Visual Universitätsmedizin Mainz

Juniorprofessorship 'Experimental Hemostasis and Gnotobiotics'

Juniorprofessor Dr. Christoph Reinhardt

Mammals are colonized by a vast variety of microbes outnumbering host cells by 10 fold. These constant microbial stimuli influence host physiology and contribute to cardiovascular and metabolic disease states. Our group established germ-free mouse colonies to study the influence of microbiota on the host’s coagulation system and on thrombus formation. Our research focusses on coagulation factor signaling in the small intestine, but also on the identification of systemic effects that enhance thrombus formation. To explore the role of the enteric microbiota in thrombosis we take advantage of intravital microscopy to visualize thrombus formation and adhesion of blood cells to the injured carotid artery, the vena cava and mesenteric vessels. We also apply germ-free mouse models to identify microbiota-induced morphogenic signaling pathways that trigger remodeling and renewal of the intestinal mucosa.

Research Interests

  • Impact of gut microbes on thrombus formation by gnotobiotic mouse technology (BMBF)
  • Role of TLR2 in experimental thrombus formation 
  • Microbiota-induced mucosal remodeling in the small intestine (DFG, IFF)
  • Transciptom-based analysis of microbiota-dependent effects on endothelial cells (BIF)

Partners of Collaboration

  • Prof. Fredrik Bäckhed (Sahlgrenska Center for Cardiovascular and Metabolic Research / Wallenberg Laboratory, University of Gothenburg, Sweden)
  • PD Dr. med. Jens Kittner (II. Medizinische Klinik, Klinikum Darmstadt)
  • Prof. Steffen Maßberg (Medizinische Klinik und Poliklinik I, LMU München, Germany)
  • Prof. Wolfram Ruf (Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, USA & CTH, Universitätsmedizin Mainz)
  • Prof. Kerstin Steinbrink (Hautklinik, Universitätsmedizin Mainz)
  • Prof. Dr. med. Philip Wenzel (CTH, Universitätsmedizin Mainz)
  • Merixell Nus, PhD (Addenbrooke’s Hospital, University of Cambridge) 
  • Dr. Konrad Aden (Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel) 
  • Dr. Tim Hendrikx (CEMM, Medizinische Universität Wien) 
  • Dr. sc. nat. (ETH) Hans Christian Probst (Institut für Immunologie, Universitätsmedizin Mainz) 
  • Dr. rer. nat. Madhusudhan Thati (CTH, Universitätsmedizin Mainz) 
  • Prof. Markus Bosmann (School of Medicine, Boston University) 
  • Prof. Huige Li (Institut für Pharmakologie, Universitätsmedizin Mainz) 

Research Funding

  • GFK Fellowship 
  • Boehringer Ingelheim Foundation (BIF)
  • DFG Sachbeihilfe RE 3450/5-2 (Mikrobiota-induzierte morphogenetische Adaptation der Dünndermstruktur)
  • BMBF TRP X19 TRP X30 
  • NMFZ
  • Wilhelm Sander Foundation

Team - Juniorgroup Translational Research in T&H

Jun. Prof. Dr. Reinhardt
Christoph Reinhardt, Jun. Prof. Dr.
Position: Juniorgroup leader, GFK Fellow, Scientist in the DZHK

06131 17-8280
06131 17-6238
christoph.reinhardt@unimedizin-mainz.de
Further Information

Bayer
Franziska Bayer
Position: PhD student

06131 17-8284

Eckelt
Anja Eckelt
Position: PhD student

06131 17-8284
eckelta@uni-mainz.de

Formes
Henning Formes
Position: PhD student

06131 17-8284
henning.formes@uni-mainz.de

Karwot
Cornelia Karwot
Position: Technical Assistant

06131 17-8284
cornelia.karwot@unimedizin-mainz.de

PhD Kiouptsi
Klytaimnistra Kiouptsi, PhD
Position: Postdoc

06131 17-8354
Klytaimnistra.Kiouptsi@unimedizin-mainz.de

PhD Malinarich González
Frano Hernán Malinarich González , PhD
Position: Post Doc

f.malinarich@uni-mainz.de

PhD Mann
Amrit Mann, PhD
Position: Post Doc

06131 17-8364
amrit.mann@unimedizin-mainz.de

PhD Pontarollo
Giulia Pontarollo, PhD
Position: Postdoc

06131 17-8354
giulia.pontarollo@unimedizin-mainz.de

Former team members

Nives Hörmann
Dr rer. nat. Inês Brandão
Dr. med. vet. Sven Jäckel
Dr. rer. biol. hum. Avinash Khandagale
Dr. rer. nat. Maren Lillich
Dr. rer. nat. Cecilia Maria Perera
Dr. med. vet. Eivor Wilms
Dr. rer. nat. Bettina Kollar
Dr. med. vet. Alexandra Grill
Anna Lässiger-Herfurth

