Members of SPP 1656

Research Sketch:

Co-evolution of the intestinal microbiota with its host has resulted in a state of mutual benefit. Besides contributing to host nutrition, physiology and mucosal immunity, the intestinal microbiota protects the host from enteric infections, a function designated as colonization resistance. By expression of virulence and fitness factors, enteric pathogens may exploit structures and signaling pathways of the host in order to subvert specific functions of the immune system. While host-pathogen interactions have been studied in detail during the past decades, the role of the microbiota in this interaction is largely elusive, and the trilateral interaction between enteric pathogens, the intestinal microbiota and the host is not well understood. Focus of our work is to address whether and how virulence factors of enteric pathogens, e.g. Yersinia enterocolitica affect this interrelationship, and whether and how specific components of the microbiota might be used to interfere with Yersinia pathogenicity. Gnotobiotic mouse models and metagenomic analyses will provide new insights into the intricate interaction between Yersinia, the intestinal microbiota and the mucosal immune system, and might result in novel strategies for treatment of enteric infections.

Selected Publications:

Autenrieth SE, Warnke P, Wabnitz GH, Lucero Estrada C, Pasquevich KA, Drechsler D, Günter M, Hochweller K, Novakovic A, Beer-Hammer S, Samstag Y, Hämmerling GJ, Garbi N, Autenrieth IB (2012) Depletion of dendritic cells enhances innate anti-bacterial host defense through modulation of phagocyte homeostasis. PLoS Pathog Feb;8(2):e1002552

Autenrieth SE, Linzer T-R, Hiller C, Keller B, Warnke P, Köberle M, Bohn E, Biedermann T, Bühring H-J, Hammerling GJ, Rammensee HG, Autenrieth IB (2010). Immune evasion by Yersinia enterocolitica: differential targeting of dendritic cell subpopulations in vivo. PLoS Pathog, (2010) Nov 24;6(11):e1001212

Köberle M, Klein-Günther A. Schütz M, Fritz M, Berchtold S, Tolosa E, Autenrieth IB, Bohn E. (2009). Yersinia enterocolitica targets cells of the innate and adaptive immune system by injection of Yops in a mouse infection model. PLoS Pathog. Aug; 5(8):e1000551

Research Sketch:

We are interested in the evolutionary forces shaping diversity of the intestinal microbiota and its contribution to health and disease. A combination of bacterial metagenomics, evolutionary functional genomics and population genetics is applied to identify the complex interactions between hosts, their bacteria and the environment.

Selected Publications:

Rausch P, Künzel S, Suwandi A, Grassl GA, Rosenstiel P, Baines JF. Multigenerational influences of the Fut2 gene on the dynamics of the gut microbiota in mice. Front Microbiol. in press.

Rausch P, Basic M, Batra A, Bischoff SC, Blaut M, Clavel T, Gläsner J, Gopalakrishnan S, Grassl GA, Günther C, Haller D, Hirose M, Ibrahim S, Loh G, Mattner J, Nagel S, Pabst O, Schmidt F, Siegmund B, Strowig T, Volynets V, Wirtz S, Zeissig S, Zeissig Y, Bleich A, Baines JF. Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities. Int J Med Microbiol. 2016 Mar 15. pii: S1438-4221(16)30019-4

Rausch P, Steck N, Suwandi A, Seidel JA, Künzel S, Bhullar K, Basic M, Bleich A, Johnsen JM, Vallance BA, Baines JF, Grassl GA. Expression of the blood-group-related gene B4galnt2 alters susceptibility to Salmonella infection. PLoS Pathogens, 2015; 11(7):e1005008

Research Sketch:

We seek to better understand the pathogenesis of inflammatory and infectious diseases as well as cancer of the gut. Our research specifically aims at understanding the intimate relationship between gut bacteria and the intestinal epithelium. Intestinal epithelial cells express receptors for bacterial surface molecules and are located at the frontline to the intestinal microflora. By binding to these receptors, bacteria are able to influence the physiology of intestinal epithelial cells. As an example, gut bacteria influence survival and cell death within the intestinal epithelium, homeostatic processes that have to be strictly regulated to prevent inflammation and cancer development in the gut. Vice versa, specialized intestinal epithelial cells like Paneth cells and goblet cells express molecules, with which they control the access of gut bacteria to the epithelial surface, shape microbial communities and even kill certain bacteria. Using preclinical model systems, we evaluate how these mechanisms are regulated and whether dysregulations within the relationship of gut bacteria and the host epithelium contribute to diseases like inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and colorectal cancer.

Selected Publications:

Research Sketch:

Our research focuses on the interaction of nutrition and intestinal barrier function and their impact on health maintenance and longevity. In particular, we study the role of alterations of intestinal microbiota composition and barrier function as triggers in aging-associated health decline but also in the development of liver diseases. Using in vitro and mouse models, we aim to delineating molecular mechanisms involved in the loss of intestinal barrier function related to aging- and nutrition-associated impairments of intestinal barrier function. Herein, we especially focus on the role of dietary composition and energy bioavailability. Furthermore, diet-based prevention and therapeutic strategies to prevent alterations of intestinal barrier function and subsequently health impairments associated with these alterations are studied. 

Selected Publications:

Jin CJ, Sellmann C, Engstler AJ, Ziegenhardt D, Bergheim I. Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatits (NASH). Br J Nutr. 2015 Dec 14;114(11):1745-55.

Sellmann C, Jin CJ, Degen C, De Bandt JP, Bergheim I. Oral glutamine supplementation protects female mice from nonalcoholic steatohepatits. J Nutr. 2015 Oct;145(10):2280-6.

Jegatheesan P, Beutheu S, Ventura G, Nubret E, Sarfati G, Bergheim I, De Bandt JP. Citrulline and nonessential amino acids prevent fructose-induced nonalcoholic fatty liver disease in rats. J Nutr. 2015 Oct;145(10):2273-9.

Sellmann C, Priebs J, Landmann M, Degen C, Engstler AJ, Jin CJ, Gärttner S, Spruss A, Huber O, Bergheim I. Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time. J Nutr Biochem. 2015 Nov, 26(11):1183-92.

Engstler AJ, Aumiller T, Degen C, Dürr M, Weiss E, Maier IB, Schattenberg JM, Jin CJ, Sellmann C, Bergheim I. Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease. Gut 2015, May 25. pii: gutjnl-2014-308379. doi: 10.1136/gutjnl-2014-308379. [Epub ahead of print]

Research Sketch:

Our research is focused on nutrition and the gastrointestinal (GI) tract. In particular, we study the role of the GI barrier and the interaction between diet, commensal bacteria and the host’s mucosal immune system in the intestine under normal and inflammatory conditions. For example, we aim to define molecular mechanisms how diet, food components and the intestinal microbiota affect the GI barrier at the level of mucus, enterocytes, immune cells and enteric neurons. In turn, we want to know how the GI barrier may shape the intestinal microbiota and the intestinal mucosal immune response. Such interactions are thought to be of relevance for inflammatory (e.g. IBD, IBS) and for metabolic diseases (e.g. obesity, fatty liver disease) and thus might have major impact on health and disease.

Selected Publications:

Bergheim I, Weber S, Vos M, Krämer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. Journal of Hepatology 2008; 48:983-92.

Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. American Journal of Physiology 2009; 296:G685-95.

Hagenlocher Y, Bergheim I, Zacheja S, Schäffer M, Bischoff SC, Lorentz A. Cinnamon extract inhibits degranulation and de novo synthesis of inflammatory mediators in mast cells. Allergy 2013; 68:490-7.

Research Sketch:

We investigate the role of the gastrointestinal microbiota in health and disease. Diet has been identified as the main factor shaping the human gut microbiome. Various nutrition-related diseases are associated with the disturbances in the gut microbiome, but the mechanisms underlying these interactions are poorly understood. Therefore, diet-related activities of the intestinal microbiota and their consequences for the host are in the center of our research. Specific topics are:

• Role of commensal bacteria in the development of inflammatory bowel disease
• Contribution of intestinal bacteria to the development of obesity
• Conversion of dietary constituents by intestinal bacteria

The overall objective is to better understand the molecular basis of host-diet-microbe interactions in the gastrointestinal tract. We use gnotobiotic animal models and defined microbial communities to identify bacterial factors that affect regulatory and adaptive host functions.

Selected Publications:

Schumann S, Alpert C, Engst W, Klopfleisch R, Loh G, Bleich A, Blaut M (2014) Mild gut inflammation modulates the proteome of intestinal Escherichia coli. Environ Microbiol 16:2966-2979

Woting A, Pfeiffer N, Loh G, Klaus S, Blaut M (2014) Clostridium ramosum promotes high-fat diet-induced obesity in gnotobiotic mouse models. MBio 5:e01530-01514

Budnowski J, Hanske L, Schumacher F, Glatt H, Platz S, Rohn S, Blaut, M (2015) Glucosinolates are mainly absorbed intact in germfree and human microbiota-associated mice. J Agric Food Chem 63:8418-8428

Research Sketch:

The institute for laboratory animal science and the central animal facility of MHH (Ztm), one of the largest experimental animal facilities in Europe, are closely intertwined and directed in personal union; therefore, the group aims at interrelating basic research to laboratory animal science. Our current research interests are the pathophysiology of the gastro-intestinal mucosa (particularly animal models of inflammatory bowel diseases, IBD), gnotobiology and infection models, as well as projects related to laboratory animal medicine. In the latter, we focus on murine pathogens and their effect of on animal models and sanitation methods (e.g., parvovirus of mice or murine norovirus) as well as on innovative strategies for severity assessment in laboratory animals. Experimental work on IBD is based on genetic (quantitative trait) analysis and focuses on the identification of genes and microbial factors mediating colitis susceptibility. Furthermore, the institution has a long tradition of gnotobiotic work, including generation and maintenance of germ-free models and their utilization in experimental settings. This expertise has been successfully incorporated in various collaborations and cooperative research projects. Within the priority program, we make these techniques and experience available to the members of the SPP 1656.

Selected Publication:

Buchheister, S., Buettner, M., Basic, M., Noack, A., Breves, G., Buchen, B., Keubler, L.M., Becker, C., A. Bleich (2017). “CD14 Plays a Protective Role in Experimental Inflammatory Bowel Disease by Enhancing Intestinal Barrier Function.” Am J Pathol.187(5):1106-1120.

Nicklas, W., L. Keubler and A. Bleich (2015). "Maintaining and Monitoring the Defined Microbiota Status of Gnotobiotic Rodents." ILAR J 56(2): 241-249.

Bleich, A. and J. G. Fox (2015). "The Mammalian Microbiome and Its Importance in Laboratory Animal Research." ILAR J 56(2): 153-158.

Basic, M., L. M. Keubler, M. Buettner, M. Achard, G. Breves, B. Schroder, A. Smoczek, A. Jorns, D. Wedekind, N. H. Zschemisch, C. Gunther, D. Neumann, S. Lienenklaus, S. Weiss, M. W. Hornef, M. Mahler and A. Bleich (2014). "Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice." Inflamm Bowel Dis 20(3): 431-443.

Research Sketch:

The intestinal microbiota plays a crucial role in the conversion of dietary non-nutritive plant compounds and thereby affects their metabolism, bioavailability and effects on human health. Based on its enormous gene pool, the intestinal microbiota has a large metabolic potential and, thus, many reactions taking place in the intestinal tract are catalyzed by the resident bacteria. Knowledge on the bacterial species responsible for the conversion of many bioactive compounds ingested with diet is still limited even though these bacterial activities may contribute to different metabotypes of the human host. Our research is focused on the isolation and identification of human gut bacteria that are able to activate or inactivate dietary plant compound. We also aim to identify and further characterize the bacterial enzymes catalyzing key steps in the underlying conversion pathways. The in vivo activities of identified bacteria and their consequences for host health are studied using gnotobiotic animal models.

Selected Publications:

Braune A, Engst W, Blaut M (2016) Identification and functional expression of genes encoding flavonoid O- and C-glycosidases in intestinal bacteria. Environ Microbiol 18:2117-2129

Braune A, Blaut M (2016) Bacterial species involved in the conversion of dietary flavonoids in the human gut. Gut Microbes 7:216-234

Schröder C, Matthies A, Engst W, Blaut M, Braune A (2013) Identification and expression of genes involved in the conversion of daidzein and genistein by the equol-forming bacterium Slackia isoflavoniconvertens. Appl Environ Microbiol 79:3494-3502

Research Sketch:

The intestinal tract of mammals harbors diverse and complex bacterial communities. However, the symbiotic to pathogenic relationships between host and bacteria, and the underlying influence of bacterial activities on host functions, are still largely unknown. Nutritional factors are also intrinsic elements of the intestinal ecosystem and interact with both host and bacterial cells. To understand the human intestinal ecosystem and its implication in terms of health maintenance, bacteriological studies are essential. Our research activities are focused on the study of intestinal microbial communities by using next-generation sequencing and anaerobic culturing, with a particular focus on the description of community members and their functions. We also perform functional studies for the assessment of specific diet-microbe-host interactions in pre-clinical models, for instance on the role of bile acids conversion by gut bacteria in the context of metabolic and inflammatory disorders.

Selected publications:

Lagkouvardos, Pukall, Abt, Foesel, Meier-Kolthoff, Kumar, Bresciani, Martinez, Just, Ziegler, Brugiroux, Garzetti, Wenning, Bui, Wang, Hugenholtz, Plugge, Peterson, Hornef, Baines, Smidt, Walter, Kristiansen, Nielsen, Haller, Overmann, Stecher, Clavel (2016) The Mouse Intestinal Bacterial Collection (miBC) provides host-specific insight into cultured diversity and functional potential of the mouse gut microbiota. Nature Microbiol, in press

Lagkouvardos, Kläring, Heinzmann, Platz, Scholz, Engel, Schmitt-Kopplin, Haller, Rohn, Skurk, Clavel (2015) Gut metabolites and bacterial community networks during a pilot intervention study with flaxseeds in healthy adult men. Mol Nutr Food Res 59:1614

Daniel, Moghaddas Gholami, Berry, Desmarchelier, Hahne, Loh, Mondot, Lepage, Rothballer, Walker, Böhm, Wenning, Wagner, Blaut, Schmitt-Kopplin, Kuster, Haller, Clavel (2014) High-fat diet alters gut microbiota physiology in mice. ISME J 8:295

