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Escherichia coli strain Nissle 1917 (O6:K5:H1) is a nonpathogenic fecal isolate that has been used as a probiotic agent in human and animal medicine since the early 1920s to treat chronic inflammatory and infectious diseases of the human and animal intestine (15, 16, 29). Probiotics are defined as viable microorganisms with physiologically Consumption of fructose leads to metabolic syndrome, but it is also known to increase iron absorption. Present study investigates the effect of genetically modified Escherichia coli Nissle 1917 (EcN) synbiotic along with fructose on non-heme iron absorption. Charles foster rats weighing 150-200 g were fed with iron-deficient diet for 2 months. Benefiting from its good biocompatibility and ideal targeting ability as a biological carrier, Escherichia coli Nissle 1917 (ECN) has been focused on the treatment strategies of inflammatory bowel disease and tumor. The advantage of a bacterial carrier is that it can express exogenous protein while also acting as a natural capsule by releasing Since its first isolation a century ago, the gut inhabitant Escherichia coli strain Nissle 1917 has been shown to have probiotic activities; however, it is yet not fully elucidated which differential factors play key roles in its beneficial interactions with the host. To date, no metabolomics studies have been reported investigating the Structural analysis of lipopolysaccharide (LPS) isolated from semirough, serum-sensitive Escherichia coli strain Nissle 1917 (DSM 6601, serotype O6:K5:H1) revealed that this strain's LPS contains a bisphosphorylated hexaacyl lipid A and a tetradecasaccharide consisting of one E. coli O6 antigen repeating unit attached to the R1-type core. Site De Rencontre De Jeune Gratuit. Escherichia coli (E. coli) to pospolita bakteria występująca w mikroflorze jelita grubego u ludzi i zwierząt stałocieplnych. W większości to nieszkodliwe bakterie, niektóre jednak powodować mogą poważne zatrucia pokarmowe, zapalenia żołądka, czy jelit. Jest jednak jeden wyjątkowy szczep, który stosuje się do zapobiegania i leczenia wszelkich dolegliwości trawiennych – Escherichia coli Nissle 1917. Bakterie te zostały odkryte ponad 100 lat temu, przez fryburskiego higienistę, prof. dr Alfreda Nissle, który założył we Freiburgu w 1938 r. prywatny instytut badań bakteriologicznych, którym kierował aż do śmierci w 1965 r. Podczas I wojny światowej, w 1917 roku, w pewnej grupie żołnierzy, w szpitalu wojskowym nieopodal Freiburga, wybuchła czerwonka. Tylko jeden żołnierz pozostał zdrowy, nie wykazując żadnych objawów choroby jelit. Widząc to, prof. Nissle przebadał jego kał pod kątem zawartości bakterii jelitowych i wyizolował szczep E. coli, który następnie użył do leczenia pozostałych żołnierzy. Od tego czasu, szczep ten zaczęto nazwać E. coli Nissle 1917, i stosować go w leczeniu różnych zaburzeń żołądkowo-jelitowych. Na Uniwersytecie we Freiburgu, studenci prof. Nissle, podczas zajęć praktycznych z mikrobiologii, mieszali własne próbki kału z czystymi hodowlami patogennych szczepów Salmonelli. Zazwyczaj obserwowali szybki rozrost Salmonelli, wypierających tym samym, inne bakterie jelitowe. Były jednak i takie przypadki, w których rozrost był nieznaczny, a nawet wcale niezauważalny. W ten sposób powstała hipoteza, że mikroflora niektórych próbek kału zawiera takie szczepy, które hamują rozwój mikroorganizmów patogennych. Później podejrzenia te zostały potwierdzone w laboratorium, w trakcie badań hodowli mieszanin szczepów Salmonella z różnymi izolatami E. coli, uzyskanymi z próbek kału zdrowych ludzi. Okazało się, że patogenne szczepy E. coli posiadają dodatkowe geny, tzw. „geny zjadliwości”, które czynią je chorobotwórczymi. Escherichia coli Nissle 1917 natomiast, wyróżnia się na tle innych bakterii ze swojej rodziny, tym, że na drodze ewolucji, poprzez poziomy transfer genów z innych bakterii jelitowych, nabyła dodatkowe elementy genetyczne, nazywane „Wyspami Genomowymi”. To one są odpowiedzialne m. in. za zdolność hamowania rozwoju różnego rodzaju enteropatogenów. Tę szczególną właściwość, prof. Nissle nazwał „aktywnością antagonistyczną”. Niepatogenny szczep bakterii Escherichia coli wykazuje wiele korzystnych właściwości, pełni istotne funkcje w ludzkim organizmie. Odpowiedzialny jest za rozkład produktów spożywczych, bierze udział w produkcji witamin z grupy B i K, poprawia wchłanianie żelaza. Jest bakterią tlenową, więc po przez zużycie tlenu obecnego w jelitach przyczynia się do wytworzenia pozytywnego środowiska dla anaerobów – bakterii beztlenowych. Wspomaga proces zasiedlania innych bakterii probiotycznych jednocześnie usuwając patogeny z mikroflory jelit. Szczep E-coli Nissle 1917 posiada właściwości probiotyczne oraz adhezyjne – przyczepia się do ścian jelitowych uszczelniając je i wpływając aprobująco na wchłanianie organizmu. Szczep Escherichia coli Nissle 1917 sprzyja tworzeniu substancji przeciwzapalnych i autogennych antybiotyków oraz wpływa pozytywnie na system immunologiczny. Niepatogenna E-coli sprawdza się w leczeniu