Original articles

  • Kiouptsi K, Jäckel S, Wilms E, Pontarollo G, Winterstein J, Karwot C, Groß K, Jurk K, Reinhardt C. 2020. The Commensal Microbiota Enhances ADP-Triggered Integrin α IIb β 3 Activation and von Willebrand Factor-Mediated Platelet Deposition to Type I Collagen. Int J Mol Sci 21(19):E7171.

    • Roewe J, Stavrides G, Strueve M, Sharma A, Marini F, Mann A, Smith SA, Kaya Z, Strobl B, Mueller M, Reinhardt C, Morrissey JH, Bosmann M. 2020. Bacterial polyphosphates interfere with the innate host defense to infection. Nat Commun 11:4035.

    • Ascher S, Wilms E, Pontarollo G, Formes H, Bayer F, Müller M, Malinarich F, Grill A, Bosmann M, Saffarzadeh M, Brandao I, Gross K, Kiouptsi K, Kittner JM, Lackner KJ, Jurk K, Reinhardt C. Gut Microbiota Restricts NETosis in Acute Mesenteric Ischemia-Reperfusion Injury. Arterioscler Thromb Vasc Biol 2020 Online ahead of print.

    • Kiouptsi K, Pontarollo G, Todorov H, Braun J, Jäckel S, Koeck T, Bayer F, Karwot C, Karpi A, Gerber S, Jansen Y, Wild P, Ruf W, Daiber A, Van Der Vorst E, Weber C, Döring Y, Reinhardt C. Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice. Gut Microbes 2020:1-15.

    • Schaupp L, Muth S, Rogell L, Kofoed-Branzk M, Melchior F, Lienenklaus S, Ganal-Vonarburg SC, Klein M, Guendel F, Hain T, Schütze K, Grundmann U, Schmitt V, Dorsch M, Spanier J, Larsen PK, Schwanz T, Jäckel S, Reinhardt C, Bopp T, Danckwardt S, Mahnke K, Heinz GA, Mashreghi MF, Durek P, Kalinke U, Kretz O, Huber TB, Weiss S, Wilhelm C, Macpherson AJ, Schild H, Diefenbach A, Probst HC. Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells. Cell 2020;181(5):1080-1096 e1019.

    • Todorov H, Kollar B, Bayer F, Brandao I, Mann A, Mohr J, Pontarollo G, Formes H, Stauber R, Kittner JM, Endres K, Watzer B, Nockher WA, Sommer F, Gerber S, Reinhardt C. alpha-Linolenic Acid-Rich Diet Influences Microbiota Composition and Villus Morphology of the Mouse Small Intestine. Nutrients 2020;12(3).

    • Grill A, Kiouptsi K, Karwot C, Jurk K, Reinhardt C. Evaluation of blood collection methods and anticoagulants for platelet function analyses on C57BL/6J laboratory mice. Platelets. 2019 Dec 8:1-8.

    • Sonner JK, Keil M, Falk-Paulsen M, Mishra N, Rehman A, Kramer M, Deumelandt K, Röwe J, Sanghvi K, Wolf L, von Landenberg A, Wolff H, Bharti R, Oezen I, Lanz TV, Wanke F, Tang Y, Brandao I, Mohapatra SR, Epping L, Grill A, Röth R, Niesler B, Meuth SG, Opitz CA, Okun JG, Reinhardt C, Kurschus FC, Wick W, Bode HB, Rosenstiel P, Platten M. Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology. Nat Commun. 2019 Oct 25;10(1):4877.

    • Müller-Calleja N, Hollerbach A, Ritter S, Pedrosa DG, Strand D, Graf C, Reinhardt C, Strand S, Poncelet P, Griffin JH, Lackner KJ, Ruf W. Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis. Blood (2019). doi: 10.1182/blood.2019001530.

