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Article ; Online: Recent advances and emerging therapies in the non-surgical management of ulcerative colitis [version 1; referees

Jan Wehkamp / Eduard F. Stange

F1000Research, Vol

3 approved]

2018 Volume 7

Abstract: The so-called “biologicals” (monoclonal antibodies to various inflammatory targets like tumor necrosis factor or integrins) have revolutionized the treatment of inflammatory bowel diseases. In ulcerative colitis, they have an established role in inducing ...

Abstract	The so-called “biologicals” (monoclonal antibodies to various inflammatory targets like tumor necrosis factor or integrins) have revolutionized the treatment of inflammatory bowel diseases. In ulcerative colitis, they have an established role in inducing remission in steroid-refractory disease and, thereafter, maintaining remission with or without azathioprine. Nevertheless, their limitations are also obvious: lack of primary response or loss of response during maintenance as well as various, in part severe, side effects. The latter are less frequent in anti-integrin treatment, but efficacy, especially during induction, is delayed. New antibodies as well as small molecules have also demonstrated clinical efficacy and are soon to be licensed for ulcerative colitis. None of these novel drugs seems to be much more effective overall than the competition, but they provide new options in otherwise refractory patients. This increasing complexity requires new algorithms, but it is still premature to outline each drug’s role in future treatment paradigms.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Endoscopic Balloon Dilation for Crohn’s Disease-Associated Strictures

Thomas Klag / Jan Wehkamp / Martin Goetz

Clinical Endoscopy, Vol 50, Iss 5, Pp 429-

2017 Volume 436

Abstract: Management of intestinal strictures associated with Crohn’s disease (CD) is clinically challenging despite advanced medical therapy directed toward mucosal healing to positively influence the natural course of CD-associated complications. Although ... ...

Abstract	Management of intestinal strictures associated with Crohn’s disease (CD) is clinically challenging despite advanced medical therapy directed toward mucosal healing to positively influence the natural course of CD-associated complications. Although medical therapy is available for inflammatory strictures, therapy of fibrostenotic strictures is the domain of surgery and endoscopy. Endoscopic balloon dilation (EBD) has been recognized as a well-established first-line procedure in terms of safety and efficacy. Although surgery is a valuable treatment modality for the management of CD-related strictures, EBD can help prevent multiple surgical interventions, which might in the long-term lead to a risk of short bowel syndrome. In this review we discuss requirements, techniques, safety, short- and long-term outcomes, as well as combinations of this procedure with surgical and medical treatment in CD-associated intestinal strictures.
Keywords	Crohn’s disease ; Stricture ; Stenosis ; Balloon dilation ; Constriction ; pathologic ; Internal medicine ; RC31-1245 ; Diseases of the digestive system. Gastroenterology ; RC799-869
Subject code	610
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Korean Society of Gastrointestinal Endoscopy
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Curbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota.

Koeninger, Louis / Osbelt, Lisa / Berscheid, Anne / Wendler, Judith / Berger, Jürgen / Hipp, Katharina / Lesker, Till R / Pils, Marina C / Malek, Nisar P / Jensen, Benjamin A H / Brötz-Oesterhelt, Heike / Strowig, Till / Jan Wehkamp

Communications biology

2021 Volume 4, Issue 1, Page(s) 47

Abstract: The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm ... ...

Abstract	The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm properties to counter this threat. The peptide is based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1. Pam-3 exhibited prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and additionally eradicated already established biofilms in vitro, primarily by disrupting membrane integrity of its target cell. Importantly, prolonged exposure did not result in drug-resistance to Pam-3. In mouse models, Pam-3 selectively reduced acute intestinal Salmonella and established Citrobacter infections, without compromising the core microbiota, hence displaying an added benefit to traditional broad-spectrum antibiotics. In conclusion, our data support the development of defensin-derived antimicrobial agents as a novel approach to fight multidrug-resistant bacteria, where Pam-3 appears as a particularly promising microbiota-preserving candidate.
MeSH term(s)	Animals ; Biofilms/drug effects ; Disease Models, Animal ; Drug Resistance, Multiple, Bacterial ; Enterobacteriaceae Infections/drug therapy ; Female ; Gastrointestinal Diseases/drug therapy ; Gastrointestinal Microbiome/drug effects ; Male ; Mice, Inbred C57BL ; Microbial Sensitivity Tests ; Salmonella Infections, Animal/drug therapy ; Mice
Language	English
Publishing date	2021-01-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-020-01582-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Quality of life in inflammatory bowel diseases

Ronald Keller / Nazar Mazurak / Laura Fantasia / Stefano Fusco / Nisar P Malek / Jan Wehkamp / Paul Enck / Thomas Klag

Intestinal Research, Vol 19, Iss 1, Pp 45-

it is not all about the bowel

2021 Volume 52

Abstract: Background/Aims The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD) are chronic diseases mostly affecting young patients. As they are diseases accompanying patients for their entire life, and the quality of life (QUOL) ...

