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

Project C1     1st period    2nd period

Prof. Dr. Jörg-Dieter Schulzke    &  Priv.-Doz. Dr. Roland Bücker 

1Clinical Physiology / Nutritional Medicine,
2Med. Klinik m.S. Gastroenterologie, Infektiologie & Rheumatologie, CBF,
Charité - Universitätsmedizin Berlin

Toxin effects on paracellular intestinal barrier function

Hypotheses and Aims: cholerae, Campylobacter concisus and other pathogenic bacteria release zonula occludens toxins (ZOT) and ZOT-related toxins, which can affect the tight junction of gastrointestinal epithelia. These toxins are considered to cause diarrhea (leak flux diarrheal mechanism) and progression of inflammatory bowel diseases (leaky gut concept).

Methods: The doctoral student will study tight junction structure and function in cell and mouse models, organoids and human tissue specimens with molecular methods e.g. confocal microscopy and RNA sequencing (including pathway analysis) and with functional electrophysiological measurements. Effects of the toxins are studied by cloning and overexpression of toxins and are interpreted in comparison to the effects of whole bacteria and bacterial supernatants.

Work plan: The central part of this project is concerned with extra- and intracellular signaling either directly at the epithelium or via the mucosal immune system, which is studied in co-cultures of epithelial cell models and/or organoids, together with M1-macrophages. Proinflammatory functionality is finally investigated using an inflammation-prone mouse model.

3rd cohort PhD doctoral student

Jana Krause

2nd cohort PhD doctoral student

Martina Schneemann

  • Schneemann M, Heils L, Moos V, Weiß F, Krug SM, Weiner J, Beule D, Gerhard R, Schulzke JD, Bücker R (2023) A colonic organoid model challenged with the large toxins of Clostridioides difficile TcdA and TcdB exhibit deregulated tight junction proteins. Toxins 15: 643 (19 pages). doi: 10.3390/toxins15110643 (IF 3.9)

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  • Heils L, Schneemann M, Gerhard R, Schulzke JD, Bücker R (2023) CDT of Clostridioides difficile induces MLC-dependent intestinal barrier dysfunction in HT-29/B6 epithelial cell monolayers. Toxins (Basel) 15(1): 54 (15 pages). doi: 10.3390/toxins15010054 (°IF 4.2)

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  • Weiß F, Holthaus D, Kraft M, Klotz C, Schneemann M, Schulzke JD, Krug SM (2022) Human duodenal organoid derived monolayers serve as a suitable barrier model for duodenal tissue. Ann. NY Acad. Sci. 1515(1): 155-167, doi: 10.111/nyas.14804 (IF 5.2)

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  • 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)

2nd cohort MD doctoral student

Jan-Leo Kaak
08.08.2024: Doctoral examination passed, Dr. med., "Störung der intestinalen epithelialen Barrierefunktion durch Microcystin in Caco-2-Zellen"

  • Kaak JL, Lobo de Sá FD, Turner JR, Schulzke JD, Bücker R (2022) Unraveling the intestinal epithelial barrier in cyanotoxin microcystin-treated Caco-2 cell monolayers. Ann. NY Acad. Sci. 1516(1): 188-196, doi: 10.1111/nyas.14870 (IF 5.2)

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Helena Hader  

  • Hader H, Hering NA, Schulzke JD, Bücker R, Rosenthal R (2023) Myrrh protects against IL-13-induced epithelial barrier breakdown in HT-29/B6 cells. Front. Pharmacol. 14: 1301800 (11 pages). doi: 10.3389/fphar.2023.1301800 (IF 4.4)

1st cohort PhD doctoral student

Praveen Kumar Nattramilarasu

13.09.2021: Doctoral examination passed, "Campylobacter concisus impairs colonic epithelial sodium channel function and aggravates epithelial barrier dysfunction via mucosal immune activation", Dr. rer. nat. (PhD), Freie Universität Berlin, magna cum laude

  • Nattramilarasu PK, Lobo de Sá FD, Schulzke JD, Bücker R (2021) Immune-mediated aggravation of the Campylobacter concisus-induced epithelial barrier dysfunction. Int. J. Mol. Sci. 22(4): 2043 (23 pages). doi: 10.3390/ijms22042043, Supplement PDF (IF 6.2)

  • 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. 21(2): e373 (23 pages) [PubMed] [WebPage] [PDF] [Supplements] (IF 5.9)

  • Lobo de Sá FD, Heimesaat MM, Bereswill S, Nattramilarasu PK, Schulzke JD, Bücker R (2021) Resveratrol prevents Campylobacter jejuni-induced leaky gut by restoring occludin and claudin-5 in the paracellular leak pathway. Front. Pharmacol. 12: 640572. doi: 10.3389/fphar.2021.640572 (IF 6.0)

  • Butkevych E, Lobo De Sá FD, Nattramilarasu PK, Bücker R (2020) Contribution of epithelial apoptosis and subepithelial immune responses in Campylobacter jejuni-induced barrier disruption Front. Microbiol. 11: 344 (14 pages) [PubMed] [WebPage] [PDF] (IF 5.6)

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  • 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) [Pubmed] [WebPage] [PDF] (IF 4.6)

1st cohort MD doctoral students

Karem Awad

30.09.2022: Doctoral examination passed, Dr. med., "Epitheliale Barrierefunktion des Kolons beim Reizdarmsyndrom des Mischtyps"

Lucas Heils  
31.08.2024: Doctoral examination passed, Dr. med., "Die Auswirkungen des binären Clostridioides difficile Toxins CDT auf die epitheliale Barriere"

  • Heils L, Schneemann M, Gerhard R, Schulzke JD, Bücker R (2023) CDT of Clostridioides difficile induces MLC-dependent intestinal barrier dysfunction in HT-29/B6 epithelial cell monolayers. Toxins (Basel) 15(1): 54 (15 pages). doi: 10.3390/toxins15010054 (°IF 5.1)

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Sholpan Omarova  

Eduard Butkevych  

 

Project-related publications

  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