliminary Studi
37、es,Open-label trial in adults with active Crohns Received Lactobacillus salivarius instead of corticosteroids 25 patients enrolled 19 patients avoided other therapies for 3 monthsDisease activity score decreased from 217 to 150,McCarthy et al, Gut 2001,Lactobacilli and Bifidobacteria Why They Are Sa
38、fe,Many exposures in pediatrics Fermented foods Probiotics The hosts own microflora Oral cavity Ileum and colon Vagina,Cases of infection extremely rare Account for 0.05% to 0.4% of infective endocarditis and bacteremia Less than 1 case per million people Review of 143 human clinical trials from 196
39、1-1988 Over 7500 subjects No reported adverse events,Lactobacilli and Bifidobacteria Why They Are Safe,Lactobacilli and Bifidobacteria Why They Are Safe,Increasing probiotic consumption has not led to increased opportunistic infections National Public Health Institute-Finland 1995-1999 Increasing ca
40、ses of bacteremia (all types) Increasing use of probiotics Constant level of Lactobacillus bacteremia,Probiotics Safe, however.,Several reports of fungemia associated with use of yeast-based probiotics (S. boulardii) Difficult to determine pathogenicity Virulence factors for pathogens (adherence, co
41、lonization) are common in probiotic bacteria When bacteremia occurs, often polymicrobial and in critically ill host,Invasive Lactobacillus Infection,Occasional reports of invasive infections Bacteremia (rare) Endocarditis: 16 reported cases (1992-2001) 5 cases with yogurt or probiotic Only 1 confirm
42、ed to be identical to probiotic Liver abscess (74 yo woman) Daily consumption of probiotic drink Indistinguishable from probiotic strain,Probiotics Practical Issues,Purified strains of bacteria Selected for ability to: Survive acid/bile in upper GI tract Colonize Adhere Must have shelf viability Sho
43、uld have quality control,Probiotics Practical Issues,Not FDA regulated Quality control is poor 80% of preparations tested had 1% or less of the bacterial concentration on the label Numerous preparations on the market Which strains work best? Do different strains work better for different diseases? D
44、o combinations work better than single strains?,Probiotics Practical Issues,Typically $1 to $3 per day VSL3: $56 for 20 day supply Culturelle (LGG): $55 for 30 day supply Custom Probiotics CP-1: $40 for 30 day supply May need several months of therapy to see an effect Likely stop working after disco
45、ntinued Concentration (dose) highly variable,Probiotics Summary,An old concept, with a new attitude Potential therapy for many GI related diseases Largely unproven, but growing body scientific evidence Patients will need guidance as to which ones to use, when to use them, how to use them,Probiotics
46、Necrotizing Enterocoltis,Randomized, controlled trial in 367 VLBW infants Received breast milk with probiotic (Lactobacillus and Bifidobacterium) versus breast milk alone Incidence of NEC lower in probiotic group (1.1% versus 5.3%, p= 0.04) with cases of severe NEC in control group versus none in probiotic group,Lin et al, J Pediatr, 2005,