Research Interests:

It is now firmly established that immune recognition at mucosal interfaces occurs continuously but does not lead to an overt inflammatory response. Constitutive immune activation at barrier surfaces instructs immune effector functions which promote tissue homeostasis, epithelial integrity and repair. For such homeostatic circuitry, an intimate and often mutualistic relationship between innate immune cells, the indigenous microbiota and epithelial cells has been established. We and others have identified the first molecular pathways of how lymphoid cells within the intestinal mucosa are functionally dependent on molecular cues from the environment and how they contribute to maintaining tissue homeostasis and to promoting host-microbe mutualism. Specifically, our discovery of novel lineages of mucosa-resident innate lymphocytes, now collectively referred to as innate lymphoid cells (ILCs), has provided strong evidence for such bidirectional crosstalk between immune system components and the environment resulting in signals that promote organ homeostasis. Interestingly, the transcriptional networks promoting organ homeostasis strikingly resemble those reported for the maintenance of epithelial homeostasis in invertebrates. Thus, these lines of research are beginning to reveal previously unappreciated immune functions of innate lymphocytes that apparently consisted in increasing barrier function by promoting epithelial regeneration and by maintaining organ homeostasis. Our current and future research is focused on a molecular understanding of how innate immune system components are instructed by environmental cues (microbiota, nutrient compounds), how innate lymphoid cells (ILCs) dynamically shape the microbial ecosystem residing on mucosal surfaces and how these interactions promote at the same time immunity to intestinal infections and organ homeostasis or epithelial adaptation.

Selected Publications:

Klose, C.S.N., E.A.Kiss, V.Schwierzeck, K.Ebert, T.Hoyler, Y.d’Hargues, N.Göppert, A.L.Croxford, A.Waisman, Y.Tanriver, and A.Diefenbach. 2013. A T-bet gradient controls the fate and function of CCR6^- RORgt⁺ innate lymphoid cells. Nature. 494:261-265.

Ganal, S.C., S.L.Sanos, C.Kallfass, K.Oberle, C.Johner, C.Kirschning, S.Lienenklaus, S.Weiss, P.Staeheli, P.Aichele, and A.Diefenbach. 2012. Priming of natural killer cells by non-mucosal mononuclear phagocytes requires instructive signals from the commensal microbiota. Immunity. 37:171-186.

Kiss, E.A., C.Vonarbourg, S.Kopfmann, E.Hobeika, D.Finke, C.Esser, and A.Diefenbach. 2011. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 334:1561-1565.

Research Sketch:

Nature provides an enormous diversity of lipid molecules. Fatty acids (FA) are the building blocks of various lipids, including cell membrane phospholipids (PL). For numerous cellular processes, such as cell growth or differentiation, as well as for key cellular functions, FA and PL must be synthesized de novo. Exogenous lipid uptake from nutrition leads to endogenous lipid synthesis and remodeling of PL acyl chains. The focus of our current and future research is to understand the principles of cellular uptake of FA from the diet as well as the metabolism and dynamics of FA and PL synthesis under physiological and pathophysiological conditions. It is of particular interest for us how gut microbiota affect these metabolic processes and what are underlying molecular mechanisms. As tool to gain insight into the metabolism and dynamics of lipid species, stable isotope-labeled tracers combined with mass spectrometric analysis are applied.

Selected Publications:

Ecker, J., and G. Liebisch. 2014. Application of stable isotopes to investigate the metabolism of fatty acids, glycerophospholipid and sphingolipid species. Prog Lipid Res. 54:14-31.

Ecker, J., G. Liebisch, M. Englmaier, M. Grandl, H. Robenek, and G. Schmitz. 2010. Induction of fatty acid synthesis is a key requirement for phagocytic differentiation of human monocytes. PNAS. 107:7817-22.

Ecker, J., G. Liebisch, M. Scherer, and G. Schmitz. 2010. Differential effects of conjugated linoleic acid isomers on macrophage glycerophospholipid metabolism. J Lipid Res. 51:2686-94.

Research Sketch:

The dramatic increase of inflammatory bowel diseases in the industrialized world implies a complex interaction of host genetic predispositions and environmental factors. The gut acts as a highly selective barrier and communication organ between the environment and the intestinal immune system responsible for the regulation of metabolism and immunity in the host. It has been proposed to complement the search for disease susceptibility genes in the human genome with the analysis of the gut "microbiome", considering the fact that health or disease is being determined by the complex interaction of the host with its gut microbial ecosystem. The peaceful and productive coexistence of the host with its gut microbiota is tightly controlled at various levels and a failure of this homeostasis is thought to contribute to the development of inflammatory bowel diseases. We are focusing in the understanding for the role of bacteria-host interactions in the development or prevention of chronic inflammatory or infectious disorders of the mammalian gastrointestinal system. Our aims are: 1) To  identify commensal bacteria or components of commensal bacteria preventing intestinal inflammation, 2) to clarify the interaction between commensal bacteria and the intestinal host target cells, resulting in prevention of intestinal inflammation 3) the identification of the cell signaling processes induced by commensal bacteria and supporting maintenance of intestinal homoeostasis

Selected Publications:

Gronbach K, Flade I, Holst O, Lindner B, Ruscheweyh HJ, Wittmann A, Menz S, Schwiertz A, Adam P, Stecher B, Josenhans C, Suerbaum S, Gruber AD, Kulik A, Huson D, Autenrieth IB and Frick JS. The dichotomic role of LPS: induction or prevention of intestinal inflammation. Gastroenterology, in press

Gronbach K, Eberle U, Müller M, Ölschläger TA, Dobrindt U, Leithäuser F, Niess JH, Döring G, Reimann J, Autenrieth IB, and Frick JS. Safety of probiotic Escherichia coli strain Nissle 1917 depends on intestinal microbiota and adaptive immunity of the host. Infect Immun. 2010 Jul;78(7):3036-46.

Frick JS, MacManus CF, Scully M, Glover LE, Eltzschig HK and Colgan SP. Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis. J Immunol. 2009 Apr 15;182(8):4957-64

Research sketch:

Despite growing evidence for the fundamental role of the human microbiota for health and disease, few examples exist where direct mechanistic links between specific microbiota features and human health have been described. Similarly, the term dysbiosis, although widely used to describe disturbed host-microbiota interactions, is poorly defined and the biological relevance of commonly used microbiota parameters for dysbiosis, such as taxonomic composition, remains unclear. As a consequence, it is generally impossible to predict beneficial or detrimental effects of a specific microbiota on a given host. To address the need for functionally and clinically relevant microbiota parameters, the goal of our group is to use microbial genomics and bioinformatics to quantify microbiota features of immunological relevance, in order to search for novel diagnostic biomarkers and therapeutic targets.

Selected publications:

Dutta SK, Girotra M, Garg S, Dutta A, von Rosenvinge EC, Maddox C, Song Y, Bartlett JG, Vinayek R, Fricke WF. 2014. Efficacy of combined jejunal and colonic fecal microbiota transplantation for recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol 12(9):1572-6. doi: 10.1016/j.cgh.2013.12.032.

