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TiO2 nanoparticles abrogate the protective effect of the Crohn’s disease-associated variation within the PTPN22 gene locus
  1. Marlene Schwarzfischer1,
  2. Anna Niechcial1,
  3. Kristina Handler2,
  4. Yasser Morsy1,
  5. Marcin Wawrzyniak1,
  6. Andrea S Laimbacher1,
  7. Kirstin Atrott1,
  8. Roberto Manzini1,
  9. Katharina Baebler1,
  10. Larissa Hering1,
  11. Egle Katkeviciutė1,
  12. Janine Häfliger1,
  13. Silvia Lang1,
  14. Maja E Keller3,
  15. Jérôme Woodtli3,
  16. Lisa Eisenbeiss3,
  17. Thomas Kraemer3,
  18. Elisabeth M Schraner4,
  19. Mahesa Wiesendanger4,
  20. Sebastian Zeissig5,
  21. Gerhard Rogler1,
  22. Andreas E Moor2,
  23. Michael Scharl1,
  24. Marianne R Spalinger1
  1. 1Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
  2. 2Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
  3. 3Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland
  4. 4Institutes of Veterinary Anatomy and Virology, University of Zurich, Zurich, Switzerland
  5. 5Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, and Department of Medicine I, University Medical Center Dresden, Dresden, Germany
  1. Correspondence to Professor Michael Scharl, Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland; michael.scharl{at}usz.ch

Abstract

Objective Inflammatory bowel disease (IBD) is a multifactorial condition driven by genetic and environmental risk factors. A genetic variation in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been associated with autoimmune disorders while protecting from the IBD subtype Crohn’s disease. Mice expressing the murine orthologous PTPN22-R619W variant are protected from intestinal inflammation in the model of acute dextran sodium sulfate (DSS)-induced colitis. We previously identified food-grade titanium dioxide (TiO2, E171) as a neglected IBD risk factor. Here, we investigate the interplay of the PTPN22 variant and TiO2-mediated effects during IBD pathogenesis.

Design Acute DSS colitis was induced in wild-type and PTPN22 variant mice (PTPN22-R619W) and animals were treated with TiO2 nanoparticles during colitis induction. Disease-triggering mechanisms were investigated using bulk and single-cell RNA sequencing.

Results In mice, administration of TiO2 nanoparticles abrogated the protective effect of the variant, rendering PTPN22-R619W mice susceptible to DSS colitis. In early disease, cytotoxic CD8+ T-cells were found to be reduced in the lamina propria of PTPN22-R619W mice, an effect reversed by TiO2 administration. Normalisation of T-cell populations correlated with increased Ifng expression and, at a later stage of disease, the promoted prevalence of proinflammatory macrophages that triggered severe intestinal inflammation.

Conclusion Our findings indicate that the consumption of TiO2 nanoparticles might have adverse effects on the gastrointestinal health of individuals carrying the PTPN22 variant. This demonstrates that environmental factors interact with genetic risk variants and can reverse a protective mechanism into a disease-promoting effect.

  • inflammatory bowel disease
  • gastrointestinal immune response
  • gut immunology
  • IBD basic research

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article file or its supplementary material. RNAseq data are available at https://www.ncbi.nlm.nih.gov/bioproject/, Project ID PRJNA860794.

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Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article file or its supplementary material. RNAseq data are available at https://www.ncbi.nlm.nih.gov/bioproject/, Project ID PRJNA860794.

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Footnotes

  • Contributors MSchw: data acquisition, analysis, interpretation, drafting the manuscript. KH: processing and analysis of scRNAseq data. YM: processing and analysis of bulk RNAseq data. AN, MWa, KA, AL, RM, KB, LH, EK, JH, SL: data acquisition and analysis. MK, JW, LE, TK: ICP-MS and data analysis. EMS, MWi: electron microscopy and data interpretation. SZ, AM: study design. GR: study design and funding. MScha: conceived study, study design, supervision, data interpretation, funding and is the guarantor. MRS: study design, supervision, data interpretation.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.