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The probioticEscherichia colistrain Nissle 1917 (DSM 6601, Mutaflor), generally considered as beneficial and safe, has been used for a century to treat various intestinal diseases. However, Nissle 1917 hosts in its genome thepkspathogenicity island that codes for the biosynthesis of the genotoxin colibactin. Colibactin is a potent DNA alkylator, suspected to play a role in colorectal cancer development. We show in this study that Nissle 1917 is functionally capable of producing colibactin and inducing interstrand crosslinks in the genomic DNA of epithelial cells exposed to the probiotic. This toxicity was even exacerbated with lower doses of the probiotic, when the exposed cells started to divide again but exhibited aberrant anaphases and increased gene mutation frequency. DNA damage was confirmedin vivoin mouse models of intestinal colonization, demonstrating that Nissle 1917 produces the genotoxin in the gut lumen. Although it is possible that daily treatment of adult humans with their microbiota does not produce the same effects, administration of Nissle 1917 as a probiotic or as a chassis to deliver therapeutics might exert long term adverse effects and thus should be considered in a risk versus benefit evaluation.ImportanceNissle 1917 is sold as a probiotic and considered safe even though it is known since 2006 that it encodes the genes for colibactin synthesis. Colibactin is a potent genotoxin that is now linked to causative mutations found in human colorectal cancer. Many papers concerning the use of this strain in clinical applications ignore or elude this fact, or misleadingly suggest that Nissle 1917 does not induce DNA damage. Here, we demonstrate that Nissle 1917 produces colibactinin vitroandin vivoand induces mutagenic DNA damage. This is a serious safety concern that must not be ignored, for the interests of patients, the general public, health care professionals and ethical probiotic manufacturers.

Studies involving manipulation of intestinal microflora with probiotic species have suggested potential effectiveness in multiple gastrointestinal diseases including inflammatory bowel diseases. Resulting benefits of probiotics include competitively excluding pathogens, improvement of mucosal barrier function, and hence maintaining the gut homeostasis and modulating the immune system by inducing the release of cytokines. Few lactobacillus strains are also known to modulate the perception of pain by inducing effects similar to that of morphine in the intestinal epithelial cells. Probiotic products like VSL#3 (Bifidobacterium longum, B. breve, B. infantis, Lactobacillus plantarum, L. acidophilus, L. paracasei, L. bulgaricus, Streptococcus thermophilus), Culturelle (L. rhamnosus GG), Florastor (S. boulardii), Align (B. infantis), DanActive (L. casei), Mutaflor (E. coli Nissle 1917) are current examples of treatments. Probiotics are also increasingly being added in dairy as well as non-dairy products like drinks, yoghurts, etc. Most studies regarding the anti-inflammatory effects of probiotics are preliminary and seem promising but require further clinical trials. There is also scope for studies on the dosage, duration of therapies, ways of administration, and strain combinations.

Introduction and study aim: IBS is the most common functional disorder of gastrointestinal (GI) tract. It is shown that intestinal microbiota plays an important role in the pathogenesis of Irritable Bowel Syndrome (IBS). Recent studies have been shown that probiotics could be effective in the improvement of IBS symptoms by changing gut normal microflora. In this study we investigated the probiotics’ efficacy in prevention of small intestinal bacterial overgrowth (SIBO) recurrence among patients with IBS. Patients and Methods: In a double blind clinical trial, patients with IBS and SIBO who were diagnosed based on positive Hydrogen breath test, initially received antibiotics for a period of 10 days and then randomly divided into 2 groups (Mutaflor probiotic and placebo) after confirmation of negative Hydrogen breath test. After 3 months treatment, breath tests were repeated and frequency of SIBO recurrence was compared between 2 groups. Results: Among 172 patients with IBS and SIBO, 159 cases included the study and after antibiotic treatment and negative breath tests, eventually 156 patients were analyzed. Both groups had similar demographic characters such as age, sex, IBS type and PPI consumption. Frequency of SIBO recurrence were significantly lower in the probiotic group than the placebo group (P=0.033). Frequency rate of constipation and mixed type of IBS were almost similar in both groups (P>0.05) and only there was a significant difference in SIBO frequency between 2 groups as diarrhea dominant IBS (P