    • Kiouptsi K, Jäckel S, Pontarollo G, Grill A, Kuijpers MJE, Weber C, Sommer F, Nagy M, Neideck C, Jansen Y, Ascher S, Formes H, Karwot C, Bayer F, Subramaniam S, Molitor M, Wenzel P, Rosenstiel P, Todorov H, Gerber S, Walter U, Jurk K, Heemskerk JWM, van der Vorst EPC, Döring Y, Reinhardt C. The microbiota promotes atherothrombosis in late atherosclerotic Ldlr-deficinet mice. mBio. 2019;10(5):e02298-19.

    • Hewel C, Kaiser J, Wierczeiko A, Linke J, Reinhardt C, Endres K, Gerber S. Common miRNA Patterns of Alzheimer's Disease and Parkinson's Disease and Their Putative Impact on Commensal Gut Microbiota. Front Neurosci 2019;13:113.

    • Kiouptsi K, Finger S, Garlapati VS, Knorr M, Brandt M, Walter U, Wenzel P, Reinhardt C. Hypoxia evokes increased PDI and PDIA6 expression in the infarcted myocardium of ex-germ-free and conventionally-raised mice. Biol Open 2018.

    • Khandagale A, Kittner JM, Mann A, Ascher S, Kollar B, Reinhardt C. Coagulation factor 9-deficient mice are protected against dextran sulfate sodium-induced colitis. Biol Open 2018;7(7).

    • Westmeier D, Solouk-Saran D, Vallet C, Siemer S, Docter D, Götz H, Männ L, Hasenberg A, Hahlbrock A, Erler K, Reinhardt C, Schilling O, Becker S, Gunzer M, Hasenberg M, Knauer SK, Stauber RH. Nanoparticle decoration impacts airborne fungal pathobiology. Proc Natl Acad Sci U S A 2018;115(27):7087-7092.

    • Lindskog Jonsson A, Caesar R, Akrami R, Reinhardt C, Fak Hallenius F, Boren J, Bäckhed F. Impact of Gut Microbiota and Diet on the Development of Atherosclerosis in Apoe(-/-) Mice. Arterioscler Thromb Vasc Biol 2018.

    • Lagrange J, Kossmann S, Kiouptsi K, Wenzel P (2018) Visualizing Leukocyte Rolling and Adhesion in Angiotensin II-Infused Mice: Techniques and PitfallsJ Vis Exp. 2018 Jan 4;(131).

    • Kiouptsi K, Grill A, Mann A, Döhrmann M, Lillich M, Jäckel S, Malinarich F, Formes H, Manukyan D, Subramaniam S, Khandagale A, Karwot C, Thal SC, Bosmann M, Scharrer I, Jurk K, Reinhardt C (2017) Mice deficient in the anti-haemophilic coagulation factor VIII show increased von Willebrand factor plasma levels. PloS one 12: e0183590

    • Kiouptsi K, Gambaryan S, Walter E, Walter U, Jurk K, Reinhardt C (2017) Hypoxia impairs agonist-induced integrin αIIbβ3 activation and platelet aggregation. Sci Rep. 7(1):7621

    • Klier M, Gowert NS, Jäckel S, Reinhardt C, Elvers M (2017) Phospholipase D1 is a regulator of platelet-mediated inflammation. Cell Signal 38: 171-181

    • Jäckel S, Kiouptsi K, Lillich M, Hendrikx T, Khandagale A, Kollar B, Hörmann N, Reiss C, Subramaniam SWilms E, Ebner K, von Brühl ML, Rausch P, Baines JF, Haberichter S, Lämmle B, Binder CJ, Jurk K, Ruggeri ZM, Massberg S, Walter U, Ruf W, Reinhardt C (2017) Gut microbiota regulate hepatic von Willebrand Factor synthesis and arterial thrombus formation via Toll-like receptor-2. Blood

    • Busch CJ, Hendrikx T, Weismann D, Jäckel S, Walenbergh SM, Rendeiro AF, Weisser J, Puhm F, Hladik A, Göderle L, Papac-Milicevic N, Haas G, Millischer V, Subramaniam S, Knapp S, Bennett KL, Bock C, Reinhardt C, Shiri-Sverdlov R, Binder CJ (2017) Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice. Hepatology 65: 1181-1195

