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Dietary nanoparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study

English title Dietary nanoparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study
Applicant Rogler Gerhard
Number 170109
Funding scheme Project funding (special)
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pathophysiology
Start/End 01.10.2016 - 31.01.2019
Approved amount 286'000.00
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All Disciplines (2)

Discipline
Pathophysiology
Immunology, Immunopathology

Keywords (7)

environmental factors; intestinal barrier function; inflammasome; nanoparticles; ulcerative colitis; extraintestinal manifestations; NLRP3

Lay Summary (German)

Lead
Nanopartikel finden Verwendung als Nahrungsmittelzusatz, als Streuhilfe oder Nahrungsmittelfarbstoff. Sie können bei manchen Menschen mit einer Darmentzündung über die Darmschleimhaut aufgenommen werden und Entzündungsreaktionen im Körper auslösen. Diesen Mechanismus wollen wir weiter untersuchen.
Lay summary
Titandioxid ist ein weißes Pigment, das z.B. als Weißmacher in Zahnpasta, Zuckerguss oder Marshmallows verwendet wird. Da Nanopartikel zunehmend in der Nahrungsmittelindustrie Verwendung finden und sich demzufolge in der Umwelt anhäufen, stellt sich die Frage nach möglichen Risiken der Aufnahme.
Das Protein NLRP3  ist ein Mitglied der sog. intrazellulären Pattern Recognition Receptors (PRRs) Familie und konstitutioneller Bestandteil des Inflammasoms. Das Inflammasom ist ein Komplex, der neben dem sog. NLRP3-Protein auch Caspase1 enthält. Caspase1 aktiviert die pro-entzündlichen Botenstoffe Interleukin (IL)-1β und IL-18.
Vor kurzem konnten kleine anorganische Partikel wie Asbestfasern oder Mono-Natriumuratkristalle (Harnsäurekristalle, die Auslöser der Gicht) als Aktivatoren von NLRP3 identifiziert werden. Daher lag es nahe, sich zu fragen, ob anorganische Titandioxid-Partikel ebenfalls mögliche Aktivatoren des Inflammasom-Komplexes sind und damit Entzündungsreaktionen in der Zelle auslösen können. Eine Entzündungsinduktion durch Titandioxid-Partikel konnte sowohl in der Lunge durch Titandioxid-Aerosole wie auch in Darmzellen nachgewiesen werden. Titandioxid-Partikel drangen in Darm-Epithelzellen ein und führten zu einem Zusammentreten des Inflammasom-Komplexes. Dies hatte die Produktion von pro-entzündlichen Botenstoffen zur Folge. Bei Patienten mit einer Störung der Darmbarriere konnten erhöhte Spiegel von Titandioxid im Blut wiedergefunden werden, was zeigt, dass unter bestimmten Krankheitsbedingungen eine Aufnahme dieser Partikel aus der Nahrung möglich ist. Ob dies Entzündungsreaktionen im Körper verstärkt, müssen nun weitere Untersuchungen zeigen. Insbesondere soll gezeigt werden, ob Titandioxid nach der Aufnahme über den Darm sich in anderen Geweben ansammelt und auch dort Entzündungsreaktionen hervorruft
Direct link to Lay Summary Last update: 29.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome
Ruiz Pedro A, Morón Belen, Becker Helen M, Lang Silvia, Atrott Kirstin, Spalinger Marianne R, Scharl Michael, Wojtal Kacper A, Fischbeck-Terhalle Anne, Frey-Wagner Isabelle, Hausmann Martin, Kraemer Thomas, Rogler Gerhard (2017), Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome, in Gut, 66(7), 1216-1224.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Andreas Geier, University of Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christoph Müller, Pathology, Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Lars French, Department of Dermatology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. Valerie Pittet, CHUV Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ECCO 2019 Individual talk TiO2nanoparticles abrogate the protective effect of the autoimmunity-associated PTPN22R619W variant during acute DSS colitis 07.03.2019 Wien, Austria Rogler Gerhard; De Vallière Cheryl; Scharl Michael;
Workshop on Possible adverse effects of food additive E171 (titanium dioxide), Talk given at a conference Titantiom dioxide in the gut 05.07.2018 Amsgterdam, Netherlands Rogler Gerhard;


Knowledge transfer events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Netherlands Consumer Safety Agency Talk 05.07.2018 Amsterdam, Netherlands