wrzodziejącego zapalenia jelita grubego, zespołu jelita drażliwego, w walce z alergiami pokarmowymi, a także wykazuje korzystne działanie w profilaktyce raka jelita grubego. Niedobór tej bakterii w organizmie przynieść może przykre skutki w postaci częstego występowania nawracających infekcji moczowo-płciowych, czy oddechowych, a to wszystko za sprawą obniżonej odporności śluzówek. Niestety, wraz z pojawieniem się antybiotyków, zgasło zainteresowanie mikroflorą jelitową i terapeutycznym zastosowaniem żywych bakterii. Dopiero niedawno, medyczne osiągnięcia i rozwój mikrobiologii, spowodowały, że wcześniejsze doświadczenia mogły zostać dokładnie potwierdzone, a leczenie probiotykami znalazło się na powrót w centrum zainteresowania lekarzy i naukowców. Obecnie jest to prawdopodobnie najintensywniej badany szczep bakteryjny. Use of Escherichia coli Nissle 1917 producing recombinant colicins for treatment of IBD patients Roman Kotłowski. Med Hypotheses. 2016 Aug. Abstract Patients with Crohn's Disease and Ulcerative Colitis infected with Adherent-Invasive Escherichia coli strains constitute the largest group among Inflammatory Bowel Disease subjects, when taking into account all known etiological agents of the disease. A possible link between these pathogenic bacteria and inflammation process has gained the confidence in recently published papers. Observed enteric neuroglial cells apoptosis and epithelial gaps of ileum are probably the key manifestations of inflammation, which has been shown in IBD patients in contrary to the samples taken from healthy individuals. The cascade of consecutive events from bacterial infection via inflammation to excessive apoptosis in IBD patients leads up to the aim of our hypothesis about designing of new therapeutic strategy directed to Adherent-Invasive E. coli strains. The main advantage of biological method, which will rely on application of E. coli Nissle 1917 strain as a carrier for specific recombinant colicins against AIEC strains, could probably cause a long-lasting remission of inflammation in CD and UC patients. Copyright © 2016 Elsevier Ltd. All rights reserved. Similar articles Point mutations in FimH adhesin of Crohn's disease-associated adherent-invasive Escherichia coli enhance intestinal inflammatory response. Dreux N, Denizot J, Martinez-Medina M, Mellmann A, Billig M, Kisiela D, Chattopadhyay S, Sokurenko E, Neut C, Gower-Rousseau C, Colombel JF, Bonnet R, Darfeuille-Michaud A, Barnich N. Dreux N, et al. PLoS Pathog. 2013 Jan;9(1):e1003141. doi: Epub 2013 Jan 24. PLoS Pathog. 2013. PMID: 23358328 Free PMC article. Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation. Dogan B, Suzuki H, Herlekar D, Sartor RB, Campbell BJ, Roberts CL, Stewart K, Scherl EJ, Araz Y, Bitar PP, Lefébure T, Chandler B, Schukken YH, Stanhope MJ, Simpson KW. Dogan B, et al. Inflamm Bowel Dis. 2014 Nov;20(11):1919-32. doi: Inflamm Bowel Dis. 2014. PMID: 25230163 Invasive Escherichia coli are a feature of Crohn's disease. Sasaki M, Sitaraman SV, Babbin BA, Gerner-Smidt P, Ribot EM, Garrett N, Alpern JA, Akyildiz A, Theiss AL, Nusrat A, Klapproth JM. Sasaki M, et al. Lab Invest. 2007 Oct;87(10):1042-54. doi: Epub 2007 Jul 30. Lab Invest. 2007. PMID: 17660846 Activity of Species-specific Antibiotics Against Crohn's Disease-Associated Adherent-invasive Escherichia coli. Brown CL, Smith K, Wall DM, Walker D. Brown CL, et al. Inflamm Bowel Dis. 2015 Oct;21(10):2372-82. doi: Inflamm Bowel Dis. 2015. PMID: 26177305 [Crohn disease, ulcerative colitis. When bacteria attack the intestinal wall....]. Duchmann R, Lochs H, Kruis W. Duchmann R, et al. MMW Fortschr Med. 1999 Dec 16;141(51-52):48-51. MMW Fortschr Med. 1999. PMID: 10949626 Review. German. Cited by Efficient markerless integration of genes in the chromosome of probiotic E. coli Nissle 1917 by bacterial conjugation. Seco EM, Fernández LÁ. Seco EM, et al. Microb Biotechnol. 2022 May;15(5):1374-1391. doi: Epub 2021 Nov 9. Microb Biotechnol. 2022. PMID: 34755474 Free PMC article. Adherent-Invasive E. coli: Update on the Lifestyle of a Troublemaker in Crohn's Disease. Chervy M, Barnich N, Denizot J. Chervy M, et al. Int J Mol Sci. 2020 May 25;21(10):3734. doi: Int J Mol Sci. 2020. PMID: 32466328 Free PMC article. Review. New Approaches for Escherichia coli Genotyping. Kotłowski R, Grecka K, Kot B, Szweda P. Kotłowski R, et al. Pathogens. 2020 Jan 21;9(2):73. doi: Pathogens. 2020. PMID: 31973175 Free PMC article. K5 Capsule and Lipopolysaccharide Are Important in Resistance to T4 Phage Attack in Probiotic E. coli Strain Nissle 1917. Soundararajan M, von Bünau R, Oelschlaeger TA. Soundararajan M, et al. Front Microbiol. 2019 Nov 29;10:2783. doi: eCollection 2019. Front Microbiol. 2019. PMID: 31849915 Free PMC article. Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine. Kumar M, Garand M, Al Khodor S. Kumar M, et al. J Transl Med. 2019 Dec 13;17(1):419. doi: J Transl Med. 2019. PMID: 31836022 Free PMC article. Review. MeSH terms Substances LinkOut - more resources Full Text Sources ClinicalKey Elsevier Science Other Literature Sources scite Smart Citations Medical MedlinePlus Health Information The probiotic Escherichia coli strain Nissle 1917 interferes with invasion of human intestinal epithelial cells by different enteroinvasive bacterial pathogens Artur Altenhoefer et al. FEMS Immunol Med Microbiol. 