Treating Microbiota and/or the Barrier Dig Dis 2013;31:385–387 DOI: 10.1159/000354706
Probiotics Wolfgang Kruis Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany
Key Words Probiotics · Inflammatory bowel disease · Treatment · Microbiota
Abstract Ample research has described multiple biological activities of probiotics in animals and in humans. Probiotics interfere with local and systemic immune reactions and thus exert an influence on the barrier function of the intestinal mucosa. Therefore, attempting inflammatory bowel disease treatment with probiotics seems reasonable. In fact, a growing number of trials have studied the therapeutic effects in ulcerative colitis and Crohn’s disease. Promising results have been found and in some, indications such as maintenance of remission of ulcerative colitis and pouchitis guidelines recommend therapy with probiotics already today. However, many open questions still remain and the urgent need for high-quality trials requires much more research in the future. © 2013 S. Karger AG, Basel
animals or in bowels diverted from the intestinal stream [1]. In light of the crucial role of the enteric flora it is intriguing to treat IBD by treating the enteric flora. The enteric flora can be altered by several routes, among them are antibiotics, probiotics, prebiotics and others. Around 1900, the later Noble Prize laureate Ilia I. Metchnikow introduced the term probiotics [2]. Over time, a number of definitions have been used. A more recent but probably not the last definition is ‘live microorganisms, which when consumed in adequate amounts, confer a health effect on the host’ [3]. It was as early as 1917 when Alfred Nissle published successful treatment of ulcerative colitis (UC) with a probiotic strain of Escherichia coli [4]. For many years, probiotic therapy remained in the non-academic shadow of complementary and alternative medicine. In recent years however, as a result of major efforts in academic medicine, an overwhelming amount of knowledge of the biological and therapeutic effectivity of probiotics has been collected [5].
Treatment of Inflammatory Bowel Disease with Probiotics Introduction
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0385$38.00/0 E-Mail [email protected] www.karger.com/ddi
General Considerations Targets of treatment with probiotics are multifaceted and include induction as well as maintenance of remission in Crohn’s disease (CD), in UC, and also in the situation of ileal pouch after proctocolectomy. On the other side, definition of probiotics is not generally established and therapeutic approaches may comprise different bacProf. Dr. Wolfgang Kruis Klinik für Innere Medizin Evangelisches Krankenhaus Kalk Buchforststrasse 2, DE–51103 Köln (Germany) E-Mail kruis @ evkk.de
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 5/20/2018 9:59:39 AM
Current hypotheses of the pathogenesis of inflammatory bowel disease (IBD) assign a key role to the invasion of bacteria from the enteric flora through the impaired mucosal barrier with subsequent stimulating local immunoreactions. The key player in this concept are bacteria, and in fact no inflammation occurs either in germ-free
terial strains, living bacteria, lysates or compounds of bacteria, or even yeast. Following common standards of medical therapy, the therapeutic use of probiotics should also be differentiated considering details of indication and biological specificity. Although treatment with probiotics is generally thought to be very safe and tolerable, serious adverse events and even life-threatening incidences are also known [6]. Therefore, ‘in choosing a probiotic strategy, clinicians should adhere to selection from a reputable supplier, with appropriate documentation of contents and shelf life; anticipation of strain-specific effects; avoidance of cocktails without documentation of the activities of each ingredient with absence of interstrain antagonism’ [7]. Usually, only pharmaceutical products but not nutritional supplements can fulfill these requirements.
Treatment with Probiotics in Patients with Ileal Pouch
Pouchitis is a common problem in patients with ileal pouch. While induction of remission with antibiotics is standard, no medication other than probiotics has been shown in controlled trials to primarily prevent and to successfully treat chronically active pouchitis. Using the probiotic mixture VSL#3 (8 strains), primary prevention of pouchitis after closure of the ileostomy and secondary prevention of recurring pouchitis after induction of remission with antibiotics has been shown in several placebo-controlled trials [9]. All studies showed positive results leading to European guidelines recommendation for the use of VSL#3 for pouchitis [13].
