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

English title Dietary microparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study
Applicant Rogler Gerhard
Number 138291
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 01.01.2012 - 30.09.2014
Approved amount 283'646.00
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All Disciplines (2)

Discipline
Pathophysiology
Immunology, Immunopathology

Keywords (8)

inflammatory bowel disease; inflammasome; microparticles; TiO2; DAMPS; mucosal barrier; large nested project; Swiss Inflamatory Bowel Disease Cohort Study

Lay Summary (English)

Lead
Lay summary

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) which represent a chronic, relapsing inflammation of the intestine. They are characterized by a 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.

Data from twin studies indicate that the genetic background may be responsible for 50% of the risk or “susceptibility” to develop CD. Genome wide association studies (GWAS) have identified more than 70 "risk" genes,, among them many genes involved in innate immune functions, such as the "pattern recognition receptor NLRP3"

However, obviously genetic susceptibility is not a sufficient condition as otherwise there would be 100% concordance of disease in monozygotic twin pairs. Environmental factors as well must play an important role. This is further supported by the fact that there is only low development in genetic risk factors over ten thousands of years. In contrast, the incidence of CD and UC has dramatically increased in Western countries in the last 100 years. This further supports the concept of “Western lifestyle factor(s)” that trigger chronic intestinal inflammation in a genetically susceptible host.

Microparticles 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 76 mg. Indicators that TiO2 may have hazardous potential were found in animal and in vitro studies. In intestinal biopsies, aggregates of titanium were detected. These sites of titanium uptake correspond to regions where first signs of inflammation in Crohn’s disease (CD) manifest.

We have found that TiO2 particles are taken up by cells of the intestinal mucosa. The presence of TiO2 triggered inflammatory reaction in the mucosal cells.

Based on our recent findings we aim to further analyze
1) whether TiO2 is an environmental factor contributing to the pathogenesis of IBD
2) whether TiO2 may contribute to extraintestinal manifestations in IBD
3) whether there is evidence for other microparticles to activate inflammatory reactions

The long term goal will be a better understanding of mucosal tolerance and the development of new treatment options for chronic mucosal inflammatory diseases such as CD.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome.
Ruiz Pedro, Morón Belen, Becker Helen, Lang Silvia, Atrott Kirstin, Spalinger Marianne, Wojtal Kaspar, Fischbeck-Terhalle Anne, Fischbeck-Terhalle Anne, Frey-Wagner Isabelle, Hausmann Martin, Kraemer Thomas, Rogler Gerhard (2016), Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome., in Gut, epu ahead of print(10.1136/gu), gutjnl-201-gutjnl-201.
Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice.
Pineton de Chambrun G Body-Malapel M Frey-Wagner I ..... Rogler G Colombel JF .... Desreumaux P (2014), Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice., in Mucosal Immunol., 7(3), 589-601.
Nanopartikel und ihr potentieller Einfluss auf die Darmmukosa
Helen Becker Martina Bertschinger Gerhard Rogler (2014), Nanopartikel und ihr potentieller Einfluss auf die Darmmukosa, in Tag Brigitte, Mausbach Julian (ed.), edition weimar, European Academy of Sciences and Arts, Weimer, 57-70.
Microparticles and their impact on intestinal immunity.
Becker Helen M Bertschinger Martins M Rogler Gerhard (2013), Microparticles and their impact on intestinal immunity., in Dig Dis, 30 (Suppl 3), 47-54.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Jürg Tschopp, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Valerie Pittet, Prof. Dr. John-Paul Vader, CHUV Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christoph Müller, Pathology, Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Knowledge transfer events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Internationale Tagung «Nanomedizin» Talk 02.11.2012 Zürich, Switzerland


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Internationale Tagung «Nanomedizin» International 2013

Awards

Title Year
Le Vaillant Preis 2014 2015
Ehrenpreis der Schweizer Gastroenterologischen Gesellschaft, SGG 2013

Associated projects

Number Title Start Funding scheme
134274 Schweizer IBD Kohorten Studie 01.04.2011 Cohort Studies Large
170109 Dietary nanoparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study 01.10.2016 Project funding (special)
148422 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2014 Cohort Studies Large
153380 The G-protein coupled pH receptor TDAG8 modulates intestinal inflammation 01.04.2014 Project funding (special)

Abstract

SummaryMicroparticles 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 76 mg. To date, no restrictions for the use of TiO2 and AlSi 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. These sites of titanium uptake correspond to regions where first signs of inflammation in Crohn’s disease (CD) manifest. CD and 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 (>70) 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 inflammasome8. 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. We found that TiO2 particles are taken up by both IEC and macrophages and accumulate in the cytoplasm. Intracellular presence of TiO2 triggered activation of caspase-1, increased caspase-1/NLRP3 association and release of IL-1ß or IL-18, indicating inflammasome activation. Furthermore, TiO2 caused the production of reactive oxygen species. In preliminary experiments patients with CD or UC showed significantly increased TiO2 blood levels.Based on our recent findings we aim to further analyze 1) whether TiO2 is an environmental factor contributing to the pathogenesis of IBD 2) whether TiO2 may contribute to extraintestinal manifestations in IBD 3) whether there is evidence for other microparticles to activate the inflammasomeSpecific aims A. To test the effects of alimentary microparticles in animal models of IBDB. To quantify presence of TiO2 in the mucosa, organs affected by extraintestinal manifestations and blood samples of patients with IBD (patients of the SIBDCS)C. To asses the activation of the inflammasome by (AlSi, Kaolin, E559) and silicon dioxide (SiO2, E551) and quantify the presence in samples of SIBDCS patientsThe long term goal will be a better understanding of mucosal tolerance and the development of new treatment options for chronic mucosal inflammatory diseases such as CD.
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