Rapidly growing antibiotic resistance among gastrointestinal pathogens, and the ability of antibiotics to induce the virulence of these pathogens makes it increasingly difficult to rely on antibiotics to treat gastrointestinal infections. The probiotic Escherichia coli strain Nissle 1917 (EcN) is the active component of the pharmaceutical preparation Mutaflor® and has been successfully used in the treatment of gastrointestinal disorders. Gut bacteriophages are dominant players in maintaining the microbial homeostasis in the gut, however, their interaction with incoming probiotic bacteria remains to be at conception. The presence of bacteriophages in the gut makes it inevitable for any probiotic bacteria to be phage resistant, in order to survive and successfully colonize the gut. This study addresses the phage resistance of EcN, specifically against lytic T4 phage infection. From various experiments we could show that (i) EcN is resistant toward T4 phage infection, (ii) EcN's K5 polysaccharide capsule plays a crucial role in T4 phage resistance and (iii) EcN's lipopolysaccharide (LPS) inactivates T4 phages and notably, treatment with the antibiotic polymyxin B which neutralizes the LPS destroyed the phage inactivation ability of isolated LPS from EcN. Combination of these identified properties in EcN was not found in other tested commensal E. coli strains. Our results further indicated that N-acetylglucosamine at the distal end of O6 antigen in EcN's LPS could be the interacting partner with T4 phages. From our findings, we have reported for the first time, the role of EcN's K5 capsule and LPS in its defense against T4 phages. In addition, by inactivating the T4 phages, EcN also protects E. coli K-12 strains from phage infection in tri-culture experiments. Our research highlights phage resistance as an additional safety feature of EcN, a clinically successful probiotic E. coli strain.

A century ago, Alfred Nissle discovered that intentional intake of particular strains of Escherichia coli could treat patients suffering from infectious diseases. Since then, one of these strains became the most frequently used probiotic E. coli in research and was applied to a variety of human conditions. Here, properties of that E. coli Nissle 1917 strain are compared with other commercially available E. coli probiotic strains, with emphasis on their human applications. A literature search formed the basis of a summary of research findings reported for the probiotics Mutaflor, Symbioflor 2, and Colinfant. The closest relatives of the strains in these products are presented, and their genetic content, including the presence of virulence, genes is discussed. A similarity to pathogenic strains causing urinary tract infections is noticeable. Historic trends in research of probiotics treatment for particular human conditions are identified. The future of probiotic E. coli may lay in what Alfred Nissle originally discovered: to treat gastrointestinal infections, which nowadays are often caused by antibiotic-resistant pathogens.

Escherichia 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 effects.

Ulcerative colitis (UC) is a chronic inflammatory disease, whose etiology is still unclear. Its pathogenesis involves an interaction between genetic factors, immune response and the "forgotten organ", Gut Microbiota. Several studies have been conducted to assess the role of antibiotics and probiotics as additional or alternative therapies for Ulcerative Colitis. Escherichia coli Nissle (EcN) is a nonpathogenic Gram-negative strain isolated in 1917 by Alfred Nissle and it is the active component of microbial drug Mutaflor(®) (Ardeypharm GmbH, Herdecke, Germany and EcN, Cadigroup, In Italy) used in many gastrointestinal disorder including diarrhea, uncomplicated diverticular disease and UC. It is the only probiotic recommended in ECCO guidelines as effective alternative to mesalazine in maintenance of remission in UC patients. In this review we propose an update on the role of EcN 1917 in maintenance of remission in UC patients, including data about efficacy and safety. Further studies may be helpful for this subject to further the full use of potential of EcN.

The usefulness of prophylactic antibiotics to prevent recurrent urinary tract infections in children was recently questioned. Some groups have attempted to use probiotics, most commonly lactobacillus, to prevent recurrent infections by altering the intestinal bacterial reservoir with variable results. Mutaflor® is a possible alternative probiotic in which the active agent is Nissle 1917. Nissle 1917 is a commensal Escherichia coli strain that eradicates pathogenic bacteria from the gastrointestinal tract. Due to its ability to alter the intestinal biome we hypothesized that Mutaflor may have the potential to prevent recurrent urinary tract infections. Thus, we used an in vitro assay to analyze the effectiveness of Nissle 1917 for eradicating pediatric uropathogens.We established a collection of 43 bacterial pediatric uropathogens. With each isolate a microcin-type assay was performed to determine the effectiveness of Nissle 1917 on bacterial growth inhibition and competitive overgrowth.Nissle 1917 adversely affected the growth of 34 of the 43 isolates (79%) isolates. It inhibited the growth of 21 isolates and overgrew 13. The percent of species adversely affected by Nissle 1917 was 40% for Pseudomonas, 50% for E. coli, Enterococcus and Staphylococcus, 100% for Klebsiella and Enterobacter, and 0% for Citrobacter and Serratia.Nissle 1917, the active agent in Mutaflor, inhibited or out competed most bacterial isolates. These mechanisms could be used in vivo to eradicate uropathogens from the gastrointestinal tract. Further study is needed to determine whether Mutaflor can prevent recurrent urinary tract infections in children.