    • Kossmann S, Lagrange J, Jäckel S, Jurk K, Ehlken M, Schönfelder T, Weihert Y, Knorr M, Brandt M, Xia N, Li H, Daiber A, Oelze M, Reinhardt C, Lackner K, Gruber A, Monia B, Karbach SH, Walter U, Ruggeri ZM, Renné T, Ruf W, Münzel T, Wenzel P  (2017) Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension. Sci Transl Med 9

    • Subramaniam S, Jurk K, Hobohm L, Jäckel S, Saffarzadeh M, Schwierczek K, Wenzel P, Langer F, Reinhardt C, Ruf W (2017) Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood 129: 2291-2302

    • Karbach SH, Schönfelder T, Brandao I, Wilms E, Hörmann N, Jäckel S, Schüler R, Finger S, Knorr M, Lagrange J, Brandt M, Waisman A, Kossmann S, Schäfer K, Münzel T, Reinhardt C, Wenzel P (2016) Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction. Journal of the American Heart Association 5

    • Luther N, Shahneh F, Brähler M, Krebs F, Jäckel S, Subramaniam S, Stanger C, Schönfelder T, Kleis-Fischer B, Reinhardt C, Probst HC, Wenzel P, Schäfer K, Becker C (2016) Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution. Circ Res 119: 1286-1295

    • Manukyan D, Müller-Calleja N, Jäckel S, Luchmann K, Monnikes R, Kiouptsi K, Reinhardt C, Jurk K, Walter U, Lackner KJ (2016) Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice. Journal of thrombosis and haemostasis 14: 1011-20

    • Stark K, Philippi V, Stockhausen S, Busse J, Antonelli A, Miller M, Schubert I, Hoseinpour P, Chandraratne S, von Brühl ML, Gaertner F, Lorenz M, Agresti A, Coletti R, Antoine DJ, Heermann R, Jung K, Reese S, Laitinen I, Schwaiger M, Walch A, Sperandio M, Nawroth PP, Reinhardt CJäckel S, Bianchi ME, Massberg S (2016) Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 128: 2435-2449

    • Bollmann F, Jäckel S, Schmidtke L, Schrick K, Reinhardt CJurk K, Wu Z, Xia N, Li H, Erkel G, Walter U, Kleinert H, Pautz A. Anti-Inflammatory and Anti-Thrombotic Effects of the Fungal Metabolite Galiellalactone in Apolipoprotein E-Deficient Mice. PloS one. 10:e0130401. 2015.

    • Brandao I, Hörmann N, Jäckel S, Reinhardt C.  TLR5 expression in the small intestine depends on the adaptors MyD88 and TRIF, but is independent of the enteric microbiota. Gut microbes:1-5, 2015.

    • Hörmann N, Brandao I, Jäckel S, Ens N, Lillich M, Walter U, Reinhardt C. Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa. PloS one. 9:e113080, 2014.

    • Brandt M, Schönfelder T, Schwenk M, Becker C, Jäckel S, Reinhardt C, Stark K, Massberg S, Münzel T, von Brühl ML, Wenzel P. Deep vein thrombus formation induced by flow reduction in mice is determined by venous side branches. Clin Hemorheol Microcirc. 56:145-152, 2014.

    • Tenzer S, Docter D, Kuharev J, Musyanovych A, Fetz V, Hecht R, Schlenk F, Fischer D, Kiouptsi KReinhardt C, Landfester K, Schild H, Maskos M, Knauer SK, Stauber RH. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nanotechnol. 8:772-781, 2013.

    • Reinhardt C, Bergentall M, Greiner TU, Schaffner F, Ostergren-Lundén G, Petersen LC, Ruf W, Bäckhed F. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature. 483(7391):627-31, 2012.

    • Caesar R, Reigstadt CS, Kling Bäckhed H, Reinhardt C, Ketonen M, Östergren-Lundén G, Cani PD, Bäckhed F. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut. 61:1701-7, 2012.

    • Massberg S, Grahl L. von Bruehl M-L, Manukyan D, Pfeiler S, Goosmann C. Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT and Engelmann B. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 16, 887-96, 2010.

    • Reinhardt C,  von Brühl ML, Manukyan D, Grahl L, Lorenz M, Altmann B, Dlugai S, Hess S, Konrad I, Orschiedt L, Mackman N, Ruddock L, Massberg S, Engelmann B. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest. 118, 1110-22, 2008.

