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Probiotics in GI Tract Disease <ul><li>Hala Fatima M.D. </li></ul><ul><li>Assistant Professor of Clinical Medicine </li></...
What are Probiotics? <ul><li>Live microorganisms which when administered in adequate amounts confer a health benefit to th...
Interaction of Probiotics and Microflora
Antibiotic Associated Diarrhea <ul><li>A recent meta-analysis (34 placebo controlled trials) concluded that probiotics are...
Antibiotic Associated Diarrhea <ul><li>Not all studies used the same definition of AAD </li></ul><ul><li>Pooled analysis i...
Antibiotic Associated Diarrhea <ul><li>McFarland LV  et al.  diarrhea and the treatment of Clostridium Meta-analysis of pr...
Antibiotic Associated Diarrhea In Children <ul><li>A meta-analysis of RCT showed that probiotics reduce the risk of AAD in...
Clostridium Difficile Diarrhea <ul><li>McFarland LV  et al.  Meta-analysis of probiotics for the prevention of antibiotic ...
Inflammatory Bowel Disease <ul><li>Pouchitis: level 1 evidence </li></ul><ul><li>UC &CD: levels 2 & 3 evidence </li></ul>
Probiotics in Inflammatory Bowel Disease
Maintenance of Medical-Induced Remission of Crohn’s Disease Reference Study n Duration Probiotic Control Relapse rate (Pro...
Treatment of Acute Active Crohn’s Disease Reference Study n Duration Probiotic Control Remission rate (Probiotic) Remissio...
Maintenance of Surgical-Induced Remission of Crohn’s Disease Reference Study n Duration Probiotic Control Relapse rate (Pr...
Maintenance of Remission in Ulcerative Colitis Reference Study n Duration Probiotic Control Response to Probiotic (Remissi...
Treatment of Acute Ulcerative Colitis Reference Study n Duration Probiotic Control Response to Probiotic (Remission) Respo...
Pouchitis <ul><li>Maintenance of antibiotic-induced remission </li></ul><ul><li>Treatment of acute active pouchitis </li><...
Clinical Trials in Pouchitis: Maintenance of Anti-biotic Induced Remission VSL#3:  4 strains of Lactobacillus (acidophilus...
Clinical Trials in Pouchitis: Acute Active Pouchitis Reference Study n Duration Probiotic Control Response to Probiotic (R...
Clinical Trials in Pouchitis: Post-Operative Prevention Reference Study n Duration Probiotic Control Response to Probiotic...
Pouchitis <ul><li>Gionchetti P  et al.High-dose probiotics for the treatment of active pouchitis.  Dis Colon Rectum. 2007 ...
Irritable Bowel Syndrome <ul><li>Several controlled trials, all short-term, modest magnitude of benefit </li></ul><ul><li>...
Irritable Bowel Syndrome <ul><li>VSL#3 reduced bloating ; no effect on pain, gas or urgency (Kim et al. Aliment Pharmacol ...
Other GI Disorders <ul><li>Lactose Intolerance:  </li></ul><ul><ul><li>Meta-analysis show inconsistent results (Levri et a...
Safety (2) <ul><li>Infection: extremely rare- represent 0.05% -0.4% of infective endocarditis or bacteremia </li></ul><ul>...
Safety (2) <ul><li>Reports of Saccharomyces cervisiae fungemia; some with CVC as the playing a role </li></ul><ul><li>Pros...
Summary (1) <ul><li>Probiotics are effective in reducing the incidence of antibiotic induced diarrhea; no definite informa...
Summary (2) <ul><li>Evidence for use strongest in pouchitis esp. with VSL#3. Reasonable option along with medical therapy....
Summary (3) <ul><li>Irritable bowel syndrome — benefit of probiotics remains unproven. Bifidobactrium infantis </li></ul><...
