Gastro 118/3

SELECTED SUMMARIESHenry J. Binder, M.D.
Selected Summaries Editor Yale University School of MedicineNew Haven, Connecticut 06520-8019 STAFF OF CONTRIBUTORS Laurence Blendis, Toronto, Canada Ronald L. Koretz, Sylmar, CA Mitchell L. Schuber t, Richmond, VA Rober t Bresalier, Detroit, MI Kris V. Kowdley, Seattle, WA Fergus Shanahan, Wilton, Cork, Ireland Guadalupe Garcı´a-Tsao, New Haven, CT Wayne Lencer, Boston, MA David I. Soybel, Boston, MA William L. Hasler, Ann Arbor, MI Pankaj Pasricha, Galveston, TX Jacques Van Dam, Boston, MA Cyrus Kapadia, New Haven, CT William Sandborn, Rochester, MN David C. Whitcomb, Pittsburgh, PA PROBIOTIC THERAPY WITH E. COLI without systemic disturbance were treated with 30 mg/day FOR ULCERATIVE COLITIS: prednisolone. Patients with severe disease received 60 mg/day TAKE THE GOOD WITH THE BAD prednisolone as inpatients. Any patient whose clinical condi-tion worsened or who did not achieve remission in 12 weeks Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon was excluded from the trial. Remission was defined as general- ATR (Centre for Digestive Diseases and Department of Micro- ized well-being as well as no more than 3 formed stools daily biology, University of Leeds, Leeds, England). Non-pathogenic and endoscopic and histological confirmation of inactive Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomized trial. Lancet 1999;354:635–639.
The follow-up portion of the study pertains to objective 2, the maintenance phase of the study. The doses of mesalamine Based on the hypothesis that resident pathogenic bacteria and E. coli were reduced to 1.2 g/day and 2 capsules daily, contribute to the inflammatory process in ulcerative colitis, an respectively. The steroid preparation (either enema or oral) was equivalence study comparing an oral preparation of nonpatho- tapered over 2 weeks (enema) or 4 months (oral). The patients genic Escherichia coli with mesalamine was performed. The were then followed up until relapse or 12 months maximum.
study had 2 primary objectives: (1) to compare the therapies for Confirmation of relapse was made endoscopically and histologi- rate of remission and time to remission in active colitis and (2) to compare the therapies for rate of relapse and time to relapse For the statistical analysis, the investigators assumed the after achieving remission.
E. coli preparation would not have superior remission rates A total of 116 patients with active ulcerative colitis were compared with mesalamine, and therefore performed only recruited for the study. The investigators defined active 1-sided testing of the null hypothesis. The study was designed ulcerative colitis as patients with at least 4 liquid stools daily with a power of 80% to exclude, with 90% (1-sided) confi- over the previous 7 days, with at least erythema on sigmoidos- dence, a difference of ⬎20 percentage points in favor of copy, and histological confirmation of active colitis. At each mesalamine. The investigators assumed a relapse rate of 20% at assessment, a clinical activity index, a modification from a year to reach a statistical power of 80% when calculating the Rachmilewitz (BMJ 1989;298:82–86), was performed. During number of patients needed in the trial.
the induction of remission phase of the study, eligible patients The results of the trial were that 75% and 68% of the were randomized in a double-blinded, double-dummy design mesalamine and E. coli groups achieved remission, respectively.
to receive either mesalamine, 800 mg 3 times daily, or a The relapse rate in both groups was markedly higher than the nonpathogenic strain of E. coli (serotype O6:D5:H1) named investigators anticipated, 73% for mesalamine group and 67% Nissle 1917 (Mutaflor; Ardeypharm GmbH, Herdecke, Ger- for E. coli group. The time to relapse was not significantly many), 2 capsules twice daily (2.5 ⫻ 1010 viable bacteria per different between the groups. The investigators concluded that capsule). Before treatment, all patients were treated with a E. coli seems to be as effective as mesalamine in maintaining 1-week course of oral gentamicin, 80 mg 3 times daily, to remission of ulcerative colitis.
