Probiotics in GI Tract Disease

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  • Resident microflora act as a barrier that prevents colonization of opportunistic and pathogenic microorganisms. Changes in the GI bacterial population caused by diet, antibiotics or other factors can alter enteric and systemic immune function
  • Normal microflora and probiotics interact with the host in metabolic activities and immune function and prevent colonization of opportunistic and pathogenic microorganisms
  • These contradictory results may have been due to the differences in the study population enrolled, type of probiotic, the dose of probiotic or the duration of treatment 44% of adult studies showed efficacy of probiotics and 67% of children studies showed efficacy. Two single probiotics showed significant efficacy for AAD: Saccharomyces boulardii and Lactobacillus rhamnosus GG. Also mixtures of two probiotics showed significant efficacy. The meta-analysis for other single probiotic strain preparations was not significantly protective for AAD, but the strains were diverse and so clinical conclusions should be made with caution.
  • Several lines of experimental evidence implicate enteric flora in the pathogenesis of ulcerative colitis and Crohn’s disease: incidence of inflammation is greatest in the area of highest bacterial concentrations; interruption of fecal stream is associated with disease improvement; inflammation and mucosal ulceration can be induced by direct instillation of fecal contents form an inflamed gut into a non-inflamed gut of susceptible individuals and many other proposed mechanisms. In each of these models, enteric flora is required for the induction of the inflammatory process, regardless of the underlying genetic predisposition or immunologic defect.
  • Competitive exclusion: probiotics compete with microbial pathogens for a limited number of receptors present on the surface epithelium Immuno-modulation of GALT
  • Evidence for the use of probiotics in the maintenance of CD is not persuasive, with only Guslandi study reporting positive results. Malchow et al.: Investigated the role of E coli in pts with corticosteroid-induced remission. 28 pts with CDAI >150 were treated with prednisolone 60 mg/d in a standard tapering regimen over 14 weeks. Pts were randomized at the beginning of the steroid therapy to receive either E.coli or placebo for 1 yr. Intent to treat analysis. Initial remission rate was 92% with placebo and 86% with E.coli (ns). Once remission was achieved with steroids, the % of pts that remained in remission at the end of 1 yr was 70% in the E.coli group and 30% in the placebo group (ns) Guslandi et al.: Examined the role of Sacchromyces boulardii. Pts were in medical induced remission for at least 3 mo CDAI<150; were off all meds for 3 mo at the time of entry into the study. They were then randomized to receive mesalamine alone or mesalamine+Sacchromyces boulardii for 6 mo. Clinical remission was seen in 10/16 pts on mesalamine alone in 15/16 in pts on mesalamine+Sacchromyces. This was an encouraging result in contrast to the previous study. Two studies using LGG have not confirmed the effectiveness. In the study by Bousvaros et al. 7% of intervention group and 20% of placebo group were found to have high fecal concentrations of lactobacilli. They used inulin as the placebo which is a prebiotic that could have masked any difference in efficacy between the groups
  • Very few RCT for probiotics in Crohn’s disease Malchow et al showed no difference in the time needed to induce remission (median 21 days in E coli group vs. 23 days in placebo) and no difference in induction of remission (75% E coli and 92% placebo) Gupta et al: Children with mild to moderately active disease with PCDAI >10 in conjunction with concomitant therapy with prednisone and immunomodulatory agents. Significant improvement in PCDAI score 1week later and the improvement was sustained throughout the 6 mo of the study. In 3 pts, it was possible to taper the dose of steroids. 3 pts had relapse within 4-12 weeks of d/c lactobacillus McCarthy et al: Pts were given the opportunity to use lactobacillus salivarius instead of steroids. 25 enrolled; 4 dropped out due to exacerbation; 2 required corticosteroid therapy. 19 completed 3 months of treatment and were able to avoid other therapy. CDAI in these pts fell from a mean of 217 at entry to 150 at 3 months.
  • The study by Campieri et al is the only study that has shown benefit of VSL#3 in preventing post-op recurrence. Prantera et al showed no benefit. Two randomized DB controlled trials using lactobacillus johnsonii have reported no effect in preventing recurrence in pts with surgically induced remission.