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Probiotics in GI Tract Disease

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Probiotics in GI Tract Disease

  1. 1. Probiotics in GI Tract Disease <ul><li>Hala Fatima M.D. </li></ul><ul><li>Assistant Professor of Clinical Medicine </li></ul><ul><li>Department of Medicine </li></ul><ul><li>Division of Gastroenterology/Hepatology </li></ul><ul><li>Indiana University School of Medicine </li></ul>
  2. 2. What are Probiotics? <ul><li>Live microorganisms which when administered in adequate amounts confer a health benefit to the host </li></ul><ul><li>Not all have similar therapeutic effects </li></ul>
  3. 3. Interaction of Probiotics and Microflora
  4. 4. Antibiotic Associated Diarrhea <ul><li>A recent meta-analysis (34 placebo controlled trials) concluded that probiotics are associated with: </li></ul><ul><ul><li>52% decrease in antibiotic-associated diarrhea </li></ul></ul><ul><ul><li>8% reduction in traveler’s diarrhea </li></ul></ul><ul><ul><li>57% reduction in risk of acute diarrhea in kids and 26% in adults </li></ul></ul><ul><ul><li>Effects did not vary significantly among the probiotic strains </li></ul></ul><ul><ul><li>Sazawal S et al.Efficacy of probiotics in prevention of acute diarrhea: a meta-analysis of masked, randomized, placebo-controlled trials. Lancet Infect Dis. 2006 Jun;6(6):374-82. </li></ul></ul>
  5. 5. Antibiotic Associated Diarrhea <ul><li>Not all studies used the same definition of AAD </li></ul><ul><li>Pooled analysis included all diarrhea cases whether or not they were due to C difficile </li></ul><ul><li>Insufficient data to suggest dose and duration of the probiotic preparation </li></ul>
  6. 6. Antibiotic Associated Diarrhea <ul><li>McFarland LV et al. diarrhea and the treatment of Clostridium Meta-analysis of probiotics for the prevention of antibiotic associated difficile disease. Am J Gastroenterol. 2006 Apr;101(4):812-22 </li></ul><ul><ul><li>25 RCTs, total of 2810 patients with AAD </li></ul></ul><ul><ul><li>13 studies(52%) reported a significant reduction of AAD in probiotic treated group compared with placebo; 12 studies showed no difference </li></ul></ul>Probiotic # of RCT p value Saccharomyces boulardii 6 <0.0001 Lactobacillus rhamnosus GG 6 0.006 Single strains 6 0.06 Mixtures of two probiotics 7 <0.0001
  7. 7. Antibiotic Associated Diarrhea In Children <ul><li>A meta-analysis of RCT showed that probiotics reduce the risk of AAD in children; for every 7 pts that would develop diarrhea while being treated with antibiotics, one fewer will develop AAD if also receiving probiotics. </li></ul><ul><li>Szajewska H et al.Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials. J Pediatr. 2006 Sep;149(3):367-372. </li></ul>
  8. 8. Clostridium Difficile Diarrhea <ul><li>McFarland LV et al. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006 Apr;101(4):812-22 </li></ul><ul><ul><li>Six RCTs for treatment of CDD, total of 354 patients; all adults: 3 trials exclusively for recurrent CDD </li></ul></ul><ul><ul><li>2 trials (33%) showed a significant reduction in CDD recurrences in the probiotic treated group as compared with placebo; 4 studies showed no difference </li></ul></ul><ul><ul><li>Only Saccharomyces boulardii showed significant reduction in recurrences. Lactobacillus rhamnosus GG and Lactobacillus plantarum did not show significant differences </li></ul></ul><ul><li>A Pillai et al. Cochrane Database of Systematic Reviews 2008 </li></ul><ul><ul><li>Four studies examined the use of probiotics in conjunction with conventional antibiotics (vancomycin or metronidazole) for the treatment of recurrence or an initial episode of C. difficile colitis in adults. </li></ul></ul><ul><ul><li>Insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for C. difficile colitis. No evidence to support the use of probiotics alone in the treatment of C. difficile colitis. </li></ul></ul>