Fricke WF, Rasko DA. 2014. Bacterial genome sequencing in the clinic: bioinformatic challenges and solutions. Nat Rev Genet 15(1):49-55. doi: 10.1038/nrg3624.

von Rosenvinge EC, Song Y, White JR, Maddox C, Blanchard T, Fricke WF. 2013. Immune status, antibiotic medication and pH are associated with changes in the stomach fluid microbiota. ISME J 7(7):1354-66. doi: 10.1038/ismej.2013.33.

Research Sketch:

The focus of our research is the bidirectional host-microbe communication. Analysis of involved signaling pathways revealed so far unrecognized signalosome components of cytokine and pattern recognition receptors driving early decisions in the innate and adaptive host immune responses as well as in tissue homoeostasis. One of the major antibacterial and immunmodulatory effectors controlled by these host signals at mucosal surfaces is bactericidal/permeability increasing protein (BPI). By evaluating the role of BPI bone marrow chimeric mice or our newly generated animals with a conditional deletion in epithelial cells of the gastrointestinal tract the relative contribution of both cell compartments to the bidirectional host-microbiota communication in the gut will be clarified. To foster standardization of next generation sequencing microbiome data acquisition and analysis our core facility organizes multicentre external quality assessments schemes (EQAS).   

Selected Publications:

Goldwich A, Burkard M, Olke M, Daniel C, Amann K, Hugo C, Kurts C, Steinkasserer A, Gessner A. Podocytes are nonhematopoietic professional antigen-presenting cells. J Am Soc Nephrol. 2013 May;24(6):906-16.

Sitte S, Gläsner J, Jellusova J, Weisel F, Panattoni M, Pardi R, Gessner A. JAB1 is essential for B cell development and germinal center formation and inversely regulates Fas ligand and Bcl6 expression. J Immunol. 2012 Mar 15;188(6):2677-86.

Holweg A, Schnare M, Gessner A. The bactericidal/permeability-increasing protein (BPI) in the innate defence of the lower airways. Biochem Soc Trans. 2011, 39 (4):1045-50. 

Research sketch:

In our laboratory we try to understand the interaction of enteropathogenic bacteria with the host and its microbiota. In particular, we’re focussing on the host and bacterial mechanisms leading to the development of acute and chronic inflammation, intestinal fibrosis and stricture formation. Our main research interests include, i) identification of the bacterial factors contributing to acute and chronic infection, inflammation and fibrosis, ii) characterization of the host mechanisms involved in inflammation and intestinal fibrosis and iii) the role of the microbiota in modulating host-pathogen interactions.  

Selected Publications:

Rausch P, Künzel S, Suwandi A, Grassl GA, Rosenstiel P, Baines JF. Multigenerational influences of the Fut2 gene on the dynamics of the gut microbiota in mice. Front Microbiol. in press.

Rausch P, Basic M, Batra A, Bischoff SC, Blaut M, Clavel T, Gläsner J, Gopalakrishnan S, Grassl GA, Günther C, Haller D, Hirose M, Ibrahim S, Loh G, Mattner J, Nagel S, Pabst O, Schmidt F, Siegmund B, Strowig T, Volynets V, Wirtz S, Zeissig S, Zeissig Y, Bleich A, Baines JF. Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities. Int J Med Microbiol. 2016 Mar 15. pii: S1438-4221(16)30019-4

Rausch P, Steck N, Suwandi A, Seidel JA, Künzel S, Bhullar K, Basic M, Bleich A, Johnsen JM, Vallance BA, Baines JF, Grassl GA. Expression of the blood-group-related gene B4galnt2 alters susceptibility to Salmonella infection. PLoS Pathogens, 2015; 11(7):e1005008

Claes AK, Steck N, Schultz D, Zähringer U, Lipinski S, Rosenstiel P, Geddes K, Philpott DJ, Heine H, Grassl GA. Salmonella enterica serovar Typhimurium ΔmsbB triggers exacerbated inflammation in Nod2 deficient mice. PLOS One. 2014. 25;9(11):e113645

Grassl GA*, Valdez Y*, Bergstrom KSB, Vallance BA, Finlay BB. Chronic enteric Salmonella infection in mice leads to severe and persistent intestinal fibrosis. Gastroenterology. 2008;134(3):768-80.

Research Sketch:

The gut mucosa is the largest and most dynamic immunological environment of our body and is often the frontline of pathogen exposure. Therefore an efficient intestinal barrier is essential to maintain intestinal homeostasis by avoiding excessive exposure of the gut immune system to microbial antigens. The major interest of our group is to understand the interaction between the intestinal microbiota and the first line of innate defence, represented by the single layer of epithelial cells. Homeostasis of this cell layer is achieved by a tightly controlled activation of proliferation, differentiation and cell death. We specifically aim to investigate the influence of the microbial flora in regulating a new form of cell death, called necroptosis and necroptosis driven intestinal inflammation.

Selected Publications:

Wittkopf N*, Günther C*, Martini E, He Y, Neurath MF, Schuchmann M, Becker C. Cellular FLICE-inhibitory protein allows intestinal epithelial cell survival and immune homeostasis by controlling the activation level of caspase-8. Gastroenterology, accepted for publication, * These authors contributed equally to this work

Günther C., H. Neumann, M.F. Neurath, C. Becker. Apoptosis, necrosis and necroptosis: Cell death regulation in the intestinal epithelium.
Gut. 2013. 62(7):1062-71.

Günther C., Martini E., Wittkopf N., Amann K., Weigmann B., Neumann H., Waldner M.J., Hedrick S.M., Tenzer S., Neurath M.F., Becker C. Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature. 2011. 477(7364):335-9.

Research Sketch:

Intestinal epithelial cells sense the presence of enteropathogenic microorganisms, forward this information to neighboring cells and underlying immune cells and provide efficient antimicrobial protection. Also under homeostatic conditions, the epithelium contributes actively to the maintenance of the mucosal barrier and repair following transient mucosal damage. Own results illustrate epithelial stimulation during microbial infection and identify regulatory mechanisms that help to maintain host-microbial homeostasis under physiological conditions. The most striking example of the dynamic function of the gut epithelium is the transition from the sterile and protected situation before birth to the mucosal surface of the adult intestine that is permanently exposed to the enteric microbiota and nutritional stimuli. Own results have identified both adaptive and developmentally regulated mechanisms that help to maintain host-microbial homeostasis and facilitate the establishment of a stable and highly diverse enteric microbiota. They illustrate the active role of the intestinal epithelium during the establishment and maintenance of mucosal immune homeostasis as well as antimicrobial host defense.

Selected Publications:

Dupont, A., Litvak, Y., Zhang, K., Sommer, F., Basic, M., Kühnel, M., Bäckhed, F., Fulde, M., Rosenshine, I., Hornef, M.W. Infection with enteropathogenic Escherichia coli (EPEC) is restricted to the perinatal period in mice. PLoS Pathog. 12(5):e1005616, 2016.

Torow, N., Yu, K., Hassani, K., Bleich, A., Lochner, M., Brenneke, A., Weiss, S., Förster, R., Pabst, O., Hornef, M.W. Active suppression of intestinal CD4+TCRαβ+ T lymphocyte maturation during the postnatal period. Nat Commun. 6: 7725, 2015.

