DFG Research Training Group "TJ-Train" (GRK 2318)
Tight junctions and their proteins
Molecular features and actions in health and disease

Project C1

Prof. Dr. Jörg-Dieter Schulzke1     &   Priv.-Doz. Dr. Hanno Troeger2   

1Institute of Clinical Physiology,
2Med. Klinik m.S. Gastroenterologie, Infektiologie & Rheumatologie, CBF,
Charité - Universitätsmedizin Berlin

Toxin effects on paracellular intestinal barrier function

Hypotheses and Aims: Bacterial toxins can either directly permeabilize tight junctions e.g. by cleavage of tight junction proteins or (much more common) can induce signaling in epithelial cells which dysregulates tight junctions. Signaling can be via Ca2+ influx through pores formed by toxins or receptor activation and results in tight junction disassembly (often via endocytosis of tight junction proteins). Depending on the respective tight junction alterations either bacterial translocation, leak flux diarrhea as the result of barrier changes against ions and water or inflammatory responses due to increased antigen uptake are the consequences.

Methods: The working plan is to perform infection experiments in cell and animal models including co-cultures of epithelial (HT-29/B6) and immune cells (M1-macrophages) for characterizing signaling mechanisms and functionality. The panel of methods includes electrophysiological measurements, morphological studies as EM and confocal laser scanning microscopy, and molecular techniques like immunoblotting with densitometry and mRNAseq for expression analysis with subsequent Upstream Regulator Analysis for signaling events.

Work plan: For a toxin of a food-borne pathogen with barrier effects and induction of chronic inflammation which is also discussed in the context of IBD permission, the signaling pathways leading to tight junction alterations, the contribution of immune cells and the functional consequences of the toxin exposure to the intestinal barrier will be investigated. Pro-inflammatory functionality is investigated using an inflammation mouse model, the IL-10-/- mouse, under the influence of the toxin produced by inoculating wild type bacteria in comparison to a toxin-negative mutant strain. Cell and animal model results will be confirmed in a small number of biopsies from infected patients and/or normal colon biopsies exposed to the bacterium.

PhD doctoral student

  • Praveen Kumar Nattramilarasu

    • Publications

  • Nattramilarasu PK, Bücker R, Lobo de Sá FD, Fromm A, Nagel O, Lee IM, Butkevych E, Mousavi S, Genger C, Kløve S, Heimesaat MM, Bereswill S, Schweiger MR, Nielsen HL, Troeger H, Schulzke JD (2020) Campylobacter concisus impairs sodium absorption in colonic epithelium via ENaC dysfunction and claudin-8 disruption. Int. J. Mol. Sci. (Special Issue "Ion and molecule transport in membrane systems 2.0") 21(2): e373 (23 pages) (°IF 4.2) [PubMed] [WebPage] [PDF] [Supplements]

  • Butkevych E, Lobo De Sá FD, Nattramilarasu PK, Bücker R (2020) Epithelial apoptosis and subepithelial immune responses in Campylobacter jejuni-induced barrier disruption Front. Microbiol. 11: 344 (14 pages) (°IF 4.3) [PubMed] [WebPage] [PDF]

  • Lobo de Sá FD, Butkevych E, Nattramilarasu PK, Fromm A, Mousavi S, Moos V, Golz JC, Stingl K, Kittler S, Seinige D, Kehrenberg C, Heimesaat MM, Bereswill S, Schulzke JD*, Bücker R (*corresponding) (2019) Curcumin mitigates immune-induced epithelial barrier dysfunction by Campylobacter jejuni. Int. J. Mol. Sci. 20(19): 4830 (19 pages) (°IF 4.2) [PDF] [WebPage] [PDF]

MD doctoral students

  • Karem Awad

  • Lucas Heils 

  • Sholpan Omarova 

Project-related publications

If a paper is not accessible, please mail to .

  1. Bücker R, Schulz E, Günzel D, Bojarski C, Lee IM, John LJ, Wiegand S, Janßen T, Wieler LH, Dobrindt U, Beutin L, Ewers C, Fromm M, Siegmund B, Troeger H, Schulzke JD (2014) α-Haemolysin of Escherichia coli: a potentiator of inflammatory activity in the colon. Gut 63: 1893-1901

  2. Schumann M, Günzel D, Buergel N, Richter JF, Troeger H, May C, Fromm A, Sorgenfrei D, Daum S, Bojarski C, Heyman M, Zeitz M, Fromm M, Schulzke JD (2012) Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in celiac disease. Gut 61: 220-228

  3. Bücker R, Krug SM, Rosenthal R, Günzel D, Fromm A, Zeitz M, Chakraborty T, Fromm M, Epple HJ, Schulzke JD (2011) Aerolysin from Aeromonas hydrophila perturbs tight junction integrity and cell lesion repair in intestinal epithelial HT-29/B6 cells. J. Infect. Dis. 204: 1283-1292

  4. Amasheh M, Fromm A, Krug SM, Amasheh S, Andres S, Zeitz M, Fromm M, Schulzke JD (2010) TNFalpha-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, pAkt, and NFkB signaling. J. Cell Sci. 123: 4145-4155

  5. Bücker R*, Troeger H* (*shared first authorship), Kleer J, Fromm M, Schulzke JD (2009) Arcobacter butzleri induces barrier dysfunction in intestinal epithelial cells. J. Infect. Dis. 200: 756-764

  6. Epple HJ, Schneider T, Troeger H, Kunkel D, Allers K, Moos V, Amasheh M, Loddenkemper C, Fromm M, Zeitz M, Schulzke JD (2009) Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients. Gut 58: 220-227

  7. Troeger H, Loddenkemper C, Schneider T, Schreier E, Epple HJ, Zeitz M, Fromm M, Schulzke JD (2009) Structural and functional changes of the duodenum in human norovirus infection. Gut 58: 1070-1077

  8. Schumann M, Richter JF, Wedell I, Moos V, Zimmermann-Kordmann M, Schneider T, Daum S, Zeitz M, Fromm M, Schulzke JD (2008) Mechanisms of epithelial translocation of the a2-gliadin-33mer in celiac sprue. Gut 57: 747-754

  9. Troeger H*, Richter JF* (*shared first authorship), Beutin L, Günzel D, Dobrindt U, Epple HJ, Gitter AH, Zeitz M, Fromm M, Schulzke JD (2007) E. coli alpha-hemolysin induces focal leaks in colonic epithelium – a novel mechanism of bacterial translocation. Cell. Microbiol. 9: 2530-2540

  10. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD (2001). Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 121: 1329-1338