Treatment with Probiotics in Patients with Crohn’s Disease Treatment with Probiotics in Ulcerative Colitis
Treatment with Probiotics for Prevention of Relapses in UC with Remission Here, a variety of different probiotic preparations were studied, controlled and open, among them E. coli Nissle 1917, bifida and lactobacilli strains and also yeast (Saccharomyces boulardii) [9]. One small placebo-controlled trial is reported with a bifidum preparation showing superiority of the probiotic [10]. The largest controlled trial with probiotic treatment for IBD comparing E. coli Nissle 1917 and the gold standard (mesalazine) demonstrated equivalent therapeutic prevention of relapses in UC [11]. In view of two additional studies [8, 12] confirming this result, European guidelines recommend E. coli Nissle 1917 as alternative treatment for maintenance of remission of UC [13]. 386
Dig Dis 2013;31:385–387 DOI: 10.1159/000354706
Induction of Remission Because of an almost complete lack of studies, therapeutic effects of probiotics for active CD cannot be sufficiently assessed [9]. A placebo-controlled pilot trial with E. coli Nissle 1917 demonstrated some minor effects but no clear signal [14]. Relapse Prevention in Medically Induced Remission Three controlled pilot studies exist. S. boulardii when compared in 32 patients combining the probiotic plus mesalazine versus mesalazine monotherapy found a significantly lower relapse rate for the combination [15]. Another pilot study comprising 23 patients brought into remission by prednisolone demonstrated a relapse rate under E. coli Nissle nearly half in comparison to placebo [14]. A small placebo-controlled study (11 patients) could not demonstrate a benefit of Lactobacillus GG [16]. Relapse Prevention in Patients after Curative Resection The results of three placebo-controlled up to mediumsized trials are available. In patients with different localizations of the disease, all after curative resection, L. rhamnosus GG [17], L. johnsonii LA1 [18] and L. johnsonii [19] were studied. No beneficial therapeutic effects on postoperative relapse rates were found.
Summary and Conclusions
Although not discussed in detail here, it can be stated that probiotic treatment for IBD seems safe and well tolKruis
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 5/20/2018 9:59:39 AM
Induction of Remission Randomized add-on therapy to standard corticosteroid treatment either with the probiotic E. coli Nissle 1917 or mesalazine showed no significant difference in accomplishing clinical remission [8]. In contrast to oral application, E. coli Nissle given as enema showed therapeutic efficacy in a placebo-controlled study [20]. A considerable number of therapeutic studies have been performed, unfortunately most often uncontrolled series [9]. A metaanalysis on three controlled trials with VSL#3, a mixture containing 8 different strains of bacteria, demonstrated therapeutic effectivity for the induction of clinical remission in UC [9]. In contrast, controlled treatment with Bifidobacterium-fermented milk was not successful.
Table 1. Therapeutic effectivity and evidence from the literature Indication
Therapeutic Evidence effectivity
Crohn’s disease Induction of remission Maintenance of remission Relapse prevention after curative resection
– – –
sparse sparse good
Ulcerative colitis Induction of remission Maintenance of remission
(+) ++
sparse guidelines
Pouchitis Primary prevention Prevention of relapses in chronic pouchitis
+ ++
good guidelines
– = No beneficial effects; (+) = beneficial effects in pilot studies; + = beneficial effects in at least 1 RCT; ++ = beneficial effects in >1 RCT.
erated. No relevant safety concerns were raised in any of the published studies, and in controlled trials no significant differences in adverse events were described. Table 1 depicts therapeutic effectivity of probiotics for the treatment of different situations in IBD and the respective evidence from the literature.
Table 2. Open questions of the use of probiotics for treatment of IBD (selection)
– – – – – – –
Which probiotics for which indication? The influence of dosing? Combination of different probiotic strains? Combination of probiotics with prebiotics? Combination of probiotics with chemical drugs? Living probiotics or lysates/DNA motives? Probiotics time limited or for ever?
In summary, some specific probiotics have proven to be therapeutically effective and safe in selected indications of IBD. In other indications of IBD, probiotics have as yet failed to show effectivity, and sometimes there have been at least signals. It is undisputable that many more clinical trials are necessary. In addition, a variety of open questions remain to be answered (table 2). In conclusion, treatment with probiotics seems a promising concept, but to become a generally established therapy it needs a lot more research in the future. Disclosure Statement The author served as medical advisor and speaker for Ardeypharm GmbH, Herdecke, Germany.