suppress native E. coli flora. The randomization was stratified for mild, moderate, or severe disease activity according to The above study has several significant flaws that limit the importance of the findings; specifically, this is a heterogeneous criteria by Truelove and Witt (BMJ 1955;2:1041–1048) to group of patients (mild to severe in illness severity), treated with ensure adequate representation of disease severity in each various corticosteroid formulations in addition to the study medica- treatment group.
tion. The mesalamine doses used were relatively low (1.2–2.4 g/day), To induce remission, all patients were treated by different and only a small number of patients were in remission at the end of the protocols depending on their respective disease activity groups.
study, resulting in an underpowered equivalence study. Nonetheless, Patients with mild proctitis were treated with hydrocortisone the hypothesis of the study is interesting and should stimulate further acetate enemas per rectum twice daily. Patients with mild-to- research into the use of probiotics in inflammatory bowel disease moderate disease extending proximal to the sigmoid colon (IBD). We briefly review some of the scientific rationale supporting SELECTED SUMMARIES 631 the role of bacteria in IBD, discuss the results of 3 other probiotic 1107–1114). Mechanisms by which Lactobacillus species promote trials, and conclude that while the possibilities for probiotics are intestinal healing include the secretion of inhibitory products with tantalizing, there is not yet a role for these agents in routine clinical antimicrobial activity (Microb Ecol Health Dis 1989;2:131–136) and suppression of bacterial adherence and translocation of other more Luminal contents have long been suspected in the initiation or pathogenic bacterial species (Gastroenterology 1999;116:1107– perpetuation of the inflammatory state. The terminal ileum, cecum, 1114). Evidence supporting the beneficial role of Lactobacillus species and rectum are areas of relative stasis, providing prolonged mucosal in humans includes Lactobacillus species decreasing the colonic pH and contact with luminal contents. Fecal diversion has been shown to the growth of pathogenic bacteria (Appl Environ Microbiology prevent ileal postoperative relapse among patients with Crohn's 1993;59:15–20), induction of growth factors (Ann Med 1990;22:37– disease (Lancet 1991;338:771–774), and the disease quickly recurs 41), and enhanced synthesis of antibodies to microbial pathogens upon reexposure (Gastroenterology 1998;114:262–267).
(Pediatr Res 1992;32:141–144). It seems that in experimental models The evidence supporting the role of luminal bacteria exists in both of colitis, altering the enteric flora toward a higher concentration of animal models as well as observations in human disease. Animal beneficial bacteria with bacteriostatic or anti-inflammatory properties models of IBD have shown that colitis does not occur in a germfree may improve host colitis.
environment, lending powerful evidence that the critical component The term probiotic was first used to describe a substance or of the fecal stream is the bacteria (Am J Pathol 1997;150:91–97, organism that contributes to the intestinal microbial balance of farm J Immunol 1998;160:385–394, Infect Immun 1998;66:5224–5231).
animals (Science 1965;47:747–748). More recently, probiotics have Importantly, colitis has been shown to be transferable by activated been defined as ‘‘living organisms, which upon ingestion in certain T cells against bacterial antigens in the C3H/HeJBir mouse model numbers, exert health benefits beyond inherent basic nutrition'' ( J Exp Med 1998;187:855–864).
(Trends Food Sci Technol 1995;6:241–245). Which and how many of In human IBD, studies indicate that the disease occurs in areas of these living organisms are chosen seem mysterious. It seems that highest bacterial contents. A variety of immunohistochemical data normal gut commensals are the logical choice only because they are (Gastroenterology 1995;108:1396–1404), specific bacterial stimula- presumed to be harmless and may proliferate and persist in the gut.
tion of T-cell clones (Gut 1999;44:812–818), and assays for mucosal Packaging, shelf life, delivery systems, and other formulation issues antibody specific for luminal bacteria (Gut 1996;38:365–375) suggest are challenges for the future.
specific bacteria or bacterial products in the pathogenesis or perpetua- Data from controlled clinical trials supporting the health- tion of chronic intestinal inflammation. Clinical data supporting the promoting claims of probiotic bacteria therapy for colitis are sparse.