2004. Free article Abstract The probiotic Escherichia coli strain Nissle 1917 (Mutaflor) of serotype O6:K5:H1 was reported to protect gnotobiotic piglets from infection with Salmonella enterica serovar Typhimurium. An important virulence property of Salmonella is invasion of host epithelial cells. Therefore, we tested for interference of E. coli strain Nissle 1917 with Salmonella invasion of INT407 cells. Simultaneous administration of E. coli strain Nissle 1917 and Salmonella resulted in up to 70% reduction of Salmonella invasion efficiency. Furthermore, invasion of Yersinia enterocolitica, Shigella flexneri, Legionella pneumophila and even of Listeria monocytogenes were inhibited by the probiotic E. coli strain Nissle 1917 without affecting the viability of the invasive bacteria. The observed inhibition of invasion was not due to the production of microcins by the Nissle 1917 strain because its isogenic microcin-negative mutant SK22D was as effective as the parent strain. Reduced invasion rates were also achieved if strain Nissle 1917 was separated from the invasive bacteria as well as from the INT407 monolayer by a membrane non-permeable for bacteria. We conclude E. coli Nissle 1917 to interfere with bacterial invasion of INT407 cells via a secreted component and not relying on direct physical contact with either the invasive bacteria or the epithelial cells. Similar articles Detection and distribution of probiotic Escherichia coli Nissle 1917 clones in swine herds in Germany. Kleta S, Steinrück H, Breves G, Duncker S, Laturnus C, Wieler LH, Schierack P. Kleta S, et al. J Appl Microbiol. 2006 Dec;101(6):1357-66. doi: J Appl Microbiol. 2006. PMID: 17105567 E. coli Nissle 1917 Affects Salmonella adhesion to porcine intestinal epithelial cells. Schierack P, Kleta S, Tedin K, Babila JT, Oswald S, Oelschlaeger TA, Hiemann R, Paetzold S, Wieler LH. Schierack P, et al. PLoS One. 2011 Feb 17;6(2):e14712. doi: PLoS One. 2011. PMID: 21379575 Free PMC article. Nonpathogenic Escherichia coli strain Nissle 1917 inhibits signal transduction in intestinal epithelial cells. Kamada N, Maeda K, Inoue N, Hisamatsu T, Okamoto S, Hong KS, Yamada T, Watanabe N, Tsuchimoto K, Ogata H, Hibi T. Kamada N, et al. Infect Immun. 2008 Jan;76(1):214-20. doi: Epub 2007 Oct 29. Infect Immun. 2008. PMID: 17967864 Free PMC article. Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice. Stritzker J, Weibel S, Hill PJ, Oelschlaeger TA, Goebel W, Szalay AA. Stritzker J, et al. Int J Med Microbiol. 2007 Jun;297(3):151-62. doi: Epub 2007 Apr 19. Int J Med Microbiol. 2007. PMID: 17448724 Effect of probiotic strains on interleukin 8 production by HT29/19A cells. Lammers KM, Helwig U, Swennen E, Rizzello F, Venturi A, Caramelli E, Kamm MA, Brigidi P, Gionchetti P, Campieri M. Lammers KM, et al. Am J Gastroenterol. 2002 May;97(5):1182-6. doi: Am J Gastroenterol. 2002. PMID: 12014725 Cited by The potential utility of fecal (or intestinal) microbiota transplantation in controlling infectious diseases. Ghani R, Mullish BH, Roberts LA, Davies FJ, Marchesi JR. Ghani R, et al. Gut Microbes. 2022 Jan-Dec;14(1):2038856. doi: Gut Microbes. 2022. PMID: 35230889 Free PMC article. Review. The microbial ecology of Escherichia coli in the vertebrate gut. Foster-Nyarko E, Pallen MJ. Foster-Nyarko E, et al. FEMS Microbiol Rev. 2022 May 6;46(3):fuac008. doi: FEMS Microbiol Rev. 2022. PMID: 35134909 Free PMC article. Review. Quantifying cumulative phenotypic and genomic evidence for procedural generation of metabolic network reconstructions. Moutinho TJ Jr, Neubert BC, Jenior ML, Papin JA. Moutinho TJ Jr, et al. PLoS Comput Biol. 2022 Feb 7;18(2):e1009341. doi: eCollection 2022 Feb. PLoS Comput Biol. 2022. PMID: 35130271 Free PMC article. Efficient markerless integration of genes in the chromosome of probiotic E. coli Nissle 1917 by bacterial conjugation. Seco EM, Fernández LÁ. Seco EM, et al. Microb Biotechnol. 2022 May;15(5):1374-1391. doi: Epub 2021 Nov 9. Microb Biotechnol. 2022. PMID: 34755474 Free PMC article. Escherichia coli Nissle 1917 secondary metabolism: aryl polyene biosynthesis and phosphopantetheinyl transferase crosstalk. Jones CV, Jarboe BG, Majer HM, Ma AT, Beld J. Jones CV, et al. Appl Microbiol Biotechnol. 2021 Oct;105(20):7785-7799. doi: Epub 2021 Sep 21. Appl Microbiol Biotechnol. 