Reviews

  • Pontarollo G, Kiouptsi K, Reinhardt C. A holobiont view on thrombosis: unravelling the microbiota's influence on arterial thrombus growth. Microb Cell 2020;7(1):28-31.
  • Lässiger-Herfurth A, Pontarollo G, Grill A, Reinhardt C. The Gut Microbiota in Cardiovascular Disease and Arterial Thrombosis. Microorganisms 2019;7(12).
  • Pontarollo G, Mann A, Brandão I, Malinarich F, Schöpf M, Reinhardt C. Protease-activated receptor signaling in intestinal permeability regulation. FEBS J. 2020;287(4):645-658.
  • Bayer F, Ascher S, Pontarollo G, Reinhardt C. Antibiotic treatment protocols and germ-free mouse models in vascular research. Front Immunol. 2019; 10:2174.
  • Reinhardt C. The Gut Microbiota as an Influencing Factor of Arterial Thrombosis. Hamostaseologie 2018.
  • Formes H, Reinhardt C. The gut microbiota - a modulator of endothelial cell function and a contributing environmental factor to arterial thrombosis. Expert Rev Hematol 2019:1-9.
  • Reinhardt C. The Involvement of Toll-like Receptor-2 in Arterial Thrombus Formation. Hamostaseologie 2018;38(4):223-228.
  • Subramaniam S, Kanse SM, Kothari H, Reinhardt C, Fletcher C. Post-transcriptional, post-translational and pharmacological regulation of tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 2018;29(8):668-682.
  • Kiouptsi K, Reinhardt C. Contribution of the commensal microbiota to atherosclerosis and arterial thrombosis. Br J Pharmacol 2018;175(24):4439-4449.
  • Westmeier D, Hahlbrock A, Reinhardt C, Frohlich-Nowoisky J, Wessler S, Vallet C, Pöschl U, Knauer SK, Stauber RH. Nanomaterial-microbe cross-talk: physicochemical principles and (patho)biological consequences. Chem Soc Rev 2018;47(14):5312-5337.
  • Khandagale A, Reinhardt C (2018) Gut microbiota - architects of small intestinal capillaries. Front Biosci (Landmark Ed) 23: 752-766
  • Ascher S, Reinhardt C (2018) The gut microbiota - an emerging risk factor for cardiovascular and cerebrovascular disease. Eur J Immunol 2018;48(4):564-575.
  • Kiouptsi K, Reinhardt C (2016) Protein disulfide-isomerase - a trigger of tissue factor-dependent thrombosis. Clin Hemorheol Microcirc 64: 279-286
  • Garn H, Bahn S, Baune BT, Binder EB, Bisgaard H, Chatila TA, Chavakis T, Culmsee C, Dannlowski U, Gay S, Gern J, Haahtela T, Kircher T, Müller-Ladner U, Neurath MF, Preissner KT, Reinhardt C, Rook G, Russell S, Schmeck B et al. (2016) Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation. J Allergy Clin Immunol 138: 47-56
  • Reinhardt C, Reigstad CS, Bäckhed F. Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr. 48(3):249-56, 2009
  • Reinhardt C. New locations of intravascular tissue factor: indications. Hamostaseologie. 27, 55-8, 2007.

Editorials

  • Reinhardt C. The Microbiota: A Microbial Ecosystem Built on Mutualism Prevails. J Innate Immun 2019:1-2.
  • Kiouptsi K, Ruf W, Reinhardt C. Microbiota-Derived Trimethylamine. Circ Res 2018;123(10):1112-1114.
  • Reinhardt C (2017) GAS6: Pouring GASoline Into the Inflammatory Inferno of Venous Thrombosis. Arteriosclerosis, thrombosis, and vascular biology 37: 1263-1265

Commentary

Becker C, Reinhardt C. Unexpected role of natural killer cell-derived interferon-γ as a driver of NETosis and DVT. J Thromb Haemost. 2019;17(2):400-402. 

March 2020

High-fat diet shapes small intestinal morphology (Todorov H, Kollar B, et al., Nutrients, 2020)

June 2020

How the gut microbiota impacts late atherosclerotic lesions. Our collaborative study with a germ-free mouse atherosclerosis model was published in Gut Microbes: Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice

July 2020

For his research on microbiota-host interactions in arterial thrombosis Christoph Reinhardt was awarded a prestigeous Gutenberg Research Fellowship from the Gutenberg Research College