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Titandioxid: Verbot in Frankreich BR3 International 2019
Media relations: print media, online media Titanium Dioxide Nanoparticles Can Exacerbate Colitis UZH News Rhaeto-Romanic Switzerland Italian-speaking Switzerland Western Switzerland German-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
166844 Multi-center, multi-national, double-blind, placebo controlled study to evaluate the efficacy and safety of an anthocyanin-rich extract (ACRE) in moderately active ulcerative colitis 01.06.2016 Investigator Initiated Clinical Trials (IICT)
153380 The G-protein coupled pH receptor TDAG8 modulates intestinal inflammation 01.04.2014 Project funding (special)
184753 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in the pathogenesis of colorectal carcinoma 01.04.2019 Project funding (Div. I-III)
138291 Dietary microparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study 01.01.2012 Project funding (special)
134274 Schweizer IBD Kohorten Studie 01.04.2011 Cohort Studies Large
172870 The role of pH sensing G-protein coupled receptors for intestinal inflammation and fibrosis 01.05.2017 Project funding (Div. I-III)
177523 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2018 Cohort Studies Large

Abstract

SummaryMicro/nano-particles are widely used as food additives or in pharmaceutical formulations and are consumed by millions of people. The most commonly used microparticles are sub-micron sized (0.1-1 µm diameter), inorganic compounds of titanium dioxide (TiO2, E171) aluminum silicate (AlSi, Kaolin, E559), silicon dioxide (SiO2, E551) and iron oxide (E172).The total daily intake of TiO2 in the Western world is estimated to be up to 76 mg. To date, no restrictions for the use of TiO2 and AlSi in dietary products are enforced by food safety authorities. Indicators that TiO2 may have hazardous potential were found in animal and in vitro studies. In intestinal biopsies, aggregates of titanium were detected in M-cells of Peyer’s patches and in underlying macrophages. Crohn's diseased (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) which represent a chronic, relapsing inflammation of the intestine characterized by an altered pro-inflammatory cytokine pattern, defective mucosal barrier and increased intestinal permeability, the so-called “leaky gut”. Both environmental and genetic factors are associated with an increased risk to develop IBD. Rising incidences of CD in industrialized countries are attributed to Western nutrition. Whereas many (>190) genetic risk factors for IBD are known, insight into environmental factors is scarce.Together with two other proteins (ASC and caspase-1) NLRP3 forms the inflammasome, an intracellular signalling platform that is activated upon a number of stimuli, such as peptidoglycans, ATP, asbestos, silica, and uric acid crystals. Nonbacterial inflammasome activators such as ATP and small inorganic substances are summarized as “danger signals” or danger associated molecular patterns (DAMPs). TiO2 was found to be another inorganic compound that may activate the inflammasome. Since the intestinal epithelium forms the first barrier against food derived TiO2, we investigated whether TiO2 is also recognized as “danger signal” by human IEC. During our recent SNF project of the role of dietary TiO2 particles we could show that TiO2 in concentrations taken up by humans aggravate experimental colitis in mice. TiO2 aggregates can be found in the spleen of these aninals. In addition, in patients with active UC we found significantly increased TiO2 serum levels as copared to patients in remission of the disaese and healthy controls indicating that mainly during active colitis TiO2 may play a disease modifiying role. In a collaboration with colleagues from Lille we coud show that aluminum similarly is able to aggravate experimental colitis. During active colonic inflammation many CD and UC patients also experience extraintestinal manifestations (EIM). So far ist the pathophysiology of EIM is completely unclear. Based on our recent findings we aim to further analyze whether 1) The amount of penetrations of dietary micro/nano-particles (titanium dioxide) in patients with active IBD depends on the extent of involved (inflamed) mucosa.2) Dietary micro/nano-particles (TiO2) are able to penetrate the mucosal barrier and may accumulate in extraintestinal tissues leading to extraintestinal manifestations of IBD 3) Dietary micro/nano-particles (titanium dioxide) may cause indirect impact on mucosal inflammation via microbiota changes and epigenetic alterations in mucosal cells 4) Physical properties of dietary micro/nano-particles allow penetration into the mucosa which are not specific for and restricted to TiO2.5) Modulation of PTPN22 activity will impact the TiO2 effect The long term goal will be a better understanding of environmental factors that contribute to chronic intestinal inflammation and a chance to modify the disease course by diets avoiding these factors.
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