2021. PMID: 34546406 Publication types MeSH terms Substances LinkOut - more resources Full Text Sources Wiley Other Literature Sources The Lens - Patent Citations Research Materials NCI CPTC Antibody Characterization Program Access through your institutionAbstractEscherichia coli strain Nissle 1917 (EcN) is a remarkable probiotic bacterium, first described by Alfred Nissle in 1916/17. As the active component of Mutaflor, EcN has been well researched over decades but detailed mechanisms by which EcN confers its probiotic effects are still elusive. EcN however, has a unique profile concerning fitness factors in the absence of any virulence factors. In several large clinical trials EcN demonstrates statistical equivalence with mesalazine in the maintenance of remission of ulcerative colitis. Also, efficacy was shown in the treatment of acute and chronic diarrhea in toddlers and children. Less convincing are the data concerning the treatment of Crohn’s disease and irritable bowel syndrome. More recently, EcN, due to its innocuous nature has been used as a delivery vehicle for vaccines, cytokines, and other substances. This chapter aims to provide an overview of clinical applications and mechanisms responsible for the observed coli Nissle 1917probioticulcerative colitisdiarrheainflammatory bowel diseasesiderophoresirritable bowel syndromeCited by (0)Copyright © 2017 Elsevier Inc. All rights reserved. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine Free W Kruis1, P Frič2, J Pokrotnieks3, M Lukáš4, B Fixa5, M Kaščák6, M A Kamm7, J Weismueller8, C Beglinger9, M Stolte10, C Wolff11, J Schulze111Evangelisches Krankenhaus Kalk, University of Cologne, Germany2Ustředná vojenská nemocnice, II interní oddělení, Praha, Czech Republic3Paula Stradina Clinical University Hospital, Riga, Latvia4IV Interni Klinika, Charles University, Praha, Czech Republic52nd Department of Medicine, Charles University Prague, Medical Faculty, Hradec Kralove, Czech Republic6Interné oddelenie NsP, Trenčín, Slovak Republic7St Mark’s Hospital, London, UK8Private Practice, Koblenz, Germany9Division of Gastroenterology, University Hospital, Basel, Switzerland10Institut für Pathologie, Klinikum Bayreuth, Germany11Ardeypharm, Herdecke, GermanyCorrespondence to: Dr W Kruis Evangelisches Krankenhaus Kalk, Buchforststr 2, 51103 Cologne, Germany; Abstract Background and aim: Evidence exists for the pathogenic role of the enteric flora in inflammatory bowel disease. Probiotics contain living microorganisms which exert health effects on the host. We compared the efficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and established therapy with mesalazine in patients with ulcerative colitis. Patients and methods: In total, 327 patients were recruited and assigned to a double blind, double dummy trial to receive either the probiotic drug 200 mg once daily (n = 162) or mesalazine 500 mg three times daily (n = 165). The study lasted for 12 months and patients were assessed by clinical and endoscopic activity indices (Rachmilewitz) as well as by histology. The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses. Results: The per protocol analysis revealed relapses in 40/110 ( patients in the E coli Nissle 1917 group and 38/112 ( in the mesalazine group (significant equivalence p = Subgroup analyses showed no differences between the treatment groups in terms of duration and localisation of disease or pretrial treatment. Safety profile and tolerability were very good for both groups and were not different. Conclusions: The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic treatment further underlines the pathogenetic significance of the enteric flora. UC, ulcerative colitisIBD, inflammatory bowel diseaseEcN, Escherichia coli Nissle 1917GCP, good clinical practiceCAI, clinical activity indexEI, endoscopic indexITT, intention to treat populationPP, per protocol population5-ASA, 5-aminosalicylic acidulcerative colitismaintenance therapyprobioticsEscherichia coli Nissle Statistics from Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. UC, ulcerative colitisIBD, inflammatory bowel diseaseEcN, Escherichia coli Nissle 1917GCP, good clinical practiceCAI, clinical activity indexEI, endoscopic indexITT, intention to treat populationPP, per protocol population5-ASA, 5-aminosalicylic acidulcerative colitismaintenance therapyprobioticsEscherichia coli Nissle Ulcerative colitis (UC) is a chronic relapsing disease. The aims of treatment are induction of remission and prevention of relapses. Guidelines1,2 recommend aminosalicylates for maintenance treatment. Aminosalicylates exert various effects on leukotrienes, cytokines, and oxygen Their mode of action in UC remains unclear. It is suggested that the sum of their anti-inflammatory activities constitutes their therapeutic principle. Thus maintenance treatment with aminosalicylates is only effective when inflammation starts, but not in the non-inflamed gut. Growing evidence exists for a role of the intestinal microflora in the pathogenesis of inflammatory bowel disease (IBD). Findings from genetically engineered animal models as well as clinical observations have elucidated the importance of commensal Antibacterial treatment showed some beneficial effects7,8 but the use of antibiotics is limited. Therefore, treatment with probiotics has been proposed. Probiotics are viable non-pathogenic microorganisms that confer health benefits to the host by improving the microbial balance of the indigenous Apart from anecdotal experience, two controlled studies with the probiotic bacterial strain Escherichia coli