DFG Research Training Group "TJ-Train" (GRK 2318/2)
Tight junctions and their proteins
Molecular features and actions in health and disease
& Prof. Dr.
Med. Klinik m.S. Gastroenterologie, Infektiologie & Rheumatologie,
Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin
Polarity of microbiota-exposed intestinal epithelia and its
relevance for the induction of celiac disease
Celiac disease (CelD) is an enteropathy, in which an immune reaction leads to villous atrophy
and crypt hyperplasia secondary to an infiltration of the small intestinal mucosa by T- and B-cells. Although immune
pathology is activated by the wheat protein gliadin, the initiator of this genetically defined disorder is unknown.
This is illustrated by the fact, that in some patients CelD initiation starts in early childhood, while in others it
is not before the age of matured adulthood when CelD is about to start. One hypothetic cofactor for CelD initiation is
the alteration of the mucosal barrier by colonization of the intestinal mucosa by either pathogenic or non-pathogenic
Thus, this project aims to uncover the role of GI pathogens as causative for an epithelial
barrier defect initiating CelD, which would then contribute to increased gliadin ‘leakage’ in the small intestinal
mucosa, thereby pushing CelD immunity. In the previous B02 project, we have examined the role of two genes (LPP
and C1orf106) in barrier function. These genes had been identified by the most recent whole genome association
studies for celiac disease (Kumar et al., Human Molecular Genetics, 2015) and were shown to induce a defined
barrier defect in intestinal epithelia.
Together with the collaborating Dept for Genetics in Groningen (Netherlands), we have
manufactured intestinal epithelial CrispRCas9 knock-out cells. In the current project we plan to analyze the
differential expression associated with the lack of LPP and C1orf106, respectively. Furthermore, we will colonize
epithelial layers with various bacteria to induce a defect of epithelial polarity that might contribute to an
increased uptake of gliadin peptides by the epithelial layer. This is determined in wild-type intestinal epithelia
versus LPP and C1orf106-knock-out cells. Thereby, we can contribute to a better understanding of gliadin uptake in
the pathogenesis of CelD.
2nd cohort PhD doctoral student
13(8): 520 (22 pages). doi: 10.3390/toxins13080520.
Schulz E, Schumann M, Schneemann M, Dony V, Fromm A, Nagel O, Schulzke JD, Bücker R (2021) Escherichia coli
alpha-hemolysin HlyA induces host cell polarity changes, epithelial barrier dysfunction and cell detachment in human colon carcinoma Caco-2 cell model via PTEN-dependent dysregulation of cell
Front. Med. (Lausanne)doi: 10.3389/fmed.2021.656047
1st cohort PhD doctoral student
Doctoral examination passed, Dr. rer. nat. (PhD), Freie Universität Berlin, magna cum laude
Delbue D* (*shared first authorship), Itzlinger A, Moerkens R, Withoff S, Branchi F, Schumann M (2019) Intestinal barrier function in gluten-related disorders.
11(10): 2325 (19 pages) [PubMed]
[WebPage] [PDF] (Review) (IF
Delbue D, Cardoso-Silva D, Branchi F, Itzlinger A, Letizia M, Siegmund B, Schumann M (2019) Celiac
disease monocytes induce a barrier defect in intestinal epithelial cells. Int. J. Mol. Sci.
20(22): 5597 (12 pages)
[PubMed] [WebPage] [PDF]
1st cohort MD doctoral student
If a paper is not accessible, please mail to
Krug SM, Siegmund B, Neurath MF, Becker C (2017)
Mend your fences: The epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease.
Cell. Mol. Gastroent. Hepatol.
4(1): 33-46 [PubMed] [WebPage]
Richter JF, Schmauder R, Krug SM, Gebert A, Schumann M (2016) A novel method for imaging sites of
paracellular passage of macromolecules in epithelial sheets. J. Control Release 229: 70-79 [PubMed]
Inflamm. Bowel Dis.
21: 1297-1305 [PubMed]
Lissner D, Schumann M, Batra A, Kredel LI, Kühl AA, Erben U, May C, Schulzke JD, Siegmund B (2015) Monocyte
and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD.
Kredel LI, Batra A, Stroh T, Kühl AA, Zeitz M, Erben U,
Siegmund B (2013) Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease.
Batra A, Heimesaat MM, Bereswill S, Fischer A, Glauben R, Kunkel D, Scheffold A, Erben U, Kühl A, Loddenkemper C, Lehr HA,
Schumann M, Schulzke JD, Zeitz M, Siegmund B (2012) Mesenteric fat-control site for bacterial translocation in colitis?
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 coeliac
protein mediates regulatory T cell development via induction of the Foxp3 transcription factor.
Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K,
Pfeffer K, Huehn J, Siegmund B, Schmitz I (2012)
Gerling M, Glauben R, Habermann JK, Kühl AA, Loddenkemper C, Lehr HA, Zeitz M, Siegmund B (2011) Characterization of
chromosomal instability in murine colitis-associated colorectal cancer.
Glauben R, Batra A, Stroh T, Erben U, Fedke I, Lehr HA, Leoni F, Mascagni P, Dinarello CA, Zeitz M, Siegmund B (2008)
Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice.
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 alpha(2)-gliadin-33mer in coeliac sprue.
Stroh T, Batra A, Glauben R, Fedke I, Erben U, Kroesen A, Heimesaat MM, Bereswill S, Girardin S, Zeitz M, Siegmund B
(2008) Nucleotide oligonerization domains 1 and 2: regulation of expression and function in preadipocytes.
Am. J. Pathol.
Batra A, Pietsch J, Fedke I, Glauben R, Okur B, Stroh T, Zeitz M,
Siegmund B (2007) Leptin-dependent toll-like receptor expression and responsiveness in preadipocytes and adipocytes.
Siegmund B, Sennello JA, Jones-Carson J, Gamboni-Robertson F, Lehr HA, Batra A, Fedke I, Zeitz M, Fantuzzi G (2004)
Leptin receptor expression on T lymphocyte modulates chronic intestinal inflammation in mice.
Siegmund B, Lehr HA, Fantuzzi G (2002) Leptin: a pivotal mediator of intestinal inflammation in mice.