References
Probiotics
9 Jonkers D, Penders J, Masclee A, Pierik M: Probiotics in the management of inflammatory bowel disease a systematic review of intervention studies in adult patients. Drugs 2012;72:803. 10 Cui HH, Chen CL, Wang JD, et al: Effects of probiotic on intestinal mucosa of patients with ulcerative colitis. World J Gastroenterol 2004;10:1521–1525. 11 Kruis W, Fric P, Pokrotnieks J, et al: Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004; 53:1617–1623. 12 Kruis W, Schutz E, Fric P, et al: Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997;11:853–858. 13 Travis SP, Stange EF, Lemann M, et al: European evidence-based consensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008;2:1–32. 14 Malchow HA: Crohn’s disease and Escherichia coli: a new approach in therapy to maintain remission of colonic Crohn’s disease? J Clin Gastroenterol 1997;25:653–658. 15 Guslandi M, Mezzi G, Sorghi M, et al: Saccharomyces boulardii in maintenance treatment
Dig Dis 2013;31:385–387 DOI: 10.1159/000354706
16
17
18
19
20
of Crohn’s disease. Dig Dis Sci 2000;45:1462– 1464. Schultz M, Timmer A, Herfarth HH, et al: Lactobacillus GG in inducing and maintaining remission of Crohn’s disease. BMC Gastroenterol 2004;4:5. Prantera C, Scribano ML, Falasco G, et al: Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut 2002;51:405–409. Marteau P, Lemann M, Seksik P, et al: Ineffectiveness of Lactobacillus johnsonii LAI for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double-blind, placebo-controlled GETAID trial. Gut 2006; 55:842–847. Van Gossum A, Dewit O, Louis E, et al: Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LAI) on early endoscopic recurrence of Crohn’s disease after ileo-caecal resection. Inflamm Bowel Dis 2007;13:135–142. Matthes H, Krummenerl T, Giensch M, Wolff C, Schulze J: Clinical trial: probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN). BMC Complement Altern Med 2010; 10:13.
387
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 5/20/2018 9:59:39 AM
1 Sartor RB: Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 2004;126:1620–1623. 2 Metchnikoff E: Essais optimists; in Mitchell PC (ed): Classics in Longevity and Aging (Series). New York, Putnam, 1908. 3 Guarner F, Schaafsma GJ: Probiotics. Int J Food Micobiol 1998;39:237–238. 4 Nissle A: Die antagonistische Behandlung chronischer Darmstörungen mit Colibakterien. Med Klinik 1918;2:29–33. 5 Holly H, Harris J, Lyon E, Beal J, Foey AD: Probiotics, prebiotics and immunomodulation of gut mucosal defences: homeostasis and immunopathology. Nutrients 2013,5:1869–1912. 6 Besselink MG, van Santvoort HC, Buskens E, et al: Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:651–659. 7 Shanahan F, Collins SM: Pharmabiotic manipulation of the microbiota in gastrointestinal disorders, from rationale to reality. Gastroenterol Clin North Am 2010;39:721–726. 8 Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT: Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet 1999;354:635–639.
Probiotics Wolfgang Kruis Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany
Key Words Probiotics · Inflammatory bowel disease · Treatment · Microbiota
Abstract Ample research has described multiple biological activities of probiotics in animals and in humans. Probiotics interfere with local and systemic immune reactions and thus exert an influence on the barrier function of the intestinal mucosa. Therefore, attempting inflammatory bowel disease treatment with probiotics seems reasonable. In fact, a growing number of trials have studied the therapeutic effects in ulcerative colitis and Crohn’s disease. Promising results have been found and in some, indications such as maintenance of remission of ulcerative colitis and pouchitis guidelines recommend therapy with probiotics already today. However, many open questions still remain and the urgent need for high-quality trials requires much more research in the future. © 2013 S. Karger AG, Basel
animals or in bowels diverted from the intestinal stream [1]. In light of the crucial role of the enteric flora it is intriguing to treat IBD by treating the enteric flora. The enteric flora can be altered by several routes, among them are antibiotics, probiotics, prebiotics and others. Around 1900, the later Noble Prize laureate Ilia I. Metchnikow introduced the term probiotics [2]. Over time, a number of definitions have been used. A more recent but probably not the last definition is ‘live microorganisms, which when consumed in adequate amounts, confer a health effect on the host’ [3]. It was as early as 1917 when Alfred Nissle published successful treatment of ulcerative colitis (UC) with a probiotic strain of Escherichia coli [4]. For many years, probiotic therapy remained in the non-academic shadow of complementary and alternative medicine. In recent years however, as a result of major efforts in academic medicine, an overwhelming amount of knowledge of the biological and therapeutic effectivity of probiotics has been collected [5].