  9. 9. Inflammatory Bowel Disease <ul><li>Pouchitis: level 1 evidence </li></ul><ul><li>UC &CD: levels 2 & 3 evidence </li></ul>
  10. 10. Probiotics in Inflammatory Bowel Disease
  11. 11. Maintenance of Medical-Induced Remission of Crohn’s Disease Reference Study n Duration Probiotic Control Relapse rate (Probiotic) Relapse rate (Placebo) p value Malchow et al. 1997 RCT 28 12 months E.Coli Nissle Placebo Response: 70% Response:30% ns Guslandi et al. 2000 Open-label 32 6 months Saccharomyces boulardii + mesalamine 2g/d Mesalamine 3g/d Response: 94% Relapse 6% Response:38% Relapse 38% 0.04 Schultz et al. 2004 RCT, DB 11 6 months LGG Placebo 60% 67% ns Bousvarous et al. 2005 RCT, DB 75 24 months LGG Placebo (inulin) 31% 17% 0.18
  12. 12. Treatment of Acute Active Crohn’s Disease Reference Study n Duration Probiotic Control Remission rate (Probiotic) Remission rate (Placebo) p value Malchow et al.1997 RCT 28 12 weeks Steroid taper +E.Coli Nissle Placebo No difference - Gupta et al.2000 Open-label 4 children 24 weeks LGG n/a 100% n/a - McCarthy et al.2001 Open-label 25 12 weeks Lactobacillus salivarius n/a 76% n/a - Fujimori et al. 2007 Open-label 10 13 months Synbiotic mixture: Bifidobacterium Breve, lactobacillus casei, Bifidobacterium longum and psyllium n/a Significant improvement n/a -
  13. 13. Maintenance of Surgical-Induced Remission of Crohn’s Disease Reference Study n Duration Probiotic Control Relapse rate (Probiotic) Relapse rate (Placebo) p value Campieri et al.2000 RCT, OL 40 12 months 3 mo of rifaximin followed by 9 mo of VSL#3 (6g) 12 mo of Mesalamine 20% Response: endoscopic 80% 40% Response: endoscopic 60% 0.05 Prantera et al. 2002 RCT, DB 45 12 months LGG Placebo 17% Response: clinical 83%; endoscopic 40% 11% Response: clinical 89%; endoscopic 65% 0.30 Marteau et al.2006 RCT, DB 98 6 months L. johnsonii Placebo 49% 64% 0.15 Van Gossum et al. 2007 RCT, DB 70 3 months L. johnsonii Placebo 15% 14% 0.91
  14. 14. Maintenance of Remission in Ulcerative Colitis Reference Study n Duration Probiotic Control Response to Probiotic (Remission) Response to Placebo (Remission) p value Rembacken et al. 1999 RCT, DB 116 12 months Escherichia coli Nissle 1917 Mesalamine 1.2g/d 26% 25% ns Kruis et al. 1997 RCT, DB 120 4 months Escherichia coli Nissle 1917 Mesalamine 1.5g/d 84% 89% 0.012 Kruis et al. 2004 RCT, DB 327 12 months Escherichia coli Nissle 1917 Mesalamine 1.5g/d 55% 64% ns Venturi et al. 1999 Open-label 20 12 months VSL#3 (6g) None 75% n/a n/a Ishikawa et al. 2003 RCT 21 12 months Yakult fermented milk Placebo 73% 10% 0.018 Cui et al. 2004 RCT, DB 30 8 months Bifidobacteria Placebo Relapse: 20% Relapse: 93% <0.01 Zocco et al. 2006 R, Open-label 180 12 months LGG LGG + meselamine 2.4g/d Mesalamine 2.4g/d Relapse: 15% Relapse: 20% 0.77 Shanahan et al. 2006 (abs) RCT, DB 157 12 months L .salivarius B .infantis Placebo No significant benefit -
  15. 15. Treatment of Acute Ulcerative Colitis Reference Study n Duration Probiotic Control Response to Probiotic (Remission) Response to Placebo (Remission) p value Rembacken et al. 1999 RCT 116 3 months Prednisone taper + gentamicin + E.coli Nissle Prednisone taper + gentamicin + mesalamine 1.2g/d 68% 75% ns Matthes et al. 2006 RCT, DB 90 1 month E.coli Nissle enema (10, 20, 40 ml) Placebo Dose-dependent response(27, 44, 53% resp) 18% 0.04 Fedorak et al. 2003 Open-label 30 4 months VSL#3 n/a 63% n/a n/a Biblioni et al. 2005 Open-label 34 1.5 month VSL#3 n/a 53% n/a n/a Tursi et al. 2004 R, Open-label 90 2 months VSL#3 + balsalazide 2.25g/d Balsalazide 4.5g/d Mesalamine 2.4g/d 80% 77% 53% 0.02 Guslandi et al. 2003 Open-label 25 1 month Saccharomyces boulardii n/a 68% n/a n/a Kato et al. 2004 RCT, DB 20 3 months Fermented milk Placebo 40% 30% ns Borody et al. 2003 Open-label 6 1 week Fecal enemas QDX5 days; retained for 6-8 hrs n/a 100% remission off std meds by 4 mo; disease free for 1-13 years FUP n/a n/a
