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  • 1. Bergström, Joakim H
    et al.
    Birchenough, George M H
    Katona, Gergely
    Schröder, Björn
    Schütte, André
    Ermund, Anna
    Johansson, Malin E V
    Hansson, Gunnar C
    Gram-positive bacteria are held at a distance in the colon mucus by the lectin-like protein ZG162016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 48, s. 13833-13838Artikel i tidskrift (Refereegranskat)
  • 2. Birchenough, George
    et al.
    Schröder, Björn
    Bäckhed, Fredrik
    Hansson, Gunnar C
    Dietary destabilisation of the balance between the microbiota and the colonic mucus barrier.2019Ingår i: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 10, nr 2, s. 246-250Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It has long been acknowledged that dietary fibres are important to maintain a healthy gut. Over the past decade, several studies have shown that loss of complex polysaccharides from the Western diet has resulted in alterations to our colonic microbiota. The concurrent increase in the incidence of inflammatory bowel disease in the Western world has driven us to explore the potential mechanistic link between diet, the microbiota and the host defence systems that normally prevent inflammation. Using mice fed a low fibre Western-style diet and robust live tissue analytical methods we have now provided evidence that this diet impairs the colonic inner mucus layer that normally separates bacteria from host cells. Western societies urgently need to develop their understanding of the molecular mechanisms of the diet-microbiota-mucus axis and its implications for inflammatory diseases.

  • 3. Hein, Kyaw Zaw
    et al.
    Takahashi, Hitoshi
    Tsumori, Toshiko
    Yasui, Yukihiko
    Nanjoh, Yasuko
    Toga, Tetsuo
    Wu, Zhihong
    Grötzinger, Joachim
    Jung, Sascha
    Wehkamp, Jan
    Schröder, Björn
    Schroeder, Jens M
    Morita, Eishin
    Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide.2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 42, s. 13039-44Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purified Trichophyton rubrum-inhibiting activity from lesional psoriasis scale extracts and identified the Cys-reduced form of S100A7/psoriasin (redS100A7) as a principal antifungal factor. redS100A7 inhibits various filamentous fungi, including the mold Aspergillus fumigatus, but not Candida albicans. Antifungal activity was inhibited by Zn(2+), suggesting that redS100A7 interferes with fungal zinc homeostasis. Because S100A7-mutants lacking a single cysteine are no longer antifungals, we hypothesized that redS100A7 is acting as a Zn(2+)-chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn(2+)-chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treated T. rubrum revealed marked signs of apoptosis, suggesting that its mode of action is induction of programmed cell death. TUNEL, SYTOX-green analyses, and caspase-inhibition studies supported this for both T. rubrum and A. fumigatus. Whereas redS100A7 can be generated from oxidized S100A7 by action of thioredoxin or glutathione, elevated redS100A7 levels in fungal skin infection indicate induction of both S100A7 and its reducing agent in vivo. To investigate whether redS100A7 and TPEN are antifungals in vivo, we used a guinea pig tinea pedes model for fungal skin infections and a lethal mouse Aspergillus infection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cell-penetrating Zn(2+)-chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi.

  • 4. Jaeger, S.U.
    et al.
    Schröder, Björn
    Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
    Meyer-Hoffert, U.
    Courth, L.
    Fehr, S.N.
    Gersemann, M.
    Stange, E.F.
    Wehkamp, J.
    Cell-mediated reduction of human β-defensin 1: a major role for mucosal thioredoxin2013Ingår i: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 6, nr 6, s. 1179-1190Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human β-defensin 1 (hBD-1) is an antimicrobial peptide expressed by epithelia and hematopoietic cells. We demonstrated recently that hBD-1 shows activity against enteric commensals and Candida species only after its disulfide bonds have been reduced by thioredoxin (TRX) or a reducing environment. Here we show that besides TRX, glutaredoxin (GRX) is also able to reduce hBD-1, although with far less efficacy. Moreover, living intestinal and lymphoid cells can effectively catalyze reduction of extracellular hBD-1. By chemical inhibition of the TRX system or specific knockdown of TRX, we demonstrate that cell-mediated reduction is largely dependent on TRX. Quantitative PCR in intestinal tissues of healthy controls and inflammatory bowel disease patients revealed altered expression of some, although not all, redox enzymes, especially in ulcerative colitis. Reduced hBD-1 and TRX localize to extracellular colonic mucus, suggesting that secreted or membrane-bound TRX converts hBD-1 to a potent antimicrobial peptide in vivo.

