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GUT-DRIVEN VASCULAR INFLAMMATION AND OXIDATIVE STRESS: EXPLORING THE MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN AN EXPERIMENTAL COELIAC DISEASE MODEL

Karin Keppeler 1, Aline Pesi 1, Simon Lange 1, Johanna Helmstaedter 1, Lea Strohm 1, Henning Ubbens 1, Charlotte Frank 1, Dominika Mihalikova 1, Marin Kuntic 1, Ivana Kuntic 1, Ksenija Vujacic-Mirski 1, Maria Teresa Bayo Jimenez 1, Stefanie Finger 1, Alexandra Rosenberger 1, Matthias Oelze 1, Philip Wenzel 1, David Leistner 2, Agnieszka Zakrzewska 3, Agnieszka Kij 3, Stefan Chlopicki 3, Thomas Muenzel 1,4, Andreas Daiber 1,4, Elena Verdu 5, Detlef Schuppan 1,6, Sebastian Steven 1,2

Affiliations

1 University Medical Center of the Johannes Gutenberg University, Mainz, Germany

2 Goethe University Hospital Frankfurt, Frankfurt am Main, Germany

3 Jagiellonian University Krakow, Krakow, Poland

4 German Center for Cardiovascular Research (DZHK), Mainz, Germany

5 McMaster University, Hamilton, Canada

6 Harvard Medical School, Boston, United States

Summary

AI Generated

A humanized mouse model of coeliac disease demonstrates that gluten challenge triggers intestinal inflammation, elevated blood pressure, vascular dysfunction, and oxidative stress, with IL-17A as a potential mediator linking gut and cardiovascular pathology.

Gluten-challenged NOD-DQ8 mice developed duodenal and jejunal T-lymphocyte infiltration and reduced villus/crypt ratio, mirroring human coeliac disease.
Gluten challenge increased blood pressure and impaired endothelium-dependent and -independent vascular relaxation compared to controls.
Pro-inflammatory gene transcripts were upregulated in both duodenum and aorta, with increased CD11b+ myeloid cell infiltration into the aortic wall and elevated oxidative stress markers in heart tissue.
Plasma IL-17A concentrations were elevated in gluten-challenged mice, and all cardiovascular complications were reversible upon return to a gluten-free diet.
The findings support a mechanistic gut-to-cardiovascular inflammatory axis in coeliac disease, relevant to researchers investigating autoimmune disease and cardiovascular risk.

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Abstract

Introduction

Coeliac disease (CeD) is an autoimmune enteropathy of the small intestine triggered by gluten. Some clinical studies comparing CeD patients to healthy controls have suggested that CeD is a cardiovascular risk factor. In this study, we aimed to investigate the cardiovascular effects of CeD in a humanized CeD mouse model, focusing on vascular inflammation, endothelial dysfunction, and oxidative stress (in relation to intestinal inflammation), which are known triggers for later cardiovascular diseases and their mechanistic causes.

Aims & Methods

NOD-human DQ8 transgenic mice with genetic deletion of the murine MHCII complex (NOD-DQ8 mice), genetically predisposed to CeD, were raised on a zein (corn)-protein-based, gluten-free diet. Gluten sensitization was performed by 3 oral gavages of pepsin-trypsin digested and TG2 deamidated gliadin (500 µg) and cholera toxin (25 µg), concomitant with the feeding of a gluten-containing diet (gliadin group) for 14 days. A control group continued the gluten-free diet during sensitization with zein. An additional group was returned to a gluten-free diet for another 14 days to assess the reversibility of CeD and cardiovascular effects. Small animal transthoracic echocardiography (TTE) as well as non-invasive blood pressure measurements were performed. Vascular function was tested by isometric tension recording. Aortic, cardiac, perivascular adipose (PVAT) and duodenal tissue were used for qRT-PCR, dot blotting, Flow Cytometry or IHC to determine the extent of vascular and intestinal inflammation as well as (nitro-)oxidative stress. Plasma proteomics was performed using Olink.

Results

As in human CeD, gluten-challenged NOD-DQ8 mice developed a duodenal and jejunal infiltration of intraepithelial T-lymphocytes (IELs) and a reduction in the villus/crypt ratio. Tail-cuff measurements showed increased blood pressure in these mice compared to the controls. Endothelium-dependent (ACh) and -independent (NTG) vascular relaxation was impaired, as tested by isometric tension measurements, and transcripts of pro-inflammatory genes (Il6, Infy, Tnfa, Cybb-Nox2, Nos2-iNos) were upregulated in the duodenum and aorta. Flow cytometry revealed increased CD11b+ myeloid cell infiltration into the aortic wall in gluten-challenged NOD-DQ8 mice. Additionally, oxidative stress parameters 3-nitrotyrosine (3-NT) and 4-hydroxy-2-nonenal (4-HNE) were elevated in the heart tissue, as demonstrated by dot-blot analysis. However, cardiac function remained unimpaired, as assessed by TTE. To investigate the inflammatory gut-vascular connection, plasma proteomics tests (Olink) were performed, which showed increased concentrations of IL-17A, confirmed by ELISA. The cardiovascular complications were reversible with the return to the gluten-free diet.