A high carriage rate of multidrug-resistant Escherichia coli (MDREC) was observed in elderly residents in long-term care facilities. A double-blinded, placebo-controlled trial was carried out to determine whether the probiotic product E. coli strain Nissle 1917 (Mutaflor) would compete with MDREC in the bowel and thereby reduce the prevalence of the multiresistant bacteria in faeces and urine. Sixty-nine patients excreting norfloxacin-resistant E. coli were randomized to probiotic or placebo groups and administered capsules twice daily. The daily dose of probiotic was 5×109–5×1010 bacteria. Faecal and urine samples were cultured at baseline and during and after the treatment period. A reduction in baseline carriage was not influenced by probiotic administration. The probiotic strain was detected in faecal specimens collected during the treatment period of only two out of 12 probiotic group subjects that were tested. Genotyping of norfloxacin-resistant E. coli isolates showed that 32 strains were prevalent among the patients. Thus, E. coli Nissle 1917 does not have the capacity to compete effectively with MDREC in the bowel of elderly patients.

Background and purpose In many patients with irritable bowel syndrome (IBS), one symptom is predominant (e.g., diarrhea, constipation, meteorism, or alternating stool consistency). For IBS therapy, probiotic drugs such as Mutaflor (active ingredient: Escherichia coli strain Nissle 1917 [EcN]) are also being used. A systematic survey on the efficacy and safety of EcN in different IBS subgroups is still missing. Patients and methods In a gastroenterologic outpatient practice, results of 150 IBS patients treated with EcN were evaluated retrospectively. Most IBS patients enrolled belonged to the subgroups "diarrhea", "meteorism", and "alternating stool consistency". Results Regarding the diarrhea subgroup, not only a statistically significant improvement in stool frequency was observed, but also a marked improvement in concomitant symptoms such as abnormal urge, flatulence, and abdominal fullness. These complaints improved under EcN therapy in the other IBS subgroups as well, so that efficacy was assessed as "good to very good" in 73.4% of all cases. Tolerance to treatment was "good to very good" in 97.9% of the cases. Conclusion The results point to the possibility of EcN being a therapeutic option for patients of various IBS subgroups which is almost free of side effects.

Introduction: Living microorganisms that enter the gut in an active state and exert a positive influence on the host are called probiotics. Numerous experimental and clinical studies were performed recently and confirm both the efficacy and modes of action of probiotic drugs. Patients and Methods: In a post-marketing-surveillance study with the probiotic Escherichia coli strain Nissle 1917 (EcN) data on the range of indications as well as on efficacy and tolerance were gathered prospectively in 446 centres. The intended treatment duration was limited to a maximum of 12 weeks. Results: EcN was used in 3807 patients with more than 20 different indications, n = 3511 of whom had gastrointestinal complaints: Among others, 1067 patients presented with chronically recurring (n = 728) or protracted diarrhoea (n = 339), 415 with inflammatory bowel disease, 679 with irritable bowel syndrome, and 253 with chronic constipation. The overall efficacy was assessed as good to very good by an average of 81.4 % of the therapists. The stool frequency and consistency as well as the symptoms of meteorism and abdominal pain were improved in very many patients. Suspected cases of side effects were documented in only 2.8 % of the patients. Conclusion: EcN is frequently used in practice for the treatment of various, mostly gastrointestinal, complaints and is well tolerated. Originalarbeit

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 (36.4%) patients in the E coli Nissle 1917 group and 38/112 (33.9%) in the mesalazine group (significant equivalence p = 0.003). 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.