Nissle 1917 (EcN) in UC already These trials showed no difference between the relapse preventing effects of EcN and standard mesalazine. However, some criticism was raised as to the validity of these The present study was undertaken to confirm that the relapse preventing effects of probiotic therapy with EcN and standard mesalazine are equivalent. MATERIALS AND METHODS The study was conducted according to the Helsinki Declaration (revised version of Hong Kong) and adhered to good clinical practice (GCP) guidelines. The study was approved by the Ethikkommission der Ärztekammer Nordrhein, Germany, as well as by the local ethics committees of the participating centres. All patients received material in their own language and gave written informed consent. Patients were included in the study if aged 18–70 years and diagnosed with UC in remission (clinical activity index (CAI) ⩽4, endoscopic index (EI) ⩽4, and no signs of acute inflammation on histological examination). In addition, inclusion criteria comprised at least two acute attacks of UC prior to the study and a duration of the current remission of no longer than 12 months. Exclusion criteria were: active UC; proctitis with up to 10 cm proximal spread; Crohn’s disease; infectious colitis; severe accompanying illnesses or major colonic surgery; use of antibiotics, sulphonamides, steroids, or other therapies for UC at entry into the trial; administration of EcN within the previous six months before trial entry; as well as known intolerance to salicylates. Study medication The investigational drug was a bacterial preparation for oral use containing non-pathogenic Escherichia coli of strain Nissle 1917 (serotype O6:K5:H1). Capsules were enteric coated to protect the microorganisms from gastric juice and contained viable bacteria (Mutaflor 100 mg; Ardeypharm GmbH, Herdecke, Germany). The control preparation was mesalazine, consisting of eudragit L coated 5-aminosalicylic acid (Salofalk500 mg; Dr Falk Pharma GmbH, Freiburg, Germany). The test group received one capsule of Mutaflor 100 mg once daily and one tablet of placebo three times daily from day 1 to day 4, and two capsules of Mutaflor 100 mg once daily and one tablet of placebo three times daily from day 5 to the end of the study. The control group received one capsule of placebo once daily and one tablet of Salofalk 500 mg three times daily from day 1 to day 4, and two capsules of placebo once daily and one tablet of Salofalk 500 mg three times daily from day 5 to the end of the study. No concomitant medication for UC was allowed throughout the study. Study design This was a randomised, double blind, double dummy trial comparing the relapse preventing effects and safety of a bacterial preparation containing viable EcN and mesalazine for 12 months in patients with UC in remission. The study was conducted in 60 hospitals and private settings in 10 European countries (see list of participating investigators in the appendix). Randomisation was carried out in a double blind manner in blocks of four patients using 1:1 allocation to the two treatment groups. Only complete blocks of random numbers were used for each centre. If patients were eligible for study entry, they were assigned to random numbers ( = patient numbers) in ascending order within each centre according to the chronological order of their randomisation and were given the corresponding study medication. Evaluation Clinic visits were required at the start and end of the study as well as after 1, 2, 3, 6, and 9 months of treatment. The primary objective of the study was to compare the number of patients experiencing a relapse of UC during the 12 month observation period between the two treatment groups. Patients were classified as suffering a relapse when all three of the following criteria were met: CAI >6 or an increase in CAI of at least 3 points with CAI = 4 being exceeded at the same time; EI >4; and histological signs of acute inflammation. CAI was defined according to At trial entry and at the end of the study, patients underwent colonoscopy where biopsies were taken. Endoscopic activity was assessed using a four point index14: granularity, vascular pattern, vulnerability of mucosa, and mucosal damage. All biopsies were examined by a single pathologist using a four point Secondary efficacy variables were the physician’s and patient’s assessment of general well being and calculation of a quality of life Additionally, time to relapse, CAI, EI, and histological findings were documented. Laboratory assessments, including erythrocyte sedimentation rate, C reactive protein, orosomucoids, blood counts, liver enzymes, creatinine, serum iron, and serum albumin were performed at trial entry and at the end of the study. Incidence and severity of adverse events were reported according to GCP for clinical trials of medication in the European Community (91/507/EWG, CPMP/ICH/135/95). Tolerance of the study medication was assessed on a four point scale (very good, good, fair, poor), and patient compliance was ascertained by pill counting. Statistical analysis