Conclusion

In our humanized CeD mouse model, active CeD increases blood pressure and impairs vascular function. We conclude that CeD increases cardiovascular risk through gut inflammation that is transferred to the cardiovascular system, leading to vascular inflammation/oxidative stress and impaired endothelial function. A possible mediator is IL-17A whose role in other autoimmune diseases like psoriasis has already been demonstrated.
With the present study, we demonstrate a mechanistic approach to explain the role of coeliac disease as a cardiovascular risk factor and provide evidence for a gut-to-cardiovascular inflammatory axis.

Conference

UEG Week Copenhagen 2023

Topics

Small Intestine & Nutrition

Submission format

Abstract

Session

Coeliac disease (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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THE ROLE OF PROBIOTICS IN THE EFFECTIVENESS OF TREATMENT AGAINST HELICOBACTER PYLORI: RESULTS OF THE EUROPEAN REGISTRY ON THE MANAGEMENT OF HELICOBACTER PYLORI INFECTION (HP-EUREG)

Diego Casas Deza 1, Javier Alcedo 2, Miguel Lafuente Blasco 3, Javier López Lorente 3, Ángeles Pérez-Aísa 4, Matteo Pavoni 5, Ilaria Maria Salacino 5, Bojan Tepes 6, Laimas Virginijus Jonaitis 7, Manuel Castro-Fernández 8, Manuel Pabon-Carrasco 8, Alma Keco-Huerga 8, Irina Voynovan 9, Luis Bujanda Fernández de Piérola 10, Alfredo J. Lucendo 11, Natasa Brglez Jurecic 12, Maja Denkovski 13, Perminder Phull 14, Luis Ricardo Rodrigo Sáez 15, Angel Lanas 16, Samuel Jesús Martínez-Domínguez 17, Jose Maria Huguet 18, Dmitry S. Bordin 9, Antonio Gasbarrini 19, Juozas Kupcinskas 7, Gülüstan Babayeva 20, Oleksiy Gridnyev 21, Marcis Leja 22, Theodore Rokkas 23, Ricardo Pinto 24, Frode Lerang 25, Doron Boltin 26, Veronika Papp 27, Ante Tonkic 28, Sinead Smith 29,30, Halis Simsek 31, Marino Venerito 32, Lyudmila Boyanova 33, Vladimir Milivojevic 34, Lumir Kunovsky 35, Tamara Matysiak-Budnik 36, Wojciech Marlicz 37, Michael Doulberis 38, Anna Cano Català 39, Luis Hernández Villalba 40, Leticia Moreira Ruiz 41, Olga P. Nyssen 42, Francis Mégraud 43, Colm O'Morain 44, Javier P. Gisbert 45

Affiliations

1 Diego Casas Deza, Zaragoza, Spain

2 Miguel Servet University Hospital, Zaragoza, Spain

3 Universidad de Zaragoza, Zaragoza, Spain

4 Agencia Sanitaria Costa del Sol, Marbella, Spain

5 IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy

6 Abakus Medico d.o.o., Rogaska Slatina, Slovenia

7 Lithuanian University of Health Sciences, Kaunas, Lithuania

8 Hospital Universitario de Valme, Sevilla, Spain

9 A.S. Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation

10 Instituto Biodonostia, San Sebastián, Spain

11 Hospital General de Tomelloso, Madrid, Spain

12 Diagnostini Center Bled, Bled, Slovenia

13 GH Novo mesto, Novo mesto, Slovenia

14 Aberdeen Royal Infirmary, Aberdeen, United Kingdom

15 University of Oviedo, Oviedo, Spain

16 University of Zaragoza University Hospital, Zaragoza, Spain

17 Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

18 Hospital General Universitario de Valencia, Valencia, Spain

19 Fondazione Policlinico Universitario Gemelli IRCCS, Università’ Cattolica, Rome, Italy

20 Azerbaijan State Advanced Training Institute for Doctors named by A. Aliyev, Baku, Azerbaijan

21 National Institute of Therapy named L.T.Malaya NAMS of Ukraine, Kharkiv, Ukraine

22 University of Latvia, Riga, Latvia

23 Henry Dunant Hospital, Athens, Greece

24 Centro Hospitalar do Porto. Universidade do Porto, Oporto, Portugal

25 Central Hosspital of Ostfold, Grålum, Norway

26 Rabin Medical Center, Petah Tikva, Israel

27 Semmelweis University, Budapest, Hungary

28 University of Split School of Medicine, Split, Croatia

29 Trinity College Dublin/, Dublin, Ireland

30 Tallaght University Hospital, Dublin, Ireland

31 Hacettepe University, Ankara, Turkey

32 Otto-von-Guericke University, Magdeburg, Germany

33 Medical University of Sofia, Sofia, Bulgaria

34 Clinical Centar of Serbia, Belgrade University, Belgrade, Serbia

35 2nd Department of Internal Medicine – Gastroenterology and Geriatrics, University Hospital Olomouc, Olomouc, Czechia

36 CHU de Nantes IMAD, Nantes, France

37 Pomeranian Medical University, Szczecin, Poland

38 Kantonsspital Aarau, Dietikon, Switzerland

39 Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Spain

40 Santos Reyes, Aranda de Duero, Spain

41 Hospital Clinic de Barcelona, Gava, Spain

42 Hospital Universitario de La Princesa, IIS-IP, and CIBERehd, Madrid, Spain

43 Hopital Pellegrin, Laboratoire de Bacteriologie, Bordeaux, France

44 Trinity College Dublin, Dublin, Ireland

45 Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa and CIBEREHD, Madrid, Spain