Torow, N., Hornef, M.W. The neonatal ‘window of opportunity’, - setting the stage for the life-long host microbial interaction and immune homeostasis. J. Immunol. 198(2):557-563, 2017

van Best, N., Hornef, M.W., Savelkoul, P.H., Penders, J. On the origin of species: Factors shaping the establishment of infant's gut microbiota. Birth Defects Res C Embryo Today. 105(4):240-51, 2015

Chassin, C., Kocur, M., Pott, J., Duerr, C.U., Gütle, D., Lotz, M., Hornef, M.W. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 8: 358-68, 2010

Research Sketch:

We are interested in gaining a better understanding of the events underlying chronic inflammation and inflammation-induced tumor development at mucosal surfaces. The current concepts of the pathogenesis underlying inflammatory bowel diseases (IBD) imbed multiple factors causing an impaired integrity of the mucosal, i.e. epithelial barrier in genetically susceptible patients that concomitantly results in the translocation of microbial content initiating a tissue-destroying immune response. Both microbiota and microbiota-derived signals resp. and immune system-related pathways have been shown to be crucially contributing to intestinal homeostasis. However, dysregulation of the intestinal homeostasis is seemingly due to abnormalities of both the microbial and immune compartment. Currently, we focus on three aspects of the microbiota-host interaction: i) identification of microbial communities and microbiota-derived metabolites in the intestinal compartment with colitogenic properties (dysbiosis) ii) studies on host-derived mechanisms critical for sensing microbiota and microbiota-derived metabolites in the context of colitis and iii) investigations on pathways and effector mechanisms underlying microbiota-driven immune cell activation and effector cell differentiation.

Selected Publications:

Punkenburg E, Vogler T, Büttner M, Amann K, Waldner M, Atreya R, Abendroth B, Mudter J, Merkel S, Gallmeier E, Rose-John S, Neurath MF, Hildner K (2016). Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer. Gut 65(7): 1139-1150.

Edelson B.T., Wumesh K.C., Juang R., Koyama M., Klekotka P.A., Sung, S.S.J., Murphy, T.L., Hildner K, Murphy K.M. (2010). Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med. 207(4):823-36.

Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, Calderon B, Schraml BU, Unanue ER, Diamond MS, Schreiber RD, Murphy TL, Murphy KM. (2008). Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science. 322 (5904):1097-100.

Research Sketch:

Although it is widely accepted that epigenetic mechanisms contribute to fixation of immune cell fates, molecular details are largely unknown. A better understanding of the events leading to engraved gene expression profiles will enable us to generate tailored immune cell subsets with epigenetically fixed functional properties for therapeutic purposes. In addition, only fragmentary knowledge has been accumulated about the impact of infections and environmental cues such as diet, commensal microbiota or chronic inflammation on immune cells’ epigenomes. These epigenetic modifications, particularly if acquired at young age, might have long-lasting and even life-long consequences for the functionality of the immune system. In our department, we are investigating how epigenetic mechanisms contribute to immune cell development, differentiation and function. 

Selected Publications:

Cording S*, Wahl B*, Kulkarni D, Chopra H, Pezoldt J, Buettner M, Dummer A, Hadis U, Heimesaat M, Bereswill S, Falk C, Bode U, Hamann A, Fleissner D, Huehn J*, and Pabst O*. 2014. The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes. Mucosal Immunol 7:359-368. *equal contribution

Yang B-H, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M, Föhse L, Prinz I, Pezoldt J, Suerbaum S, Sparwasser T, Hamann A, Floess S, Huehn J*, Lochner M* Foxp3⁺ T cells expressing RORgt represent a stable regulatory T cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9:444-457. *equal contribution

Huang Y-J, Haist V, Baumgärtner W, Floess S*, Huehn J*. 2014. Induced and thymus-derived Foxp3+ regulatory T cells share a common niche within the CD4+ T cell compartment. Eur J Immunol 44:460-468. *equal contribution

Research Sketch:

The main areas of research are the development and application of algorithms and software for analyzing genomic and metagenomic data. One of the main results of this work is the computer program MEGAN, which is has become a standard tool for metagenome analysis. Current research focuses on developing high through analysis techniques for very fast and accurate taxonomic identification of disease-related microbial strains, and on the accurate identification of microbial genes and virulence factors. In close cooperation with medical colleagues, the developed methods are applied to investigate the role of intestinal microbiota in a number of conditions such as  IBD and Aditpositas.

Selected Publications:

Research Sketch:

Together with Josef Ecker we are interested how gut microbiota affects the resorption of fatty acids, intestinal lipid synthesis and storage. Our main expertise is the development and application of methods for lipid species quantification. Furthermore, we use stable isotope labelled lipid precursor and fatty acids to trace transport and metabolism of lipids in the intestine.

Selected Publications:

Liebisch G, Ejsing CS, Ekroos K. Identification and Annotation of Lipid Species in Metabolomics Studies Need Improvement. Clin Chem. 2015 Dec;61(12):1542-4

Ecker J, Liebisch G. Application of stable isotopes to investigate the metabolism of fatty acids, glycerophospholipid and sphingolipid species. Prog Lipid Res. 2014 Apr;54:14-31

Liebisch G, Lieser B, Rathenberg J, Drobnik W, Schmitz G. High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm. Biochim Biophys Acta. 2004 Nov 8;1686(1-2):108-17.

Research sketch:

Complex interactions between environmental factors and genetic predisposition underlie the pathogenesis of many immune-mediated diseases. However, regulatory pathways that control the initiation and termination of immune responses and maintain mucosal homeostasis have been rarely identified. Here we plan to study cellular and molecular mechanisms that influence the integrity of the intestinal epithelial cell layer. Consequently, our work will help to identify therapeutic targets and approaches that can be used to guide the development of effective therapies for inflammatory bowel disease, but also allows the identification of common targets in autoimmune disease for clinical intervention in the future.

Selected publications:

Mattner J., DeBord K.L., Goff R.D., Cantu III C., Zhou D., Saint-Mezard P., Wang V., Gao Y.,  Yin N., Hoebe K., Schneewind O., Ismail N., Walker D., Beutler B., Teyton L., Savage P.B., Bendelac A. (2005). Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature. 434: 525-529

Mattner J., Savage P.B., Leung P., Oertelt S.S., Wang V., Trivedi O., Scanlon S.T., Pendem K., Teyton L., Hart J., Ridgway W.M., Wicker L.S., Gershwin M.E., Bendelac A. (2008) Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host & Microbe. 3:304-315.

Mohammed J.P., Fusakio M.E., Rainbow D.B., Moule C., Fraser H.I., Clark J., Todd J.A., Peterson L.B., Saage P.B., Wills-Karp M., Ridgway W.M., Wicker L.S., Mattner J. (2011). Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol. 187:337-349.

Research sketch:

The research of my group is mainly dedicated to the pathogenesis of inflammatory bowel diseases, chronic intestinal inflammation and colorectal cancer. Signaling cascades in the innate and adaptive mucosal immune systems as well as the interaction between bacterial signals and the immune system are of particular interest. Furthermore, novel imaging techniques including high resolution endoscopy, molecular imaging approaches and endomicroscopy are studied.  

Selected publications:

Dornhoff H, Becker C, Wirtz S, Strand D, Tenzer S, Rosfa S, Neufert C, Mudter J, Markl J, Siebler J, Neurath MF. A variant of Smurf2 protects mice against colitis-associated colon cancer by inducing transforming growth factor beta signaling. Gastroenterology 2012;142:1183-1194 e4.