  16. 16. Pouchitis <ul><li>Maintenance of antibiotic-induced remission </li></ul><ul><li>Treatment of acute active pouchitis </li></ul><ul><li>Postoperative prevention of pouchitis </li></ul>
  17. 17. Clinical Trials in Pouchitis: Maintenance of Anti-biotic Induced Remission VSL#3: 4 strains of Lactobacillus (acidophilus, plantarum, casei, bulgaricus) 3 strains of Bifidobacterium(breve, longum, infantis) 1 strain of Streptococcus thermophilus Reference Study n Duration Probiotic & daily dose Control Response to Probiotic (Remission) Response to Placebo (Remission) p value Gionchetti et al. 2000 RCT, DB 40 9 months VSL#3 (6 g) Placebo 85% 0% <0.001 Mimura et al. 2004 RCT, DB 36 12 months VSL#3 (6 g) Placebo 85% 6% <0.001 Shen et al. 2005 Open-label 31 8 months VSL#3 (6 g) None n/a -
  18. 18. Clinical Trials in Pouchitis: Acute Active Pouchitis Reference Study n Duration Probiotic Control Response to Probiotic (Remission) Response to Placebo (Remission) p value Kuisma et al. 2003 RCT, DB 20 3 months Lactobacillus rhamnosus GG Placebo 0% 0% ns Gosselink et al. 2004 Open -label 117 36 months Lactobacillus rhamnosus GG Historical controls Relapse rate: 8% Relapse rate: 35% 0.01 Laake et al. 2003 Open-label 10 1 month Cultura None 50% endoscopic improvement; no histologic improvement n/a - Laake et al. 2005 Open-label 51 1 month Cultura None Significant decrease in GI symptoms p<0.0005; decrease in eye symptoms p=0.02 59% remission n/a -
  19. 19. Clinical Trials in Pouchitis: Post-Operative Prevention Reference Study n Duration Probiotic Control Response to Probiotic (Remission) Response to Placebo (Remission) p value Gionchetti et al. 2003 RCT, DB 40 12 months VSL#3 (3g) Placebo 90% Relapse: 10% 60% Relapse: 40% <0.05
  20. 20. Pouchitis <ul><li>Gionchetti P et al.High-dose probiotics for the treatment of active pouchitis. Dis Colon Rectum. 2007 Dec;50(12):2075-82 </li></ul><ul><ul><li>23 patients with mild pouchitis (PDAI score of 7-12) </li></ul></ul><ul><ul><li>Treated with VSL#3, 2 sachets b.i.d. (3,600 billion bacteria/day) X 4 weeks </li></ul></ul><ul><ul><li>After remission treated with VSL#3, 1 sachet b.i.d. (1,800 billion bacteria), as maintenance treatment X 6 months </li></ul></ul><ul><ul><li>16/23 patients (69%) were in remission after treatment. </li></ul></ul><ul><ul><li>Conclusion: High doses of the probiotic VSL#3 are effective in the treatment of mild pouchitis </li></ul></ul>
  21. 21. Irritable Bowel Syndrome <ul><li>Several controlled trials, all short-term, modest magnitude of benefit </li></ul><ul><li>Bifidobacterium infantis significantly more effective than placebo. However, benefit confined to only one of three doses tested; no clear dose-response relationship (Whorwell et al. Am J Gastroenterol 2006) </li></ul><ul><li>Lactobacillus plantarum reduced flatulence, better overall GI function maintained at 12 months. No effect on abdominal pain (Nobaek et al. Gastroenterol 2000) </li></ul><ul><li>Combination of Lactobacillus plantarum and Bifidobacterium breve . Pain and severity scores decreased significantly in the probiotic group after 14 days of treatment (Saggioro et al. J Clin Gastroenterol 2004) </li></ul>
  22. 22. Irritable Bowel Syndrome <ul><li>VSL#3 reduced bloating ; no effect on pain, gas or urgency (Kim et al. Aliment Pharmacol Ther 2003) </li></ul><ul><li>Lactbacillus GG – no benefit (O’Sullivan et al. Dig Liver Dis 2000) </li></ul><ul><li>Multispecies probiotic :Lactobacillus rhamnosus GG, L. rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermanii JS and Bifidobacterium animalis. The composite irritable bowel syndrome score had at 5 months decreased 14 points from baseline vs. 3 points with placebo (P = 0.0083). Especially, distension and abdominal pain were affected.(Kajander et al. Aliment Pharmacol Ther 2007) </li></ul>