Treatment of Inflammatory Bowel Disease with Probiotics Introduction
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0385$38.00/0 E-Mail [email protected] www.karger.com/ddi
General Considerations Targets of treatment with probiotics are multifaceted and include induction as well as maintenance of remission in Crohn’s disease (CD), in UC, and also in the situation of ileal pouch after proctocolectomy. On the other side, definition of probiotics is not generally established and therapeutic approaches may comprise different bacProf. Dr. Wolfgang Kruis Klinik für Innere Medizin Evangelisches Krankenhaus Kalk Buchforststrasse 2, DE–51103 Köln (Germany) E-Mail kruis @ evkk.de
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 5/20/2018 9:59:39 AM
Current hypotheses of the pathogenesis of inflammatory bowel disease (IBD) assign a key role to the invasion of bacteria from the enteric flora through the impaired mucosal barrier with subsequent stimulating local immunoreactions. The key player in this concept are bacteria, and in fact no inflammation occurs either in germ-free
terial strains, living bacteria, lysates or compounds of bacteria, or even yeast. Following common standards of medical therapy, the therapeutic use of probiotics should also be differentiated considering details of indication and biological specificity. Although treatment with probiotics is generally thought to be very safe and tolerable, serious adverse events and even life-threatening incidences are also known [6]. Therefore, ‘in choosing a probiotic strategy, clinicians should adhere to selection from a reputable supplier, with appropriate documentation of contents and shelf life; anticipation of strain-specific effects; avoidance of cocktails without documentation of the activities of each ingredient with absence of interstrain antagonism’ [7]. Usually, only pharmaceutical products but not nutritional supplements can fulfill these requirements.
Treatment with Probiotics in Patients with Ileal Pouch
Pouchitis is a common problem in patients with ileal pouch. While induction of remission with antibiotics is standard, no medication other than probiotics has been shown in controlled trials to primarily prevent and to successfully treat chronically active pouchitis. Using the probiotic mixture VSL#3 (8 strains), primary prevention of pouchitis after closure of the ileostomy and secondary prevention of recurring pouchitis after induction of remission with antibiotics has been shown in several placebo-controlled trials [9]. All studies showed positive results leading to European guidelines recommendation for the use of VSL#3 for pouchitis [13].
Treatment with Probiotics in Patients with Crohn’s Disease Treatment with Probiotics in Ulcerative Colitis
Treatment with Probiotics for Prevention of Relapses in UC with Remission Here, a variety of different probiotic preparations were studied, controlled and open, among them E. coli Nissle 1917, bifida and lactobacilli strains and also yeast (Saccharomyces boulardii) [9]. One small placebo-controlled trial is reported with a bifidum preparation showing superiority of the probiotic [10]. The largest controlled trial with probiotic treatment for IBD comparing E. coli Nissle 1917 and the gold standard (mesalazine) demonstrated equivalent therapeutic prevention of relapses in UC [11]. In view of two additional studies [8, 12] confirming this result, European guidelines recommend E. coli Nissle 1917 as alternative treatment for maintenance of remission of UC [13]. 386
Dig Dis 2013;31:385–387 DOI: 10.1159/000354706
Induction of Remission Because of an almost complete lack of studies, therapeutic effects of probiotics for active CD cannot be sufficiently assessed [9]. A placebo-controlled pilot trial with E. coli Nissle 1917 demonstrated some minor effects but no clear signal [14]. Relapse Prevention in Medically Induced Remission Three controlled pilot studies exist. S. boulardii when compared in 32 patients combining the probiotic plus mesalazine versus mesalazine monotherapy found a significantly lower relapse rate for the combination [15]. Another pilot study comprising 23 patients brought into remission by prednisolone demonstrated a relapse rate under E. coli Nissle nearly half in comparison to placebo [14]. A small placebo-controlled study (11 patients) could not demonstrate a benefit of Lactobacillus GG [16]. Relapse Prevention in Patients after Curative Resection The results of three placebo-controlled up to mediumsized trials are available. In patients with different localizations of the disease, all after curative resection, L. rhamnosus GG [17], L. johnsonii LA1 [18] and L. johnsonii [19] were studied. No beneficial therapeutic effects on postoperative relapse rates were found.
Summary and Conclusions
Although not discussed in detail here, it can be stated that probiotic treatment for IBD seems safe and well tolKruis
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 5/20/2018 9:59:39 AM
Induction of Remission Randomized add-on therapy to standard corticosteroid treatment either with the probiotic E. coli Nissle 1917 or mesalazine showed no significant difference in accomplishing clinical remission [8]. In contrast to oral application, E. coli Nissle given as enema showed therapeutic efficacy in a placebo-controlled study [20]. A considerable number of therapeutic studies have been performed, unfortunately most often uncontrolled series [9]. A metaanalysis on three controlled trials with VSL#3, a mixture containing 8 different strains of bacteria, demonstrated therapeutic effectivity for the induction of clinical remission in UC [9]. In contrast, controlled treatment with Bifidobacterium-fermented milk was not successful.