Abstract	Background/Aims The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD) are chronic diseases mostly affecting young patients. As they are diseases accompanying patients for their entire life, and the quality of life (QUOL) interacts with disease activity, improving QUOL should be one of the main goals of therapy. This study aims to identify factors contributing to good or impaired QUOL. Methods Questionnaires addressing health-related QUOL and other psychological and social features were positioned on our institutions’ webpage and on the webpage of the largest self-help group for IBD in Germany. Patients were subdivided according to their QUOL score with a cutoff of <60. We used the Short Inflammatory Bowel Disease Questionnaire, the Assessment of the Demand for Additional Psychological Treatment, and the Fear of Progression Questionnaire Short Form. Results High numbers of patients in both subgroups showed an impaired QUOL (87.34% in UC, 91.08% in CD). Active extraintestinal manifestations, smoking, high fear of progression and high demand for psychotherapy were associated with reduced QUOL. In addition, polypharmacological interventions did not result in a good QUOL, but ostomies are linked to improved QUOL especially in CD patients. Conclusions Scores used in clinical day-to-day-practice mainly focusing on somatic factors do not sufficiently address important aspects concerning QUOL. Most importantly, extraintestinal manifestations show a hitherto underestimated impact on QUOL.
Keywords	quality of life ; crohn disease ; colitis ; ulcerative ; extraintestinal manifestations ; Medicine ; R ; Diseases of the digestive system. Gastroenterology ; RC799-869
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Korean Association for the Study of Intestinal Diseases
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Ustekinumab is effective in biological refractory Crohn’s disease patients–regardless of approval study selection criteria

Sadik Saman / Martin Goetz / Judith Wendler / Nisar P. Malek / Jan Wehkamp / Thomas Klag

Intestinal Research, Vol 17, Iss 3, Pp 340-

2019 Volume 348

Abstract: Background/Aims Ustekinumab is effective in active Crohn’s disease. In a retrospective study, we assessed the clinical outcome in nonresponders to anti-tumor necrosis factor therapy, and/or conventional therapy and/or the α4β7-integrin inhibitor ... ...

Abstract	Background/Aims Ustekinumab is effective in active Crohn’s disease. In a retrospective study, we assessed the clinical outcome in nonresponders to anti-tumor necrosis factor therapy, and/or conventional therapy and/or the α4β7-integrin inhibitor vedolizumab. As approval study populations do not always reflect the average “real world” patient cohort, we assessed weather patients who would not have qualified for approval studies show similar outcomes. Methods Forty-one patients with mild to severe active Crohn’s disease were treated with ustekinumab (intravenous 6 mg per kg/body weight) followed by subcutaneous ustekinumab (90 mg) at week 8. Depending on the clinical response maintenance therapy was chosen every 8 or 12 weeks. Clinical response was defined by Crohn’s Disease Activity Index (CDAI) decline, decline of stool frequency or clinical improvement. Inclusion criteria for approval studies were assessed. Results The 58.5% (24/41) showed clinical response to ustekinumab. The 58.3% of this group (14/24) achieved clinical remission. Clinical response correlated significantly with drop of stool frequency and improvement of CDAI score. The 39 out of 41 patients had no side effects and we observed no serious infections. About a third of our patients would not have met ustekinumab approval study criteria. However, patients who did not meet study criteria showed clinical improvement numerically in the same range compared to patients who would have qualified for approval studies. Conclusions Ustekinumab is effective, safe and well tolerated in a highly therapy refractory patient cohort. Even though a reasonable number of patients did not meet ustekinumab approval study criteria, approval study results seem to be representative to the overall patient cohort.
Keywords	Crohn disease ; Ustekinumab ; Biological therapy ; Medicine ; R ; Diseases of the digestive system. Gastroenterology ; RC799-869
Subject code	610 ; 616
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Korean Association for the Study of Intestinal Diseases
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Histone deacetylase-mediated regulation of the antimicrobial peptide hBD2 differs in intestinal cell lines and cultured tissue

Sabrina Stebe-Frick / Maureen J. Ostaff / Eduard F. Stange / Nisar P. Malek / Jan Wehkamp

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 11

Abstract: Abstract Histone deacetylase inhibition (HDACi) has been suggested as a promising approach to bolster TLR-mediated induction of antimicrobial peptides such as human β-defensin 2 (hBD2). In inflammatory bowel disease (IBD), Crohn’s disease (CD) patients ... ...

Abstract	Abstract Histone deacetylase inhibition (HDACi) has been suggested as a promising approach to bolster TLR-mediated induction of antimicrobial peptides such as human β-defensin 2 (hBD2). In inflammatory bowel disease (IBD), Crohn’s disease (CD) patients display an attenuated expression of hBD2 as compared to ulcerative colitis (UC). Here, we aimed to study if combining HDACi with the therapeutic E. coli Nissle 1917 (EcN), a strong hBD2 inducer, might be a feasible strategy to further modify protective immune responses. Monolayer epithelial cell lines versus cultured human biopsies from healthy controls and CD and UC patients showed diverse effects. In mono-cell systems, we observed a strong NF-kB-dependent enhancement of TLR- but also IL1β-mediated hBD2 induction after HDACi. In contrast, multicellular colonic biopsy culture showed the opposite result and HDACi was associated with an abolished TLR-mediated hBD2 induction in all tested patient groups. Of note, CD patients showed an attenuated induction of hBD2 by E. coli Nissle as compared to UC. We conclude that the role of HDACs in hBD2 regulation is context-dependent and likely modified by different cell types. Differential induction in different IBD entities suggests different clinical response patterns based on still unknown hBD2-associated mechanisms.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Curbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota

Louis Koeninger / Lisa Osbelt / Anne Berscheid / Judith Wendler / Jürgen Berger / Katharina Hipp / Till R. Lesker / Marina C. Pils / Nisar P. Malek / Benjamin A. H. Jensen / Heike Brötz-Oesterhelt / Till Strowig / Jan Wehkamp

Communications Biology, Vol 4, Iss 1, Pp 1-

2021 Volume 11

Abstract: Here, the authors designed a lipopeptide, Pam-3, based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1 with prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and antibiofilm properties. They show in ... ...

Abstract	Here, the authors designed a lipopeptide, Pam-3, based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1 with prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and antibiofilm properties. They show in mouse models, that Pam-3 selectively reduced acute intestinal Salmonella and established Citrobacter infections, without compromising the core microbiota.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: From intestinal stem cells to inflammatory bowel diseases

Michael Gersemann / Eduard Friedrich Stange / Jan Wehkamp

World Journal of Gastroenterology, Vol 17, Iss 27, Pp 3198-

2011 Volume 3203

Abstract: The pathogenesis of both entities of inflammatory bowel disease (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC), is still complex and under investigation. The importance of the microbial flora in developing IBD is beyond debate. In the ... ...

Abstract	The pathogenesis of both entities of inflammatory bowel disease (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC), is still complex and under investigation. The importance of the microbial flora in developing IBD is beyond debate. In the last few years, the focus has changed from adaptive towards innate immunity. Crohn’s ileitis is associated with a deficiency of the antimicrobial shield, as shown by a reduced expression and secretion of the Paneth cell defensin HD5 and HD6, which is related to a Paneth cell differentiation defect mediated by a diminished expression of the Wnt transcription factor TCF4. In UC, the protective mucus layer, acting as a physical and chemical barrier between the gut epithelium and the luminal microbes, is thinner and in part denuded as compared to controls. This could be caused by a missing induction of the goblet cell differentiation factors Hath1 and KLF4 leading to immature goblet cells. This defective Paneth and goblet cell differentiation in Crohn’s ileitis and UC may enable the luminal microbes to invade the mucosa and trigger the inflammation. The exact molecular mechanisms behind ileal CD and also UC must be further clarified, but these observations could give rise to new therapeutic strategies based on a stimulation of the protective innate immune system.
Keywords	Inflammatory bowel disease ; Paneth cells ; Goblet cells ; Cell differentiation ; TCF4 ; Hath1 ; KLF4 ; Diseases of the digestive system. Gastroenterology ; RC799-869 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Gastroenterology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Baishideng Publishing Group Co., Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Antimicrobial Peptides in Gastrointestinal Inflammation

Simon Jäger / Eduard F. Stange / Jan Wehkamp

International Journal of Inflammation, Vol

2010 Volume 2010

Keywords	Pathology ; RB1-214 ; Medicine ; R ; DOAJ:Pathology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2010-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Proteolytic Degradation of reduced Human Beta Defensin 1 generates a Novel Antibiotic Octapeptide

Judith Wendler / Bjoern O. Schroeder / Dirk Ehmann / Louis Koeninger / Daniela Mailänder-Sánchez / Christina Lemberg / Stephanie Wanner / Martin Schaller / Eduard F. Stange / Nisar P. Malek / Christopher Weidenmaier / Salomé LeibundGut-Landmann / Jan Wehkamp

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract Microbial resistance against clinical used antibiotics is on the rise. Accordingly, there is a high demand for new innovative antimicrobial strategies. The host-defense peptide human beta-defensin 1 (hBD-1) is produced continuously by epithelial ...

Abstract	Abstract Microbial resistance against clinical used antibiotics is on the rise. Accordingly, there is a high demand for new innovative antimicrobial strategies. The host-defense peptide human beta-defensin 1 (hBD-1) is produced continuously by epithelial cells and exhibits compelling antimicrobial activity after reduction of its disulphide bridges. Here we report that proteolysis of reduced hBD-1 by gastrointestinal proteases as well as human duodenal secretions produces an eight-amino acid carboxy-terminal fragment. The generated octapeptide retains antibiotic activity, yet with distinct characteristics differing from the full-length peptide. We modified the octapeptide by stabilizing its termini and by using non-natural D-amino acids. The native and modified peptide variants showed antibiotic activity against pathogenic as well as antibiotic-resistant microorganisms, including E. coli, P. aeruginosa and C. albicans. Moreover, in an in vitro C. albicans infection model the tested peptides demonstrated effective amelioration of C. albicans infection without showing cytotoxity on human cells. In summary, protease degradation of hBD-1 provides a yet unknown mechanism to broaden antimicrobial host defense, which could be used to develop defensin-derived therapeutic applications.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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