  • 5. Küchler, Robert
    et al.
    Schröder, Björn
    Jaeger, Simon U
    Stange, Eduard F
    Wehkamp, Jan
    Antimicrobial activity of high-mobility-group box 2: a new function to a well-known protein.2013Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, nr 10, s. 4782-93Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human intestinal tract is highly colonized by a vast number of microorganisms. Despite this permanent challenge, infections remain rare, due to a very effective barrier defense system. Essential effectors of this system are antimicrobial peptides and proteins (AMPs), which are secreted by intestinal epithelial and lymphoid cells, balance the gut microbial community, and prevent the translocation of microorganisms. Several antimicrobial proteins have already been identified in the gut. Nonetheless, we hypothesized that additional AMPs are yet to be discovered in this setting. Using biological screening based on antimicrobial function, here we identified competent antibacterial activity of high-mobility-group box 2 (HMGB2) against Escherichia coli. By recombinant expression, we confirmed this biologically new antimicrobial activity against different commensal and pathogenic bacteria. In addition, we demonstrated that the two DNA-binding domains (HMG boxes A and B) are crucial for the antibiotic function. We detected HMGB2 in several gastrointestinal tissues by mRNA analysis and immunohistochemical staining. In addition to the nuclei, we also observed HMGB2 in the cytoplasm of intestinal epithelial cells. Furthermore, HMGB2 was detectable in vitro in the supernatants of two different cell types, supporting an extracellular function. HMGB2 expression was not changed in inflammatory bowel disease but was detected in certain stool samples of patients, whereas it was absent from control individuals. Taken together, we characterized HMGB2 as an antimicrobial protein in intestinal tissue, complementing the diverse repertoire of gut mucosal defense molecules.

  • 6. Möndel, M.
    et al.
    Schröder, Björn
    Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen ,Stuttgart , Germany.
    Zimmermann, K.
    Huber, H.
    Nuding, S.
    Beisner, J.
    Fellermann, K.
    Stange, E. F.
    Wehkamp, J.
    Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans2009Ingår i: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 2, nr 2, s. 166-172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inducible epithelial human beta-defensins (hBD) play an important role in intestinal barrier function. In vitro studies showed that clinically effective probiotics induce antimicrobial hBD-2. Here, we aimed to assess the in vivo effect in healthy volunteers and also addressed how defensins affect probiotic survival. Symbioflor 2 containing one strain of several viable genotypes of Escherichia coli was administered to 23 healthy individuals. After 3 weeks, fecal hBD-2 peptide was increased in 78% (mean 3.7-fold; P<0.0001). Interestingly, the fecal hBD-2 peptide was still elevated 9 weeks after treatment (P=0.008). In vitro studies revealed that this effect was mediated by only one out of three tested E. coli genotypes and comparable to probiotic E. coli Nissle 1917 (10- to 15-fold). Functional assays showed that all tested bacteria were similarly killed by defensins allowing to speculate about a suicidal character of this effect. Defensin induction seems to be a common and important mechanism of probiotic treatment.

  • 7. Nuding, Sabine
    et al.
    Gersemann, Michael
    Hosaka, Yoshio
    Konietzny, Sabrina
    Schaefer, Christian
    Beisner, Julia
    Schröder, Björn O.
    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
    Ostaff, Maureen J
    Saigenji, Katunori
    Ott, German
    Schaller, Martin
    Stange, Eduard F
    Wehkamp, Jan
    Gastric Antimicrobial Peptides Fail to Eradicate Helicobacter pylori Infection Due to Selective Induction and Resistance2013Ingår i: PLoS ONE, E-ISSN 1932-6203, Vol. 8, nr 9, artikel-id e73867Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Although antimicrobial peptides protect mucus and mucosa from bacteria, Helicobacter pylori is able to colonize the gastric mucus. To clarify in which extend Helicobacter escapes the antimicrobial defense, we systematically assessed susceptibility and expression levels of different antimicrobial host factors in gastric mucosa with and without H. pylori infection.