Table 1. Therapeutic effectivity and evidence from the literature Indication
Therapeutic Evidence effectivity
Crohn’s disease Induction of remission Maintenance of remission Relapse prevention after curative resection
– – –
sparse sparse good
Ulcerative colitis Induction of remission Maintenance of remission
(+) ++
sparse guidelines
Pouchitis Primary prevention Prevention of relapses in chronic pouchitis
+ ++
good guidelines
– = No beneficial effects; (+) = beneficial effects in pilot studies; + = beneficial effects in at least 1 RCT; ++ = beneficial effects in >1 RCT.
erated. No relevant safety concerns were raised in any of the published studies, and in controlled trials no significant differences in adverse events were described. Table 1 depicts therapeutic effectivity of probiotics for the treatment of different situations in IBD and the respective evidence from the literature.
Table 2. Open questions of the use of probiotics for treatment of IBD (selection)
– – – – – – –
Which probiotics for which indication? The influence of dosing? Combination of different probiotic strains? Combination of probiotics with prebiotics? Combination of probiotics with chemical drugs? Living probiotics or lysates/DNA motives? Probiotics time limited or for ever?
In summary, some specific probiotics have proven to be therapeutically effective and safe in selected indications of IBD. In other indications of IBD, probiotics have as yet failed to show effectivity, and sometimes there have been at least signals. It is undisputable that many more clinical trials are necessary. In addition, a variety of open questions remain to be answered (table 2). In conclusion, treatment with probiotics seems a promising concept, but to become a generally established therapy it needs a lot more research in the future. Disclosure Statement The author served as medical advisor and speaker for Ardeypharm GmbH, Herdecke, Germany.
References
Probiotics
9 Jonkers D, Penders J, Masclee A, Pierik M: Probiotics in the management of inflammatory bowel disease a systematic review of intervention studies in adult patients. Drugs 2012;72:803. 10 Cui HH, Chen CL, Wang JD, et al: Effects of probiotic on intestinal mucosa of patients with ulcerative colitis. World J Gastroenterol 2004;10:1521–1525. 11 Kruis W, Fric P, Pokrotnieks J, et al: Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004; 53:1617–1623. 12 Kruis W, Schutz E, Fric P, et al: Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997;11:853–858. 13 Travis SP, Stange EF, Lemann M, et al: European evidence-based consensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008;2:1–32. 14 Malchow HA: Crohn’s disease and Escherichia coli: a new approach in therapy to maintain remission of colonic Crohn’s disease? J Clin Gastroenterol 1997;25:653–658. 15 Guslandi M, Mezzi G, Sorghi M, et al: Saccharomyces boulardii in maintenance treatment
Dig Dis 2013;31:385–387 DOI: 10.1159/000354706
16
17
18
19
20
of Crohn’s disease. Dig Dis Sci 2000;45:1462– 1464. Schultz M, Timmer A, Herfarth HH, et al: Lactobacillus GG in inducing and maintaining remission of Crohn’s disease. BMC Gastroenterol 2004;4:5. Prantera C, Scribano ML, Falasco G, et al: Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut 2002;51:405–409. Marteau P, Lemann M, Seksik P, et al: Ineffectiveness of Lactobacillus johnsonii LAI for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double-blind, placebo-controlled GETAID trial. Gut 2006; 55:842–847. Van Gossum A, Dewit O, Louis E, et al: Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LAI) on early endoscopic recurrence of Crohn’s disease after ileo-caecal resection. Inflamm Bowel Dis 2007;13:135–142. Matthes H, Krummenerl T, Giensch M, Wolff C, Schulze J: Clinical trial: probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN). BMC Complement Altern Med 2010; 10:13.
387
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 5/20/2018 9:59:39 AM
1 Sartor RB: Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 2004;126:1620–1623. 2 Metchnikoff E: Essais optimists; in Mitchell PC (ed): Classics in Longevity and Aging (Series). New York, Putnam, 1908. 3 Guarner F, Schaafsma GJ: Probiotics. Int J Food Micobiol 1998;39:237–238. 4 Nissle A: Die antagonistische Behandlung chronischer Darmstörungen mit Colibakterien. Med Klinik 1918;2:29–33. 5 Holly H, Harris J, Lyon E, Beal J, Foey AD: Probiotics, prebiotics and immunomodulation of gut mucosal defences: homeostasis and immunopathology. Nutrients 2013,5:1869–1912. 6 Besselink MG, van Santvoort HC, Buskens E, et al: Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:651–659. 7 Shanahan F, Collins SM: Pharmabiotic manipulation of the microbiota in gastrointestinal disorders, from rationale to reality. Gastroenterol Clin North Am 2010;39:721–726. 8 Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT: Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet 1999;354:635–639.