Summary Background : Pathogenic adherent–invasive Escherichia coli have been isolated from ileal lesions of Crohn's disease. Aim : To investigate the non-pathogenic E. coli strain Nissle 1917 (Mutaflor) as possible maintenance therapy in inflammatory bowel disease by testing its ability to prevent adherent–invasive E. coli strains from adhering to and invading human intestinal epithelial cells in vitro. Methods : Bacterial adhesion to and invasion of intestinal epithelial cells (Intestine-407) were assessed by counting the colony-forming units. The inhibitory effect of E. coli Nissle 1917 was determined after co-incubation with adherent–invasive E. coli strains or after pre-incubation of the intestinal epithelial cells with this probiotic strain prior to infection with adherent–invasive E. coli strains. Results : Strain Nissle 1917 exhibited dose- and time-dependent adherence to intestinal epithelial cells and inhibited the adhesion and invasion of various adherent–invasive E. coli strains. In co-infection experiments, the inhibitory effect on adherent–invasive E. coli adhesion reached 78–99.9%. Pre-incubation of intestinal epithelial cells with strain Nissle 1917 reduced adherent–invasive E. coli adhesion by 97.2–99.9%. The inhibitory effect on adherent–invasive E. coli invasion paralleled that on adhesion. Conclusion : As strong and significant inhibitory effects on adherent–invasive E. coli adhesion and invasion were observed in co-infection and pre-infection experiments, E. coli Nissle 1917 could be efficient for preventive or curative probiotic therapy in patients with Crohn's disease.

Escherichia coli strain Nissle 1917 (EcN) is the active principle of a probiotic preparation (trade name Mutaflor ® ) used for the treatment of patients with intestinal diseases such as ulcerative colitis and diarrhea. It has GRAS (generally recognized as save) status and has been shown to be a therapeutically effective drug ( Sonnenborn and Schulze, 2009 ). The complete genomic DNA sequence will help in identifying genes and their products which are essential for the strains probiotic nature. Genbank/EMBL/DDBJ accession number: CP007799 (chromosome).

To determine the effect of Escherichia coli Nissle (Mutaflor, Ardeypharm GmbH, Herdecke, Germany) on the intestinal colonization, level of endotoxin and liver functions in patients with liver cirrhosis.Thirty-nine patients with liver cirrhosis diagnosed by means of biopsy and clinical examinations were randomly allocated to treatment with E. coli Nissle or placebo for 42 days. Standard clinical examination, biochemical and hematological examinations, level of endotoxin and microbiological examination of the stool were performed before and after the treatment.In comparing the treatment of E. coli Nissle and placebo, significant improvement of the intestinal colonization (P0.001) in the E. coli Nissle group was described. We found a trend of significant lowering of the endotoxemia (P=0.07) and improvement of liver functions evaluated by Child-Pugh score (P=0.06).E. coli Nissle seems to be effective in the restoration of normal colonic colonization and can probably lower endotoxemia in cirrhotic patients.

The probiotic Escherichia coli strain Nissle 1917 (DSM 6601, Mutaflor), generally considered beneficial and safe, has been used for a century to treat various intestinal diseases. However, Nissle 1917 hosts in its genome the pks pathogenicity island that codes for the biosynthesis of the genotoxin colibactin. Colibactin is a potent DNA alkylator, suspected to play a role in colorectal cancer development. We show in this study that Nissle 1917 is functionally capable of producing colibactin and inducing interstrand cross-links in the genomic DNA of epithelial cells exposed to the probiotic. This toxicity was even exacerbated with lower doses of the probiotic, when the exposed cells started to divide again but exhibited aberrant anaphases and increased gene mutation frequency. DNA damage was confirmed in vivo in mouse models of intestinal colonization, demonstrating that Nissle 1917 produces the genotoxin in the gut lumen. Although it is possible that daily treatment of adult humans with their microbiota does not produce the same effects, administration of Nissle 1917 as a probiotic or as a chassis to deliver therapeutics might exert long-term adverse effects and thus should be considered in a risk-versus-benefit evaluation. IMPORTANCE Nissle 1917 is sold as a probiotic and considered safe even though it has been known since 2006 that it harbors the genes for colibactin synthesis. Colibactin is a potent genotoxin that is now linked to causative mutations found in human colorectal cancer. Many papers concerning the use of this strain in clinical applications ignore or elude this fact or misleadingly suggest that Nissle 1917 does not induce DNA damage. Here, we demonstrate that Nissle 1917 produces colibactin in vitro and in vivo and induces mutagenic DNA damage. This is a serious safety concern that must not be ignored in the interests of patients, the general public, health care professionals, and ethical probiotic manufacturers.