  23. 23. Other GI Disorders <ul><li>Lactose Intolerance: </li></ul><ul><ul><li>Meta-analysis show inconsistent results (Levri et al. J Fam Pract 2005) </li></ul></ul><ul><ul><li>Benefit remains unproven. </li></ul></ul><ul><li>Collagenous Colitis: </li></ul><ul><ul><li>Possible benefit of E.coli Nissle 1917 (Tromm et al. Z Gastroenterol 2004) </li></ul></ul><ul><ul><li>Placebo-controlled trial: Combination of Lactobacillus acidophilus and Bifidobacterium animalis caused improvement in symptoms but had no significant effect on primary endpoints (Wildt et al.Inflamm Bowel Dis 2006) </li></ul></ul><ul><ul><li>Meta- analysis Cochrane Database Syst Rev. 2008 : No evidence for the effectiveness probiotics. </li></ul></ul><ul><li>Diverticular Colitis: </li></ul><ul><ul><li>Combination of VSL#3 and an oral beclomethasone was beneficial in a case series </li></ul></ul>
  24. 24. Safety (2) <ul><li>Infection: extremely rare- represent 0.05% -0.4% of infective endocarditis or bacteremia </li></ul><ul><li>Reported case of liver abscess caused by lactobacillus rhamnosus (500 ml/d). Recovered with surgical drainage and antibiotics. </li></ul><ul><li>Bacteremia reported in premature babies with short-gut syndrome </li></ul><ul><li>Cannon et al. Eur J Clin Microbiol Infect Dis 2005. </li></ul><ul><ul><li>Review of 200 cases of lactobacillus infection 1950-2003; 114 cases of bacteremia </li></ul></ul><ul><ul><li>Mortality rate 32% </li></ul></ul><ul><ul><li>All patients had significant morbidity including malignancy </li></ul></ul><ul><ul><li>62 cases of IE with 22.9% mortality rate. </li></ul></ul>
  25. 25. Safety (2) <ul><li>Reports of Saccharomyces cervisiae fungemia; some with CVC as the playing a role </li></ul><ul><li>Prospective study from Finland reported that the marked increase in consumption of probiotics has not led to an increased rate of opportunistic infection </li></ul><ul><li>Most of the cases are in immunocompromised patients or those with serious underlying disease states, malignancy, prior surgery or on hyperalimentation. </li></ul><ul><li>Antibiotic resistance - theoretic risk </li></ul><ul><li>Overall safe and well-tolerated. </li></ul>
  26. 26. Summary (1) <ul><li>Probiotics are effective in reducing the incidence of antibiotic induced diarrhea; no definite information available regarding dose or timing – not recommended routinely </li></ul><ul><li>Unclear if probiotics can shorten the period of diarrhea in those who have already developed it </li></ul><ul><li>Studies for C diff treatment or prevention are inconclusive - routine use cannot be recommended due to reports of Saccharomyces fungemia </li></ul><ul><li>Reasonable to recommend probiotics to adults and children with presumed infectious diarrheal illness with the hope of reducing the duration of symptoms by 17 to 30 hours </li></ul>
  27. 27. Summary (2) <ul><li>Evidence for use strongest in pouchitis esp. with VSL#3. Reasonable option along with medical therapy. Long-term efficacy uncertain. </li></ul><ul><li>E.coli Nissle equivalent to 5 ASA in UC and may be used as enemas for distal disease. Could be considered in patients intolerant or resistant to 5-ASA preparations </li></ul><ul><li>Studies of probiotics in CD have been disappointing and a recent systematic review has concluded that their use could not be recommended on the available evidence (Rolfe et al. 2006) </li></ul>
  28. 28. Summary (3) <ul><li>Irritable bowel syndrome — benefit of probiotics remains unproven. Bifidobactrium infantis </li></ul><ul><li>H.pylori — Probiotics not recommended in the treatment or as an adjunct for eradication </li></ul>

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