DFG Research Training Group "TJ-Train" (GRK 2318/2)
 Tight junctions and their proteins
Molecular features and actions in health and disease

Project C3     1st period    2nd period

Priv.-Doz. Dr. Michael Schumann     &   Prof. Dr. Britta Siegmund 

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 bacteria.

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.

3rd cohort PhD doctoral student

Zitong Jiang

2nd cohort PhD doctoral student

Violaine Dony

  • 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 junctions. Toxins 13(8): 520 (22 pages). doi: 10.3390/toxins13080520. (IF 5.1) 

  • Delbue D, Lebenheim L, Cardoso-Silva D, Dony V, Krug SM, Richter JF, Manna S, Muñoz M, Wolk K, Heldt C, Heimesaat MM, Sabat R, Siegmund B, Schumann M (2021) Reprogramming intestinal epithelial cell polarity by interleukin-22. Front. Med. (Lausanne) 8: 656047. doi: 10.3389/fmed.2021.656047 (IF 5.1)  

1st cohort PhD doctoral student

Deborah Delbue
01.07.2021: Doctoral examination passed, "Defective epithelial barrier function in chronic inflammation of the intestinal mucosa", Dr. rer. nat. (PhD), Freie Universität Berlin, magna cum laude

  • Delbue D, Lebenheim L, Cardoso-Silva D, Dony V, Krug SM, Richter JF, Manna S, Muñoz M, Wolk K, Heldt C, Heimesaat MM, Sabat R, Siegmund B, Schumann M (2021) Reprogramming intestinal epithelial cell polarity by interleukin-22. Front. Med. (Lausanne) 8: 656047. doi: 10.3389/fmed.2021.656047 (IF 5.1)  

  • Cardoso-Silva D*, Delbue D* (*shared first authorship), Itzlinger A, Moerkens R, Withoff S, Branchi F, Schumann M (2019) Intestinal barrier function in gluten-related disorders. Nutrients 11(10): 2325 (19 pages) [PubMed] [WebPage] [PDF] (Review) (IF 4.5)

  • 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] (IF 4.6)

1st cohort MD doctoral student

Daphni Siampli  

Project-related publications

  1. Martini E, 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] [PDF] (Review)

  2. 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]

  3. 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. Inflamm. Bowel Dis. 21: 1297-1305 [PubMed]

  4. 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. Gut 62: 852-862

  5. 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? Mucosal Immunol. 5: 580-591

  6. 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 disease. Gut 61: 220-228 [PubMed]

  7. 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) IkBNS protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity 37: 998-1008

  8. 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. PLoS One 6: e22114

  9. 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. Gut 57: 613-622

  10. 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. Gut 57: 747-754 [PubMed]

  11. 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. J. Immunol. 181: 3620-3627

  12. 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. Am. J. Pathol. 170: 1931-1941

  13. 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. Gut 53: 965-972

  14. Siegmund B, Lehr HA, Fantuzzi G (2002) Leptin: a pivotal mediator of intestinal inflammation in mice. Gastroenterology 122: 2011-2025