use of antibiotics in IBD disease would strengthen the implications of The current trial by Rembacken et al. follows an earlier larger study luminal bacteria as instigators. However, antibiotics have only a reporting equivalence for maintenance of remission over 3 months limited role in the management of Crohn's disease (Gut 1991;32:1071– with the same nonpathogenic E. coli preparation compared with 1.5 g 1075), and a benefit of antibiotics in ulcerative colitis has been mesalamine (Aliment Pharmacol Ther 1997;11:853–858). In the difficult to demonstrate (Gastroenterol Clin North Am 1989;18:51– study by Kruis et al., 103 patients were treated over 12 weeks with either a nonpathogenic E. coli or 1.5 g/day mesalamine. No significant The potential mechanisms behind bacterial initiation or potentia- differences in relapse rate were found. In addition, 2 pilot studies have tion of chronic inflammation must be addressed before one can promoted the benefits of a new probiotic, VSL # 3 (Yovis; Sigma-Tau, speculate on the potential mechanisms of action of ‘‘beneficial'' Pomezia, Italy), that contains 300 billion/g of viable lyophilized bacteria. When considering hypotheses implicating bacteria and IBD, bacteria of 4 strains of lactobacilli, 3 strains of bifidobacteria, and 1 enhanced mucosal permeability may play a pivotal role in maintaining strain of Streptococcus salivarius subsp. thermophilus. The first pilot study a chronic inflammatory state. This enhanced permeability may be a by Venturi et al. (Aliment Pharmacol Ther 1999;13:1103–1108) primary event (i.e., an inheritable genetic predisposition in some showed a significant increase in fecal concentrations of lactobacilli, families (Gastroenterology 1996;110:1395–1403) or a secondary bifidobacteria, and S. salivarius subsp. thermophilus when used for event either as a result of direct contact with pathogenic bacteria maintenance of remission in ulcerative colitis patients. Additionally, (Gastroenterology 1996;110:1429–1437), or a consequence of intesti- 75% of the patients maintained remission over the year on therapy. In nal inflammation.
the second trial (Gastroenterology 1998;114:A985), 40 patients with The hydrophobic epithelial barrier, composed of an interaction chronic pouchitis who initially achieved remission after combination between mucin glycoproteins and the cellular expression of trefoil antibiotic treatment were randomized to placebo or VSL #3 for 9 peptides (Gastroenterology 1995;109:516–523), normally prevents months. All 20 patients randomized to placebo relapsed; in contrast, the epithelial influx of hydrophilic bacterial products (Am J Physiol 17 of 20 patients treated with VSL # 3 were still in remission at 9 1992;262:G171–G177). A defective epithelial barrier may even cause months. Although these results are provocative and the scientific data a loss of tolerance to normal resident enteric bacteria (Clin Exp supporting a pathological role of certain enteric bacteria are reason-able, it is still too soon to recommend routine use of probiotics in Immunol 1995;102:448–455). Once these hydrophilic bacterial prod- general clinical practice. The mechanistic hypotheses established at ucts have gained access to the submucosa, they can drive a variety of the bench have yet to be translated to the bedside. The choice of proinflammatory signaling pathways causing further recruitment and bacteria, the optimal dose of bacteria, and the duration of therapy all further disruption of epithelial tight junctions (Gastroenterology require further clarification. Continued investigation into the mecha- nisms by which ‘‘good'' bacteria prevent or ameliorate the chronic How might altering the enteric bacterial flora affect intestinal inflammatory state is necessary. In the future, we may well take the inflammation? Data from experimental models imply that certain ‘‘good'' bacteria with ‘‘bad,'' but first, an appropriately selected agent luminal bacteria are more pathogenic than others. Bacteroides species must be studied in well-controlled randomized trials.
have been found to be particularly pathogenic in many experimentalmodels (Infect Immun 1999;67:2969–2974), whereas Lactobacillus WILLIAM A. FAUBION, M.D.
species seem to have a beneficial effect (Gastroenterology 1999;116: WILLIAM J. SANDBORN, M.D.

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