Waldner MJ, Wirtz S, Jefremow A, Warntjen M, Neufert C, Atreya R, Becker C, Weigmann B, Vieth M, Rose-John S, Neurath MF. VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J Exp Med 2010;207:2855-68.

Neurath MF, Finotto S. Translating inflammatory bowel disease research into clinical medicine. Immunity 2009;31:357-61.

Research sketch:

The intestine hosts a vast number of microbes, collectively referred to as the microbiota, that greatly influence development and function of intestinal and systemic immune systems. A key component in host-microbiota interaction is secretory immunoglobulin A (sIgA). sIgA binds to bacteria, viruses and toxins and thus protects the mucosal epithelium. Our research aims at understanding how host-microbe interactions shape the individual´s IgA repertoire. We could show that a complex microbiota triggers immunoglobulin A repertoire diversity and that the IgA antibody repertoire is surprisingly stable during dysbiosis. Apart from the occasional encounter of pathogens, the gut mucosa mostly contacts innocuous antigens provided by food and the gut microbiota. Such antigens are not ignored but trigger well balanced immune responses that establish a state of mucosal tolerance. Failure of mucosal tolerance results in food intolerance and chronic inflammatory bowel diseases, pathologies that are markedly on the rise in developed nations. We thus focus on investigating cells, migratory processes and regulatory mechanisms involved in induction and maintenance of mucosal tolerance. 

Selected publications:

Lindner C, Wahl B, Föhse L, Suerbaum S, Macpherson AJ, Prinz I, Pabst O. .2012 Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J Exp Med. 209(2):365-77

Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, Müller W, Sparwasser T, Förster R, Pabst O.. 2011. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34(2):237-46

Schulz O, Jaensson E, Persson EK, Liu X, Worbs T, Agace WW, Pabst O.. 2009. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med. 206(13):3101-14

Research Sketch:

The main focus of our research is to understand the mechanisms regulating immune homeostasis and inflammation in barrier tissues such as the intestine.

We are particularly interested to understand how host epithelial, stromal and immune cells communicate with the microbiota and how this cross-talk determines health and disease in the intestine. We use genetic mouse models to dissect the cell-specific function of TLR and TNF receptor signalling in regulating the host-microbiota interactions and the pathogenesis of inflammatory intestinal pathologies.

Selected Publications:

Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, Huth M, Nikolaev A, Neufert C, Madison B, Gumucio D, Neurath MF & Pasparakis M (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446: 557–561

Vlantis K, Wullaert A, Sasaki Y, Schmidt-Supprian M, Rajewsky K, Roskams T & Pasparakis M (2011) Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. J Clin Invest 121: 2781–2793

Welz P-S, Wullaert A, Vlantis K, Kondylis V, Fernández-Majada V, Ermolaeva M, Kirsch P, Sterner-Kock A, van Loo G & Pasparakis M (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477: 330–334

Research Sketch:

Our group seeks to understand the principles that govern the interplay among members of our microbiota, in particular between commensals and microbes that can cause disease in humans. We focus our research on Candida albicans, the most prominent fungal species residing in healthy humans and also the major cause of serious fungal infections. A major approach that we use in the lab is to experimentally identify, map and dissect relevant gene regulatory circuits that endow this yeast with the ability to colonize different niches of the human body. Acquiring a functional and mechanistic understanding of the interdependencies that exist among microorganisms and their host may allow us to devise potential interventions that target physiologically relevant interactions to prevent infections.

Selected Publications:

Böhm L, Muralidhara P, Pérez JC (2016) A Candida albicans regulator of disseminated infection operates primarily as a repressor and governs cell surface remodeling. Mol Microbiol 100:328-344.

Pérez JC, Kumamoto CA, Johnson AD (2013) Candida albicans commensalism and pathogenicity are intertwined traits directed by a tightly knit transcriptional regulatory circuit. PLoS Biol 11:e1001510.

Pérez JC, Groisman EA (2009) Evolution of transcriptional regulatory circuits in bacteria. Cell 138:233-244.

Research Sketch:

Our expertise is the analysis of the chemical diversity of complex bio(geo)systems using an  integrated analytical approach of separation sciences, mass spectrometry and spectroscopy. In Biology this resumes for example in unravelling the (Meta)metabolomes of the rhyzosphere in microbial and(or) plant systems or of lung/gut related microbial ecosystem in various stress situations in mammalian systems. We setup comprehensive approaches such as (ultra)high resolution mass spectrometry and nuclear magnetic resonance to resolve the complex organic mixture. Current metabolomics studies are addressing in-vitro, in-vivo murine and human body fluids (plasma, urine, air breath condensates and feces) with a focus on diet impact or metabolic disorders like type 2 diabetes and obesity.

Selected Publications:

Müller, C. ; Dietz, I.* ; Tziotis, D. ; Moritz, F. ; Rupp, J.* ; Schmitt-Kopplin, P. Molecular cartography in acute Chlamydia pneumoniae infections - a non-targeted metabolomics approach. Anal. Bioanal. Chem. 405, 5119-5131 (2013)

Jansson, J.* ; Willing, B.* ; Lucio, M. ; Fekete, A. ; Dicksved, J.* ; Halfvarson, J.* ; Tysk, C.* ; Schmitt-Kopplin, P. Metabolomics reveals metabolic biomarkers of Crohn's disease. PLoS ONE 4:e6386 (2009)

Daniel, H., A. M. Gholami, D. Berry, C. Desmarchelier, H. Hahne, G. Loh, S. Mondot, P. Lepage, M. Rothballer, A. Walker, C. Bohm, M. Wenning, M. Wagner, M. Blaut, P. Schmitt-Kopplin, B. Kuster, D. Haller and T. Clavel (2013). "High-fat diet alters gut microbiota physiology in mice." ISME J.

Research sketch:

Our research focuses on studies of the immunologic and molecular mechanisms involved in the development of inflammation and cancer in the gastrointestinal tract. One part of our research is aimed at identification of novel biomarkers and important nutritional triggers of intestinal inflammation and cancer. We are further interested in the interaction between key nutritional modulators (Major emphasis is on common carbohydrates, ATIs in gluten containing cereals, and major lipids), commensal bacteria and the host’s mucosal immune system in the intestine under normal and inflammatory conditions.

Selected Publications:

Zschiebsch K, Fischer C, Pickert G, Häussler A, Radeke H, Grösch S, Ferreirós N, Geisslinger G, Werner ER, Tegeder I. (2016): Tetrahydrobiopterin Attenuates DSS-evoked Colitis in Mice by Rebalancing Redox and Lipid Signalling. J Crohns Colitis.  2016 Feb 29. pii: jjw056.

Pickert G, Lim HY, Weigert A, Häussler A, Myrczek T, Waldner M, Labocha S, Ferreirós N, Geisslinger G, Lötsch J, Becker C, Brüne B, Tegeder I. (2012): Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2-like polarization of tumor associated macrophages. Int J Cancer. Jun 30.

Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr HA, Hirth S, Weigmann B, Wirtz S, Ouyang W, Neurath MF, Becker C (2009): STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 6;206(7):1465-72.