    Materials and Methods: We investigated the expression levels of HBD1 (gene name DEFB1), HBD2 (DEFB4A), HBD3 (DEFB103A), HBD4 (DEFB104A), LL37 (CAMP) and elafin (PI3) by real time PCR in gastric biopsy samples in a total of 20 controls versus 12 patients colonized with H. pylori. Immunostaining was performed for HBD2 and HBD3. We assessed antimicrobial susceptibility by flow cytometry, growth on blood agar, radial diffusion assay and electron microscopy.

    Results: H. pylori infection was associated with increased gastric levels of the inducible defensin HBD2 and of the antiprotease elafin, whereas the expression levels of the constitutive defensin HBD1, inducible HBD3 and LL37 remained unchanged. HBD4 was not expressed in significant levels in gastric mucosa. H. pylori strains were resistant to the defensins HBD1 as well as to elafin, and strain specific minimally susceptible to HBD2, whereas HBD3 and LL37 killed all H. pylori strains effectively. We demonstrated the binding of HBD2 and LL37 on the surface of H. pylori cells. Comparing the antibacterial activity of extracts from H. pylori negative and positive biopsies, we found only a minimal killing against H. pylori that was not increased by the induction of HBD2 in H. pylori positive samples.

    Conclusion: These data support the hypothesis that gastric H. pylori evades the host defense shield to allow colonization.

  • 8.
    Schröder, Björn
    Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Bruna Stråket 16, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
    Fight them or feed them: how the intestinal mucus layer manages the gut microbiota2019Ingår i: Gastroenterology Report, ISSN 2052-0034, Vol. 7, nr 1, s. 3-12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The intestinal tract is inhabited by a tremendous number of microorganisms, termed the gut microbiota. These microorganisms live in a mutualistic relationship with their host and assist in the degradation of complex carbohydrates. Although the gut microbiota is generally considered beneficial, the vast number of microbial cells also form a permanent threat to the host. Thus, the intestinal epithelium is covered with a dense layer of mucus to prevent translocation of the gut microbiota into underlying tissues. Intestinal mucus is an organized glycoprotein network with a host-specific glycan structure. While the mucus layer has long been considered a passive, host-designed barrier, recent studies showed that maturation and function of the mucus layer are strongly influenced by the gut microbiota. In return, the glycan repertoire of mucins can select for distinct mucosa-associated bacteria that are able to bind or degrade specific mucin glycans as a nutrient source. Because the intestinal mucus layer is at the crucial interface between host and microbes, its breakdown leads to gut bacterial encroachment that can eventually cause inflammation and infection. Accordingly, a dysfunctional mucus layer has been observed in colitis in mice and humans. Moreover, the increased consumption of a low-fiber Western-style diet in our modern society has recently been demonstrated to cause bacteria-mediated defects of the intestinal mucus layer. Here, I will review current knowledge on the interaction between gut bacteria and the intestinal mucus layer in health and disease. Understanding the molecular details of this host-microbe interaction may contribute to the development of novel treatment options for diseases involving a dysfunctional mucus layer, such as ulcerative colitis.

  • 9.
    Schröder, Björn
    et al.
    Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Birchenough, George M H
    Ståhlman, Marcus
    Arike, Liisa
    Johansson, Malin E V
    Hansson, Gunnar C
    Bäckhed, Fredrik
    Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration2018Ingår i: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 23, nr 1, s. 27-40.e7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diet strongly affects gut microbiota composition, and gut bacteria can influence the colonic mucus layer, a physical barrier that separates trillions of gut bacteria from the host. However, the interplay between a Western style diet (WSD), gut microbiota composition, and the intestinal mucus layer is less clear. Here we show that mice fed a WSD have an altered colonic microbiota composition that causes increased penetrability and a reduced growth rate of the inner mucus layer. Both barrier defects can be prevented by transplanting microbiota from chow-fed mice. In addition, we found that administration of Bifidobacterium longum was sufficient to restore mucus growth, whereas administration of the fiber inulin prevented increased mucus penetrability in WSD-fed mice. We hypothesize that the presence of distinct bacteria is crucial for proper mucus function. If confirmed in humans, these findings may help to better understand diseases with an affected mucus layer, such as ulcerative colitis.