  • The first 3 studies show probiotics are similar to conventional 5 ASA in maintenance of remission. So, probiotics like E coli Nissle which have equivalent efficacy but fewer side effects than conventional drug therapies present an appealing alternative for pts and physicians. Several studies examining the use of lactobacilli or bifidobacteria have demonstrated conflicting results: Venturi: 75% remission. Significant concentrations of probiotics in fecal cultures. Only 20% relapsed. Ishikawa: Yakult fermented milk:L ( Bifidobacterium breve, Bifidobacterium bifidum, Lactobacillus acidophilus) Despite the significant difference in clinical remission rates, there were no significant differences in the colonoscopic findings at 1 year Cui: Lower relapse rates with probiotics. Probiotic arm had increased fecal concentrations of lactobacilli and bifidobacteria Zocco : Both lactobacillus arms had a prolonged relapse free time compared to 5 ASA, despite no sig diff in the overall relapse rates Shanahan: No significant benefit of either of the probiotics when compared to placebo
  • Rembacken: Randomized pts to mesalamine or E.coli Nissle. At entry, all pts were traeted with a 1 wk course of PO gentamicin to suppress their native E.coli flora. They continued their PO or rectal steroids as well and after entering remission, they were maintained on either mesalamine or E.coli for up to 12 months. Response was similar with both therapies. Median time to remission and median duration of remission was similar in both groups. Matthes: E coli enemas used in pts with left sided UC. There was a significant dose-dependent response and the time to remission was also reported to be the shortest in the group receiving the highest dose. Fedorak: These pts had failed meselamine therapy. Clinical score of <3 was achieved in 63%; 23% responded but score was >3. 13% had no response. This represents a significant improvement in a difficult to treat population Biblioni: Showed response, however, VSL#3 organisms were found in only 3/11 pts on microbiological exam of the mucosal biopsy. This finding suggests that the clinical effect observed was not the result of a direct influence if VSL#3-derived organisms at the mucosa. Tursi: Remission rates and time to remission were shortest in the combo group. These results suggest that probiotics may augment the effect of 5 ASA, although the balsalazide dose used was lower than generally used in clinical practice. Guslandi: Mild to mod degree of UC while on meselamaine therapy for 3 months; poorly tolerated steroids. Interestingly, the remission rates are very similar those of E coli Nissl and VSL#3 above. Kato: Yakult fermented milk:L ( Bifidobacterium breve, Bifidobacterium bifidum, Lactobacillus acidophilus). No sig diff, but the clinical activity scores were found to be lower in the treatment group than in the placebo group at the end of the study period. Borody: Pts who had failed maximum std therapy for UC including steroids and immunosuppressants. Fecal enemas were prepared fresh in NS. All 6 pts were able to withdraw all meds 4-6 wks post enema therapy. These results are as dramatic as the study itself!! Combination of prebiotic and probiotic was associated with improvement in histological scores in UC (Furrie et al. Gut 2005, RCT)
  • Pouchitis is a non-specific inflammation of the ileal reservoir and is a common complication following pouch surgery for ulcerative colitis. Frequency is approximately 50% after 10 years. Recent studies have demonstrated reduced counts of lactobacilli and bifidobacteria within the pouch, suggesting that it may be caused by altered luminal flora. Though the majority of patients respond to treatment with antimicrobial agents, approximately 10% of the patients experience recurrent or refractory disease
  • Gionchetti et al. conducted a randomized, double-blind, placebo-controlled trial in 40 pts with acute active pouchitis. These pts were in clinical and endoscopic remission with a score of zero in the clinical and endoscopic portion of pouchitis disease activity index (PDAI) after 1 month of treatment with ciprofloxacin (1g/day) plus rifaximin (2g/day). They were then randomized to receive VSL#3 (3 g sachets twice daily) or placebo for 9 months. Those who received placebo, 100% had relapses within the 9 mo period. In contrast, 85% who received VSL#3 were still in remission with a PDAI of zero after 9 mo. Furthermore, 100% of the pts receiving VSL#3 had relapses within 4 mo of stopping the treatment. Mimura et al. Similar RCT, double blind study. Similarly induced remission with PDAI of zero with 4 weeks of treatment with ciprofloxacin and metronidazole. Patient were then randomized to receive either placebo or VSL#3. Remission was maintained at 1 year in 85% of patients on VSL#3 vs. 6% in placebo. Important to note that in both these studies, the quantity of VSL#3 used was higher than that in the later studies and in current clinical practice. In contrast, Shen et al. (2005 reported no significant benefit of VSL#3 in maintaining antibiotic-induced remission in thirty-one patients. Patients were treated with ciprofloxacin 500 mg PO BID for 2 weeks to induce remission, and then started VSL #3 to maintain remission. After 8 months 23 patients had discontinued VSL#3 because of symptom recurrence and two had discontinued because of side effects (bloody BM, severe constipation, bloating, and gas). In the six patients who remained on VSL#3 endoscopic evidence of mild to moderate pouchitis was found to persist even though symptom scores were not significantly different from baseline. This finding suggests that VSL #3 use in these patients may help maintain symptomatic remission, but to a lesser degree VSL #3 use may improve endoscopic inflammation. Although the fact that patients purchased, stored and administered the VSL#3 themselves may have resulted in lower compliance, this methodology may more faithfully reproduce patients’ use of probiotics outside clinical trials.