Research Sketch:

The gastrointestinal epithelium builds a physical barrier separating the luminal microbiota from the host.  Although it consists only of a cellular monolayer, the gut epithelium is highly efficient in preventing bacterial penetration. One characteristic feature of the gastrointestinal epithelium is the rapid turnover that is driven by long-lived stem cells located in the base of intestinal crypts. Disruption of epithelial turnover results in a malfunction of the epithelium and increased risk for bacterial penetration. We study which cellular and molecular processes are responsible for the normal stem cell turnover in the gut. We would like to understand how the microbiota affects these signals. Furthermore, we study whether specific bacteria can colonize the stem cell compartment in the gut under physiological as well as pathological conditions and how direct or indirect interactions of bacteria with stem cells contribute to inflammatory and malignant gastrointestinal diseases.

Related publications:

Sigal M, Rothenberg ME, Logan CY, Lee JY, Honaker RW, Cooper RL, Passarelli B, Camorlinga M, Bouley DM, Alvarez G, Nusse R, Torres J, Amieva MR. Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands. Gastroenterology. 2015 Jun; 148(7):1392-1404

Earle KA, Billings G, Sigal M, Lichtman JS, Hansson GC, Elias JE, Amieva MR, Huang KC, Sonnenburg JL. Quantitative Imaging of Gut Microbiota Spatial Organization. Cell Host Microbe. 2015 Oct 14;18(4):478-88

Sigal M. & Meyer TF. Coevolution between the Human Microbiota and the Epithelial Immune System. Digestive Diseases, 2016;34(3):190-3

Research Sketch:

Intestinal microbiota and barrier function may majorly impact health maintenance and longevity, thereby also modulating healthy life-span. Furthermore, impairments of intestinal barrier function, changes in intestinal microbiota composition and alterations of the TH1/TH2 cell balance as well as redox status in the gut are discussed to be critical in the development of the low-grade inflammation, frequently found in elderly. However, the interaction between intestinal microbiota, barrier function, immune system and aging-associated degeneration and decline is only partially understood.

The aim of our work is to understand the interaction of active intestinal microbiota and intestine during aging with a particular focus on the impact of diet and energy bioavailability as factors contributing to aging-associated alterations of intestinal microbiota and intestinal barrier function in humans and mice. The project also aims to contribute to the understanding of the fundamental principles of microbe-host interaction.

Selected Publications:

Burbach K, Seifert J, Pieper DH, Camarinha-Silva A. 2016. Evaluation of DNA extraction kits and phylogenetic diversity of the porcine gastrointestinal tract based on Illumina sequencing of two hypervariable regions. MicrobiologyOpen 5:70-82

Witzig M, Camarinha-Silva A, Green-Engert R, Hoelzle K, Zeller E, Seifert J, Hoelzle LE, Rodehutscord M. 2015. Spatial variation of the gut microbiota in broiler chickens as affected by dietary available phosphorus and assessed by T-RFLP analysis and 454 pyrosequencing. Plos One 10: e0143442

Camarinha-Silva A, Chaves, D, Jáuregui, R, Schaumburg, F, Becker K, Wos-Oxley, ML, Pieper, DH. 2014. Comparing the anterior nare bacterial community of two discrete human populations using Illumina amplicon sequencing. Environmental Microbiology 16: 2939-2952.

Camarinha-Silva A, Jáuregui R, Pieper DH, Wos-Oxley ML. 2012. The temporal dynamics of bacterial communities across human anterior nares. Environmental Microbiology Reports 4: 126-132.

Research Sketch:

Our research focus is to study the interaction of the intestinal microbiota with enteric pathogens. An undisturbed microbial ecosystem in the gut mediates colonization resistance, e.g. it effectively blocks the invasion of a variety of human pathogens including Salmonella spp., E. coli and Clostridium difficile. We investigate direct microbiota-mediated effects such as competition for resources (e.g. nutrients, mucin adhesion sites) as well as production of antibacterial proteins (e.g. bacteriocins). On the other hand we address how the microbiota stimulates the host´s mucosal immune defense to strengthen the mucosal barrier against pathogens. To elucidate the mechanisms of microbiota-pathogen interaction we combine experimental in vitro approaches applying specific pathogen mutant strains, biochemical methods and microscopy techniques with mouse infections models and next generation microbiome analysis. Additionally, we develop gnotobiotic mouse models using well characterized commensal bacterial consortia isolated from mice (Oligo-Mouse-Microbiota).

Selected Publications:

Clavel T, Lagkouvardos I, Blaut M, Stecher B. The mouse gut microbiome revisited: From complex diversity to model ecosystems. Int J Med Microbiol. 2016 Mar 5. pii: S1438-4221(16)30017-0. doi: 10.1016/j.ijmm.2016.03.002. PMID: 26995267

Li H, Limenitakis JP, Fuhrer T, Geuking MB, Lawson MA, Wyss M, Brugiroux S, Keller I, Macpherson JA, Rupp S, Stolp B, Stein JV, Stecher B, Sauer U, McCoy KD, Macpherson AJ. The outer mucus layer hosts a distinct intestinal microbial niche. Nat Commun. 2015 Sep 22;6:8292. doi: 10.1038/ncomms9292.

Nedialkova L^*, Denzler R.^*, Koeppel M.B., Diehl M., Ring D., Gerlach R.G. and Stecher B. Inflammation fuels colicin Ib-dependent competition of Salmonella serovar Typhimurium and E. coli in Enterobacterial blooms. PloS Pathogens. 2014 Jan;10(1):e1003844. Epub 2014 Jan 2.

Stecher B. The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection. Microbiol Spectr. 2015 Jun;3(3). doi: 10.1128/microbiolspec.MBP-0008-2014. PMID: 26185088

Research Sketch:

The mucosal immune system of the gut is confronted with two major sources of antigens, i.e. microbial and dietary antigens. Both antigenic sources influence each other, i.e. diet impacts on the microbial composition and microbes determine the availability of intestinal metabolites. Unbalanced nutrition or malnutrition disturbs the gut barrier, often resulting in IBD.  

Our interest is to investigate the mechanism and impact of physiological immune recognition of dietary protein on immune tolerance, intestinal barrier integrity and microbial composition. These studies comprise analyses in germfree and normofloric animals in order to determine microbial dependent and independent immune reactions of the small intestine and colon. We could show that normal dietary protein are preferentially taken up by cells in the Peyer´s patches and stimulate conventional CD4⁺T cells which are distinct from Tregs. Substitution of dietary proteins by amino acids leads to a hypo-cellular small intestine with decreased T and B cells in Peyers patches, lamina propria and increased expression of inflammatory markers in the small intestine. Our interest is to study the anti-inflammatory properties of dietary protein uptake on the immunological, microbiological and metabolic level.  

Selected publications:

Visekruna A, Linnerz T, Martinic V, Vachharajani N, Hartmann S, Harb H, Joeris T, Pfefferle P, Hofer J M and U. Steinhoff. (2015) Transcription factor c-Rel plays a crucial role in driving anti-CD40-mediated innate colitis. Mucosal Immunol. 8:307-15.

Lawrenz M, Visekruna A, Kühl A., Schmidt N, Kaufmann SHE and Steinhoff U (2012) Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn´s disease? Mucosal Immunol. 2: 129-139.