The aim of the study was to statistically confirm one sided equivalent efficacy of EcN and mesalazine in preventing relapses of UC. Relapse rates were compared using the one sided test of Farrington and Manning17: this tests the null hypothesis that the difference between treatment groups is greater than or equal to the upper equivalence margin Δ of 20% versus the alternative that the true difference is less than 20% (α = upper confidence limit 95%). Assuming a 12 month relapse rate of 30% under mesalazine treatment and 35% under EcN treatment, to reach a statistical power of 80% at least n = 127 patients were required in each treatment group according to the sample size term for comparative binomial trials with the null hypothesis of non-zero risk Two sets of patients were analysed: an intention to treat population (ITT), including all patients who took at least one dose of the study medication, and a per protocol population (PP). According to generally accepted standards for equivalence and non-inferiority trials,18 primary analysis of the main objective (difference in relapse rates) was based on the PP population. Assuming 25% protocol violators, a total number of 160 patients in each treatment group was therefore planned. Baseline comparability and statistical analysis of secondary objectives was assessed using Fisher’s exact test (two sided; α = In addition, Kaplan-Meier curves were plotted. If no CAI or other parameter was documented at the individual study end, the “last observation carried forward” method was applied. Results are given as mean (SD). Statistical tests were executed using SPSS software package version under the Microsoft Windows NT operating system. For exploratory comparisons (tables 2, 3), the Student’s t test was used. RESULTS Patient characteristics In total, 327 patients were enrolled and randomised to either the EcN preparation (n = 162) or mesalazine (n = 165). The two patient groups were matched with regard to demographic, clinical, and pretreatment characteristics (table 1). The time gap between the end of the last relapse before the study and entry into the study was not longer than four weeks in of patients receiving EcN and in receiving mesalazine, and not longer than three months in and of EcN and mesalazine patients, respectively. All 327 randomised patients received at least one dose of the study medication and thus were included in the ITT and safety analysis this table:View inline Table 1 Demographic data and prestudy clinical characteristics Before unblinding the study, a steering committee assessed protocol violations in 105/327 ( patients. Major protocol deviations comprised violation of inclusion criteria (CAI ⩽4, EI ⩽4, and no signs of acute inflammation on histological examination) (32 patients in both groups), premature discontinuation of the study without relapse (see below), and unknown or not unequivocally assessed end point (EcN 29 patients, mesalazine 24 patients). Accordingly, the PP analysis set comprised 222 patients (EcN 110, mesalazine 112). Mean duration of the study observation period was 250 (144) (median 357) days in the EcN group and 287 (125) (median 360) days in the mesalazine group. The number of patients in the study at the scheduled visits is shown in fig 1. Premature discontinuation of the study for reasons other than relapse of disease occurred in 39/327 ( patients (in 19/162 ( patients in the EcN group and in 20/165 ( patients in the mesalazine group) (table 2). Newly emerged exclusion criteria during the study were start of concomitant medication in four patients on EcN. One patient on mesalazine became afraid of 5-aminosalicylic acid (5-ASA) and another patient underwent cardiac this table:View inline Table 2 Reasons for premature discontinuation of the study Relapse (primary objective) PP analysis revealed relapse in 40/110 ( patients in the EcN group and in 38/112 ( patients in the mesalazine group (fig 2), resulting in significant equivalence between the two groups (p = The corresponding one sided upper 95% confidence limit for the difference in treatment was (that is, within the equivalence range of 20%). Figure 3 depicts the probability of remaining in remission by Kaplan-Meier curves. Median time to relapse in the EcN group could not be calculated due to the large number of late censorings. In the mesalazine group it was 386 days. ITT analysis confirmed these results, showing a relapse rate of in the EcN group and in the mesalazine group (significant equivalence p = The upper limit of the 95% confidence interval for the difference in treatment was Subgroup analyses (secondary objectives) All subgroup analyses were performed in the ITT population. CAI increased in all patients by ( points over the study period, showing a slightly larger increase in the EcN group ( ( than in the mesalazine group ( ( No differences were observed in EI or histology between the start and end of the study (fig 4). Table 3 lists relapse rates with regard to duration, localisation, and pretrial treatment. There were no significant differences between the