  • Cultura: lactobacillus acidophilus, Bifidobacterium lactis Kuisima et al: randomized, double blind , placebo controlled trial , 44 subjects with acute inflamed pouches, PDAI appr. 8 (range 5 to 13). Randomized to receive Lactobacillus vs. placebo for 3 months. No difference was found in the mean pretreatment or post treatment PDAI scores between the two treatment groups. There was no significant changes seen in the concentrations of aerobic or anaerobic bacteria in the pouch. However, there was a trend towards higher fecal concentrations of total lactobacilli, but only 40% of the study subjects were colonized with lactobacillus GG. These results demonstrate the requirement for administration of multiple probiotic bacteria simultaneously (as are present in VSL#3) and/or a higher probiotic dose, or the need for pretreatment with antibiotics to induce remission prior to the probiotic therapy. Gosslink et al: Reported a lower rate of pouchitis than in historical controls. Laake et al. : Similar to the previous study, this one also did not confer a positive therapeutic effect. Non-randomized treatment of patients acting as their own controls. 10 subjects with acute pouchitis were treated with 500g of cultura. 7/10 pts had a reduced PDAI score and a 50% reduction in median values. It is possible that the endoscopic improvement could a bias of a single observer, non-blinded endoscopic assessment. 80% had more lactobacilli on microbiological assessment, however the diff did not reach statistical significance, and a week after d/c the probiotics, the levels returned to basal levels Laake 2005 showed a reduction in endoscopic and clinical disease activity, associated with an increase in fecal probiotic species. This shows that a combination of probiotic species is better than monotherapy probiotics.
  • Post-operative prevention of pouchitis: Italian group of Gionchetti et al. randomized, double blind, placebo controlled trial of VSL#3 for 12 months starting 1 week post ileostomy closure and pouch formation. Of the 20 pts randomized to VSL#3, 90% had normal pouch with PDAI of zero after 1 yr, whereas only 60% of the pts on placebo were in remission at 1 yr. Once again, in pts treated with VSL#3, there was no significant change in the concentrations of bacteroides, coliforms, clostridia or enterococci in the pouches compared with the basal levels. In contrast, fecal concentrations of lactobacilli, bifidobacteria and streptococcus thermophilus were significantly increased compared with baseline. In the placebo group, fecal concentrations of all species evaluated were similar to that before starting treatment.
  • Collagenous colitis: authors hypothesized that the benefit of E coli Nissle may have been due to the antagonistic effect against strains of Yersinia species Diverticular Colitis: may be occasionally symptomatic. Hepatic Encephalopathy: Appears to lower blood ammonia concentrations, possibly by favoring colonization with acid-resistant, non-urease producing bacteria
  • Several attempts have been made to evaluate the factors that predispose severely ill pts to infection by probiotics, but statistical analysis is lacking and the number of cases is too small to permit the drawing of any firm conclusions
  • E.coli Nissle preparation: Not available in USA. No other probiotic preparation has been validated for this indication
  • 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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