  • 10.
    Schröder, Björn
    et al.
    Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Bäckhed, Fredrik
    Signals from the gut microbiota to distant organs in physiology and disease2016Ingår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 22, nr 10, s. 1079-1089Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ecosystem of the human gut consists of trillions of bacteria forming a bioreactor that is fueled by dietary macronutrients to produce bioactive compounds. These microbiota-derived metabolites signal to distant organs in the body, which enables the gut bacteria to connect to the immune and hormone system, to the brain (the gut-brain axis) and to host metabolism, as well as other functions of the host. This microbe-host communication is essential to maintain vital functions of the healthy host. Recently, however, the gut microbiota has been associated with a number of diseases, ranging from obesity and inflammatory diseases to behavioral and physiological abnormalities associated with neurodevelopmental disorders. In this Review, we will discuss microbiota-host cross-talk and intestinal microbiome signaling to extraintestinal organs. We will review mechanisms of how this communication might contribute to host physiology and discuss how misconfigured signaling might contribute to different diseases.

  • 11.
    Schröder, Björn
    et al.
    Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; Department of Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA; Present address: Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
    Ehmann, D.
    Precht, J. C.
    Castillo, P. A.
    Küchler, R.
    Berger, J.
    Schaller, M.
    Stange, E. F.
    Wehkamp, J.
    Paneth cell α-defensin 6 (HD-6) is an antimicrobial peptide2015Ingår i: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 8, nr 3, s. 661-671Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Defensins protect human barriers from commensal and pathogenic microorganisms. Human α-defensin 6 (HD-6) is produced exclusively by small intestinal Paneth cells but, in contrast to other antimicrobial peptides (AMPs) for HD-6, no direct antibacterial killing activity has been detected so far. Herein, we systematically tested how environmental factors, like pH and reducing conditions, affect antimicrobial activity of different defensins against anaerobic bacteria of the human intestinal microbiota. Remarkably, by mimicking the intestinal milieu we detected for the first time antibacterial activity of HD-6. Activity was observed against anaerobic gut commensals but not against some pathogenic strains. Antibiotic activity was attributable to the reduced peptide and independent of free cysteines or a conserved histidine residue. Furthermore, the oxidoreductase thioredoxin, which is also expressed in Paneth cells, is able to reduce a truncated physiological variant of HD-6. Ultrastructural analyses revealed that reduced HD-6 causes disintegration of cytoplasmic structures and alterations in the bacterial cell envelope, while maintaining extracellular net-like structures. We conclude that HD-6 is an antimicrobial peptide. Our data suggest two distinct antimicrobial mechanisms by one peptide: HD-6 kills specific microbes depending on the local environmental conditions, whereas known microbial trapping by extracellular net structures is independent of the reducing milieu.

  • 12.
    Schröder, Björn O.
    et al.
    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology; Stuttgart and University of Tübingen; Tübingen, Germany.
    Stange, Eduard F.
    Wehkamp, Jan
    Waking the wimp: Redox-modulation activates human beta-defensin 12011Ingår i: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 2, nr 4, s. 262-266Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antimicrobial peptides are key players of the innate immune system and form a primary barrier against infection by microorganisms. In humans, several classes of antimicrobial peptides are produced, including the defensins. These small, cationic peptides show broad spectrum antimicrobial activity against bacteria, some fungi and some viruses. Defensins are characterized by six conserved cysteine residues which are connected via three disulphide bridges. Depending on the pattern of connectivity, human defensins are either classified as α- or β-defensins. Human β-defensin 1 (hBD-1) is constitutively expressed by epithelia, but in comparison with other antimicrobial peptides the antimicrobial activity of hBD-1 was comparably low. We recently found that after reduction of hBD-1's three disulphide bonds its antimicrobial activity is strongly enhanced. Reduction can be either performed by a reducing environment, as it is present in parts of the human intestine, the oral cavity and other locations, or enzymatically by the thioredoxin-system, which is one of the major redox regulators. Reduced hBD-1 is able to kill Gram-positive anaerobic bacteria of the human normal flora as well as an opportunistic pathogenic fungus, whereas the oxidized peptide does not show activity against these microorganisms. Herein we provide additional data about reduced hBD-1 and discuss the biological context of our findings.

