DFG Research Training Group "TJ-Train" (GRK 2318)
Tight junctions and their proteins
Molecular features and actions in health and disease
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
PhD doctoral student
Praveen Kumar Nattramilarasu
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)
[PubMed] [WebPage] [PDF]
Butkevych E, Lobo De Sá FD, Nattramilarasu PK, Bücker R (2020) Epithelial apoptosis and subepithelial immune responses in Campylobacter jejuni-induced barrier
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]
MD doctoral students
If a paper is not accessible, please mail to
Escherichia coli: a potentiator of inflammatory activity in the colon.
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,
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Aerolysin from Aeromonas hydrophila
perturbs tight junction integrity and cell lesion repair in intestinal epithelial HT-29/B6 cells.
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Amasheh M, Fromm A, Krug SM, Amasheh S, Andres S, Zeitz M, Fromm M,
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Bücker R*, Troeger H* (*shared first authorship), Kleer J, Fromm M,
Schulzke JD (2009) Arcobacter butzleri induces barrier dysfunction in intestinal epithelial cells.
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.
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.
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.
alpha-hemolysin induces focal leaks in colonic epithelium – a novel mechanism of bacterial translocation. Cell.
Troeger H*, Richter JF* (*shared first authorship), Beutin L, Günzel D, Dobrindt U, Epple HJ, Gitter AH, Zeitz M,
Fromm M, Schulzke JD (2007)
Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD (2001). Celiac disease-like abnormalities in a subgroup of patients
with irritable bowel syndrome.