Schmidt N, Gonzales E, Visekruna A, Kühl A, Loddenkemper C, Mollenkopf H, Kaufmann SHE  Steinhoff U, and T Joeris (2010). Targeting the proteasome: Partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut 59: 896-906

Heimesaat MM, Nogai A, Bereswill S,  Plickert R, Fischer A, Loddenkemper C, Steinhoff U, Tchaptchet S, Thiel E, Freudenberg MA, Göbel UB, Uharek L. (2010) MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 59:1079-87.

Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P,  Kühl A, Loddenkemper C, Haury M,  Nedospasov S, Kaufmann SHE, Steinhoff U,  Calado D and Fillatreau S (2010). MyD88-signalling in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity, 33:777-90

Research Sketch:

The focus of the research group is the interplay between the host and the microbiota. Specifically we are interested in the how the innate immune system deals with a group of bacteria, termed pathobionts, which may be harmful to the host. We are using a wide array of technologies including genetically modified mice, microbiology, immunology and next generation sequencing to characterize how both host and microbe regulate the typically symbiotic interaction and how it may turn wrong causing diseases in the host.

Selected Publications:

Research Sketch:

In the context of SPP 1656, we study the mutual interactions between the Gram-negative pathobiont Helicobacter hepaticus, the gastrointestinal microbiota, and intestinal inflammation in different mouse models of H. hepaticus-induced typhlocolitis.

In addition to this line of research, which started with the elucidation of the complete genome sequence of H. hepaticus in 2003, my laboratory studies the genetic/genomic adaptation of the carcinogenic human pathogen Helicobacter pylori to its human host, its phylogeographic population structure and mechanisms enabling chronic persistence.

Selected publications:

Yang, I., D. Eibach, F. Kops, B. Brenneke, S. Woltemate, J. Schulze, A. Bleich, A. D. Gruber, S. Muthupalani, J. G. Fox, C. Josenhans und S. Suerbaum. 2013. Intestinal microbiota composition of interleukin-10 deficient C57BL/6J mice and susceptibility to Helicobacter hepaticus-induced colitis. PLoS ONE 8:e70783.

Didelot, X., S. Nell, I. Yang, S. Woltemate, S. van der Merwe und S. Suerbaum. 2013. Genomic evolution and transmission of Helicobacter pylori in two South African families. Proc. Natl. Acad. Sci. U.S.A. 110: 13880-13885.

Nell, S., S. Suerbaum und C. Josenhans. 2010. The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nat. Rev. Microbiol. 8:564-577.

Research Sketch:

The microbiota exudes many influences on the host, especially on the metabolism and the immune system. The metabolism of the microbiota and the host are interlinked on different levels. Therefore, we are interested in the effects of acute colitis on the functional microbial diversity and its consequences on  the functioning of the metabolic synapse and altered cellular processes in endothelial cells. A combination of metaproteomics, protein-stable isotope probing (Protein-SIP) and metabolomics is applied to identify the functional diversity and carbon and nitrogen flux analysis of microbiota in the gut content and in the mucus layer in a colitis mouse model to gaining insights on the metabolic synapse between microbiota and host tissue as well as the consequences for the metabolism of the host.

Selected Publications:

Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, Knecht H, Artacho A, Eismann K, Otto W, Rojo D, Bargiela R, von Bergen M, Neulinger SC, Däumer C, Heinsen FA, Latorre A, Barbas C, Seifert J, dos Santos VM, Ott SJ, Ferrer M, Moya A (2013) Gut microbiota disturbance during antibiotic therapy: a multi-omic approach.
Gut. 2013 Nov;62(11):1591-601

Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
Science. 2013 Mar 1;339(6123):1084-8

Haange SB, Oberbach A, Schlichting N, Hugenholtz F, Smidt H, von Bergen M, Till H, Seifert J (2012) Metaproteome analysis and molecular genetics of rat intestinal microbiota reveals section and localization resolved species distribution and enzymatic functionalities.
J Proteome Res. 2012 Nov 2;11(11):5406-17

Research Sketch:

The intestinal epithelial cell lining not only has to maintain a balanced relationship towards a large number of microbiota, it also has to secure a tightly regulated homeostasis during its high-throughput regeneration. In this context the β-catenin dependent Wnt pathway is, on the one hand indispensable for intestinal epithelial proliferation and on the other, crucially involved in Paneth cell maturation and the expression of the Paneth cell defensins HD5 and HD6. These innate antimicrobial peptides are major players in regulating the composition of intestinal microbiota in addition to providing an effective barrier against potentially pathogenic threads. Paneth cells show different defects in the small intestine of Crohn’s Disease patients. We therefore focus on gaining a better understanding of the regulation of Paneth cell defensin expression with the ultimate goal of producing transferrable results that one day lead to new and causal therapies.  Our particular interest furthermore lies in elucidating Crohn’s Disease pathogenesis related impairments in the Wnt pathway.

Selected publications:

Koslowski MJ, Teltschik Z, Beisner J, Schaeffeler E, Wang G, Kubler I, Gersemann M, Cooney R, Jewell D, Reinisch W, Vermeire S, Rutgeerts P, Schwab M, Stange EF, Wehkamp J. Association of a functional variant in the Wnt co-receptor LRP6 with early onset ileal Crohn's disease. PLoS Genet 2012;8:e1002523

Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, Buchner J, Schaller M, Stange EF, Wehkamp J. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 2011, 469(7330):419-23.

J. Wehkamp, N.H. Salzman, E. Porter, S. Nuding, M. Weichenthal, R. E. Petras, B. Shen, E. Schaeffeler, M. Schwab, R. Linzmeier, R. W. Feathers, H. Chu, H. Lima, Jr., K. Fellermann, T. Ganz, E. F. Stange, C. L. Bevins; Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18129-34.

Research sketch:

Complex regulatory mechanisms work together to maintain intestinal homeostasis, and a breakdown in these pathways may finally result in IBD. Much of our understanding of intestinal immunity is built around the concept that the continuous interaction of immune cells with the microbiota regulates the fine equilibrium between pro-inflammatory and tolerogenic responses. Polymorphisms in the IL-23R gene and other regions encoding proteins implicated in the IL-23/TH17 pathway in IBD suggest that appropriate regulation of IL-23-dependent immune responses is critical for intestinal homeostasis. Within the SPP1656 consortium, we mechanistically investigate the crosstalk between IL-23 producing cells, IL-23R⁺ immune cell populations, their effector cytokines and the microflora. Moreover, as IL-23-dependent cytokines are important regulators of antimicrobial peptide production in epithelial cells, we study how cytokine induced antimicrobial peptide production affects microbial composition and diversity in the gut. In line with this, we analyze in models of infectious colitis, how IL-23-dependent production of antimicrobial factors contributes to physiological host responses to pathogens.

Selected publications:

Mchedlidze, T., Waldner, M., Zopf, S., Walker, J., Rankin, A.L., Schuchmann, M., Voehringer, D., McKenzie, A.N., Neurath, M.F., Pflanz, S., and Wirtz, S. (2013). Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357-371.

Wirtz, S., Billmeier, U., McHedlidze, T., Blumberg, R.S., and Neurath, M.F. (2011). Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology 141, 1875-1886.

Wirtz, S., Tubbe, I., Galle, P.R., Schild, H.J., Birkenbach, M., Blumberg, R.S., Neurath, M.F. (2006). Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med. 2006 203(8):1875-81.