  • 13. Schröder, Björn
    et al.
    Stange, E F
    Wehkamp, J
    Human beta-defensin 1: from defence to offence2012Ingår i: Zeitschrift für Gastroenterologie - German Journal of Gastroenterology, ISSN 0044-2771, E-ISSN 1439-7803, Vol. 50, nr 11, s. 1171-5Artikel i tidskrift (Refereegranskat)
    Abstract [de]

    The human gut is colonised by about one kilogram of commensal bacteria. These microorganisms are a potential threat, thus an efficient defence system is crucial in preventing bacterial translocation and infection. Besides other mechanisms of protection humans produce antimicrobial peptides (AMPs) that are able to kill a broad range of microorganisms. The human beta-defensin 1 (hBD-1) plays a major role because it is produced constitutively by all human epithelia and some immune cells. In contrast to other AMPs, however, the biological function of hBD-1 has remained unclear since the antibiotic activity of hBD-1 in vitro was only marginal. But still, several diseases have been associated with genetic polymorphisms in the hBD-1 encoding gene. Herein we discuss why the biological role of hBD-1 has been overlooked and how hBD-1 can be activated by chemical reduction. We elaborate on the biological significance of this activation and its importance for inflammatory bowel disease.

  • 14.
    Schröder, Björn
    et al.
    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany; University of Tübingen, 72076 Tübingen, Germany.
    Wu, Zhihong
    Nuding, Sabine
    Groscurth, Sandra
    Marcinowski, Moritz
    Beisner, Julia
    Buchner, Johannes
    Schaller, Martin
    Stange, Eduard F.
    Wehkamp, Jan
    Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 12011Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 469, nr 7330, s. 419-423Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of -200 mV to -300 mV in the colon. Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces. Human β-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity. Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system is able to reduce hBD-1 and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia.

  • 15. Stange, Eduard F.
    et al.
    Schröder, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Microbiota and mucosal defense in IBD: an update2019Ingår i: Expert Review of Gastroenterology & Hepatology, ISSN 1747-4124, E-ISSN 1747-4132, Vol. 13, nr 10, s. 963-976Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Inflammatory bowel diseases (IBD) are on the rise worldwide. This review covers the current concepts of the etiology of Crohn?s disease and ulcerative colitis by focusing on an unbalanced interaction between the intestinal microbiota and the mucosal barrier. Understanding these issues is of paramount importance for the development of targeted therapies aiming at the disease cause.

    Area covered: Gut microbiota alterations and a dysfunctional intestinal mucosa are associated with IBD. Here we focus on specific defense structures of the mucosal barrier, namely antimicrobial peptides and the mucus layer, which keep the gut microbiota at a distance under healthy conditions and are defective in IBD.

    Expert commentary: The microbiology of both forms of IBD is different but characterized by a reduced bacterial diversity and richness. Abundance of certain bacterial species is altered, and the compositional changes are related to disease activity. In IBD the mucus layer above the epithelium is contaminated by bacteria and the immune reaction is dominated by the antibacterial response. Human genetics suggest that many of the basic deficiencies in the mucosal response, due to Paneth cell, defensin and mucus defects, are primary. Nutrition may also be important but so far there is no therapy targeting the mucosal barrier.

  • 16. Troge, Anja
    et al.
    Scheppach, Wolfgang
    Schröder, Björn
    Rund, Stefan A
    Heuner, Klaus
    Wehkamp, Jan
    Stange, Eduard F
    Oelschlaeger, Tobias A
    More than a marine propeller--the flagellum of the probiotic Escherichia coli strain Nissle 1917 is the major adhesin mediating binding to human mucus.2012Ingår i: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 302, nr 7-8, s. 304-14, artikel-id S1438-4221(12)00066-5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The flagellum of the probiotic Escherichia coli strain Nissle 1917 (EcN) is not just responsible for motility, but also for EcN's ability to induce the production of human β-defensin 2. Here, we report a third function of this EcN organell. In this study we investigated the role of the EcN flagellum in adhesion to different host tissues by ex vivo and in vitro studies. Ex vivo studies with cryosections of human gut biopsies revealed that the flagellum of EcN is most likely important for efficient adhesion to the human intestinal tract. These results and in vitro studies with different epithelial cells indicated that the presence of mucus is important for efficient mediation of adhesion by the flagellum of EcN. We observed direct interaction between isolated flagella from EcN wild type and porcine mucin 2 as well as human mucus. However, we could not observe any interaction of the flagella with murine mucus. For the first time, we identified the mucus component gluconate as one receptor for the binding of flagella from EcN and were able to exclude the flagellin domain D3 as a responsible interaction partner. We propose that the flagellum of EcN is its major adhesin in vivo, which enables this probiotic strain to compete efficiently for binding sites on host tissue with several bacterial pathogens.