treatment groups for any of these characteristics. Quality of life scores on admission were ( in the EcN group and ( in the mesalazine group. Respective values after 12 months were ( and ( No significant changes occurred during the 12 month observation this table:View inline Table 3 Relapse rates according to clinical characteristics (intention to treat population) Safety and tolerance As rated by the patients, overall tolerance was very good or good in the EcN group in and in the mesalazine group in According to the physician’s assessment, the respective values were and Discontinuation of the study medication due to adverse events (relapse included) occurred in 22 ( patients (11 ( in the EcN group and 11 ( in the mesalazine group). Most frequent reasons were gastrointestinal disorders such as bloody stools, nausea, diarrhoea, mucous secretion (EcN mesalazine and abdominal pain (EcN mesalazine Generally, no unexpected drug reactions occurred during the study. No deaths but 17 serious adverse events were reported in 13/327 (4%) patients (EcN 7, mesalazine 6). Each serious adverse event occurred only once. Adverse events were reported in 68/162 ( patients treated with EcN and in 58/165 ( patients treated with mesalazine. Many adverse events reflect symptoms common for active UC such as bloody stools ( diarrhoea ( and abdominal pain ( The most frequent non-intestinal adverse events were viral infections (EcN mesalazine nausea ( and headache ( Laboratory tests showed no significant alterations. DISCUSSION Most controlled trials are designed to test differences in efficacy. In contrast, our trial was aimed at proving equivalence. Indeed, we demonstrated that the probiotic EcN provides significantly equivalent efficacy in preventing relapses of UC and is not inferior to the established gold standard mesalazine. This result was not only confirmed by statistical analysis of the PP population, which is preferred in equivalence studies,18 but also by ITT analysis. Therapeutic efficacy is usually demonstrated by superiority in a placebo controlled trial. In serious disease however when effective therapy exists that has already been tested by comparison with placebo, additional placebo controlled trials may be considered A meta-analysis19 reviewed 16 studies of maintenance therapy involving 2341 patients with UC. In four of these 16 trials, preparations containing 5-ASA were compared with placebo; in the remaining 12 studies sulphasalazine was compared. 5-ASA was observed to be significantly more effective than placebo in all dosage subgroups (<1 g/day, 1– g/day, ⩾2 g/day). A dose dependent trend was not Indeed, some studies comparing at least two doses were performed showing mainly negative or conflicting results20: Pentasa 3 g/day was not superior to g/day; balsalazide 4 g/day was better than 2 g/day; balsalazide 6 g/day was better than 3 g/day in one study but in another trial was similarly effective; and two studies with olsalazine reached different conclusions. Thus superior efficacy of doses higher than g/day has not been It can be stated that mesalazine g/day presently reflects the standard in the prevention of UC relapses and thus it qualifies as a control in an equivalence trial. Previous studies on EcN were criticised12,13 for several reasons—for example, short observation period10 or heterogeneity of patients and outcome The present trial considered this critique and followed actual standards. The observation period was 12 months, only patients with UC in remission were included, and the clinical outcome was assessed by well established endoscopic and histological activity indices resulting in a low relapse rate for the mesalazine group comparable with previous A total of 327 patients were included to achieve a statistical power sufficient to test for equivalence in a one sided set. Most likely, IBD is caused by an unrestrained inflammatory response to as yet undefined agents. Although precise identification of the antigenic stimuli has not been determined, the intestinal microflora represents a likely To manipulate the resident gut bacteria therefore seems to offer a rational approach to maintaining remission in IBD. One way of doing this, which has gained credence over recent years, is by using Mechanisms which may account for probiotic activity include production of antimicrobial agents, inhibition of adhesion of pathogens, and influence on mucosal barrier It was reported that inhibition of nuclear factor κB could be mediated by probiotic The properties of EcN are well characterised25 and its genome has been extensively It carries non-pathogenic adhesion molecules. A specific lipopolysaccharide renders it immunogenic without showing any immunotoxic Immunomodulating activity was demonstrated for specific immune responses as well as for induction of non-specific natural immunity in preterm EcN develops antagonistic activity against enterobacteria such as Salmonella enteritidis, Shigella dysenteriae, Yersinia enterocolitica, and Vibrio It prevents invasion of Salmonella typhimurium into intestinal cells,31 inhibits adhesion and invasion of adherent invasive E coli,32 and reduces concentrations of mucosa associated colonic microflora constituents in EcN is safe. Molecular genetics as well as functional analyses have revealed that EcN does not produce any virulence factors or carry any genes for pathogenicity It does not bear genes for antibiotic resistance, transferable genes or plasmids, and does not take up foreign pathogenic DNA. No formation of enterotoxins, cytotoxins, or haemolysins has been observed and there is no serum Clinical studies have demonstrated a favourable safety profile for EcN compared with placebo,35,36 mesalazine,10,11 and Our study confirms this excellent safety and tolerance record. There are other controlled studies with different probiotics. Relapse prevention with Lactobacillus GG tested negatively for maintenance therapy in surgically induced remission of Crohn’s disease38 but a small study showed positive results when Saccharomyces boulardii was added to Inflammation of the ileal pouch constructed after proctocolectomy and ileoanal anastomosis in patients with UC is of particular interest because bacterial growth seems to be of pivotal pathophysiological significance. Cases successfully treated with EcN have been A formulation comprising eight different probiotic bacteria demonstrated convincing therapeutic effects in primary prevention41 and chronic In an uncontrolled study, this preparation was able to colonise the gut and maintain remission in patients with In conclusion, the use of probiotics in IBD is in accordance with its pathogenesis. They may prevent induction of inflammatory reactions. EcN shows therapeutic efficacy and safety in maintaining remission in UC. It can be considered as an alternative to mesalazine. APPENDIX The following institutions, local principal investigators, and local coordinators participated in this study: Austria: University Hospital, Graz: W Petritsch. Czech Republic: Nemocnice Milosrdnych sester sv Karla Boromejského, Prague: J Dosedel; University Hospital, Hradec Kralove: B Fixa; Central Military Hospital, Prague: P Frič; University Hospitals, Prague: M Kment, M Lukáš; University Hospital Plzen: J Koželuhová; University Hospital Brno: H Simonová; Masaryk Hospital, Ústí nad Labem: K Mareš, J Stehlík. Estonia: Central Hospital, Tallin: B Margus; University Hospital, Tartu: R Salupere. Germany: Private Practice, Essen: A Boekstegers; University Hospital, Jena: H Bosseckert; University Hospital, Regensburg: V Gross; DRK-Kliniken Westend, Berlin: R Büchsel; Charité-Campus Virchow, Berlin: A Dignass; Private Practice, Rottenburg aN: F Dreher; Private Practice, Frankenberg: R Engelhard; Private Practice, Bad Homburg: G Ermert; Private Practice, Karlsruhe: U Farack; Private Practice, Marburg: J Hein; Kreisklinik München-Pasing, München: J Heinkelein; Mittelrhein-Klinik Bad Salzig, Boppard: R Herz; Private Practice, Bautzen: I König; Ev Krankenhaus Kalk, Köln: W Kruis; Private Practice, Münster: Th Krummenerl; Private Practice, Cottbus: A Kühn; Israelitisches Krankenhaus, Hamburg: P Layer; University Hospital, Dresden: G Lobeck; Charité-Humboldt-University, Berlin: H Lochs; Private Practice, Neuenkirchen: R Moellmann; Private Practice, Cottbus: E Muehlberg; University Hospital Großhadern, München: Th Ochsenkühn; Städtisches Klinikum Friedrichstadt, Dresden: H Porst; Krankenhaus Tabea, Hamburg: A Raedler; University Hospital, Erlangen: M Raithel; Krankenhaus Nordwest, Frankfurt: W Rösch; University Hospital, Bonn: Ch Scheurlen; Private Practice, Gera: U Schindler; Private Practice, Reutlingen: W Schmeißer; Private Practice, Regensburg: E Schütz; Krankenhaus Speyerer, Heidelberg: R Singer; University Hospital Benjamin Franklin, Berlin: R Stange; University Hospital, Frankfurt: J Stein; Klinikum der RWTH, Aachen: Th Schönfelder; University Hospital, Mainz: R Wanitschke; Private Practice, Koblenz: A Lütke, J Weismüller; St Michael Krankenhaus, Völklingen: D Woerdehoff; Private Practice, Erlangen: J Zeus. Latvia: Paula Stradina Clinical University Hospital, Riga: J Pokrotnieks. Lithuania: University Hospital, Vilnius: A Irnius; Kauno Medicinos Akademija, Kaunas: L Kupcinskas. Slovak Republic: Comenius University Hospital, Bratislava: M Huorka; City Hospital, Trencíne: M Kaščák; University Hospital, Košice: T Hildebrand. Sweden: Sabbatsberg Naersjukhuset, Stockholm: P Benno; Karolinska Institutet: A Uribe. Switzerland: Kantonsspital-University, Basel: Ch Beglinger. UK: Leeds General Infirmary, Leeds: ATR Axon; St Mark’s Hospital, London: MA Kamm. REFERENCES↵ ↵ Stange EF, Riemann J, von Herbay A, et al. Diagnosis and therapy of ulcerative colitis—results of an evidence-based consensus conference of the German Society of Digestive and Metabolic Diseases. Z Gastroenterol2001;39:19–20. ↵ Travis SP, Jewell DP. Salicylates for ulcerative colitis—their mode of action. Pharmacol Ther1994;63:135–61. ↵ Shanahan F . Probiotics and inflammatory bowel disease: is there a scientific rationale? 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escherichia coli nissle 1917