  • 17. Volk, Joana K.
    et al.
    Nyström, Elisabeth E. L.
    van der Post, Sjoerd
    Abad, Beatriz M.
    Schroeder, Bjoern
    Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Johansson, Åsa
    Svensson, Frida
    Jäverfelt, Sofia
    Johansson, Malin E. V.
    Hansson, Gunnar C.
    Birchenough, George M. H.
    The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function2019Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 216, nr 11, s. 2602-2618Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The inner mucus layer (IML) is a critical barrier that protects the colonic epithelium from luminal threats and inflammatory bowel disease. Innate immune signaling is thought to regulate IML formation via goblet cell Nlrp6 inflammasome activity that controls secretion of the mucus structural component Muc2. We report that isolated colonic goblet cells express components of several inflammasomes; however, analysis of IML properties in multiple inflammasome-deficient mice, including littermate-controlled Nlrp6−/−, detect a functional IML barrier in all strains. Analysis of mice lacking inflammasome substrate cytokines identifies a defective IML in Il18−/− mice, but this phenotype is ultimately traced to a microbiota-driven, Il18-independent effect. Analysis of phenotypic transfer between IML-deficient and IML-intact mice finds that the Bacteroidales family S24-7 (Muribaculaceae) and genus Adlercrutzia consistently positively covary with IML barrier function. Together, our results demonstrate that baseline IML formation and function is independent of inflammasome activity and highlights the role of the microbiota in determining IML barrier function.

  • 18. Wendler, J.
    et al.
    Ehmann, D.
    Courth, L.
    Schröder, Björn
    Malek, N.P.
    Wehkamp, J.
    Bacterial Periplasmic Oxidoreductases Control the Activity of Oxidized Human Antimicrobial β-Defensin 12018Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 86, nr 4, artikel-id e00875-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The antimicrobial peptide human β-defensin 1 (hBD1) is continuously produced by epithelial cells in many tissues. Compared to other defensins, hBD1 has only minor antibiotic activity in its native state. After reduction of its disulfide bridges, however, it becomes a potent antimicrobial agent against bacteria, while the oxidized native form (hBD1ox) shows specific activity against Gram-negative bacteria. We show that the killing mechanism of hBD1ox depends on aerobic growth conditions and bacterial enzymes. We analyzed the different activities of hBD1 using mutants of Escherichia coli lacking one or more specific proteins of their outer membrane, cytosol, or redox systems. We discovered that DsbA and DsbB are essential for the antimicrobial activity of hBD1ox but not for that of reduced hBD1 (hBD1red). Furthermore, our results strongly suggest that hBD1ox uses outer membrane protein FepA to penetrate the bacterial periplasm space. In contrast, other bacterial proteins in the outer membrane and cytosol did not modify the antimicrobial activity. Using immunogold labeling, we identified the localization of hBD1ox in the periplasmic space and partly in the outer membrane of E. coli. However, in resistant mutants lacking DsbA and DsbB, hBD1ox was detected mainly in the bacterial cytosol. In summary, we discovered that hBD1ox could use FepA to enter the periplasmic space, where its activity depends on presence of DsbA and DsbB. HBD1ox concentrates in the periplasm in Gram-negative bacteria, which finally leads to bleb formation and death of the bacteria. Thus, the bacterial redox system plays an essential role in mechanisms of resistance against host-derived peptides such as hBD1.

  • 19. Wendler, Judith
    et al.
    Schröder, Björn
    Dr. Margarete FischerBosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tuebingen, Germany; Present address: Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
    Ehmann, Dirk
    Koeninger, Louis
    Mailänder-Sánchez, Daniela
    Lemberg, Christina
    Wanner, Stephanie
    Schaller, Martin
    Stange, Eduard F
    Malek, Nisar P.
    Weidenmaier, Christopher
    LeibundGut-Landmann, Salomé
    Wehkamp, Jan
    Proteolytic Degradation of reduced Human Beta Defensin 1 generates a Novel Antibiotic Octapeptide2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 3640Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

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