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Immunocompetent cell targeting by food-additive titanium dioxide

John W. Wills Orcid Logo, Alicja Dabrowska Orcid Logo, Jack Robertson, Michelle Miniter, Sebastian Riedle, Huw Summers Orcid Logo, Rachel E. Hewitt Orcid Logo, Adeeba Fathima, Alessandra Barreto da Silva Orcid Logo, Carlos A. P. Bastos, Stuart Micklethwaite Orcid Logo, Åsa V. Keita, Johan D. Söderholm Orcid Logo, Nicole C. Roy Orcid Logo, Don Otter, Ravin Jugdaohsingh, Pietro Mastroeni, Andy P. Brown Orcid Logo, Paul Rees Orcid Logo, Jonathan J. Powell Orcid Logo

Nature Communications, Volume: 16, Start page: 6067

Swansea University Authors: Huw Summers Orcid Logo, Paul Rees Orcid Logo

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DOI (Published version): 10.1038/s41467-025-60248-9

Abstract

Food-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Yet paradoxically, the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell target...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Nature 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa69898
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Yet paradoxically, the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell targets of fgTiO2 in humans, most notably in the subepithelial dome region of intestinal Peyer&#x2019;s patches. Using multimodal microscopies with single-particle detection and per-cell / vesicle image analysis we achieve correlative dosimetry, quantitatively recapitulating human cellular exposures in the ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funnel fgTiO2 into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets reveal no measureable perturbation of cell signalling pathways. When chased with oral &#x394;aroA-Salmonella, pro-inflammatory signalling is confirmed, but no augmentation by fgTiO2 is revealed despite marked same-cell loading. Interestingly, Salmonella causes the fgTiO2-recipient cells to migrate within the patch and, sporadically, to be identified in the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2 in humans. 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spelling 2025-07-04T16:05:46.3883123 v2 69898 2025-07-04 Immunocompetent cell targeting by food-additive titanium dioxide a61c15e220837ebfa52648c143769427 0000-0002-0898-5612 Huw Summers Huw Summers true false 537a2fe031a796a3bde99679ee8c24f5 0000-0002-7715-6914 Paul Rees Paul Rees true false 2025-07-04 EAAS Food-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Yet paradoxically, the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell targets of fgTiO2 in humans, most notably in the subepithelial dome region of intestinal Peyer’s patches. Using multimodal microscopies with single-particle detection and per-cell / vesicle image analysis we achieve correlative dosimetry, quantitatively recapitulating human cellular exposures in the ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funnel fgTiO2 into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets reveal no measureable perturbation of cell signalling pathways. When chased with oral ΔaroA-Salmonella, pro-inflammatory signalling is confirmed, but no augmentation by fgTiO2 is revealed despite marked same-cell loading. Interestingly, Salmonella causes the fgTiO2-recipient cells to migrate within the patch and, sporadically, to be identified in the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2 in humans. Immunocompetent cells that accumulate fgTiO2 in vivo are now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles. Journal Article Nature Communications 16 6067 Springer Nature 2041-1723 4 7 2025 2025-07-04 10.1038/s41467-025-60248-9 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University Another institution paid the OA fee The authors acknowledge the UK Medical Research Council (grant number MR/R005699/1, awarded to J.J.P.), the UK Engineering and Physical Sciences Research Council (grant EP/N013506/1, awarded to H.D.S.), the UK Biotechnology and Biological Sciences Research Council (grant number BB/P026818/1, awarded to P.R.) and the Swedish Research Council (Grant No. 2021-02566, awarded to J.D.S. and Å.V.K.). Mouse Study 1 was funded by the Riddet Institute through its Centre of Research Excellence funding (awarded to N.C.R. by the New Zealand government). Additional funding was provided by the Ministry for Science and Innovation contract C11 × 1009 through Nutrigenomics New Zealand, a collaboration between AgResearch, Plant and Food Research, and the University of Auckland (awarded to D.O.). J.W.W. is grateful to Girton College and the University of Cambridge Herchel-Smith Fund for supporting him with post-doctoral Fellowships. S.R. was supported by doctoral scholarships from Massey University. 2025-07-04T16:05:46.3883123 2025-07-04T15:55:59.1008377 Faculty of Science and Engineering School of Engineering and Applied Sciences - Biomedical Engineering John W. Wills 0000-0002-4347-5394 1 Alicja Dabrowska 0000-0001-5140-8725 2 Jack Robertson 3 Michelle Miniter 4 Sebastian Riedle 5 Huw Summers 0000-0002-0898-5612 6 Rachel E. Hewitt 0000-0002-2367-1822 7 Adeeba Fathima 8 Alessandra Barreto da Silva 0000-0003-4267-0136 9 Carlos A. P. Bastos 10 Stuart Micklethwaite 0000-0001-7335-2785 11 Åsa V. Keita 12 Johan D. Söderholm 0000-0002-3250-5367 13 Nicole C. Roy 0000-0002-6744-9705 14 Don Otter 15 Ravin Jugdaohsingh 16 Pietro Mastroeni 17 Andy P. Brown 0000-0001-9692-2154 18 Paul Rees 0000-0002-7715-6914 19 Jonathan J. Powell 0000-0003-2738-1715 20 69898__34683__0cf8276fca1348be9f69952193b6f2aa.pdf 69898.VOR.pdf 2025-07-04T16:02:51.8653256 Output 19437604 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). true eng http://creativecommons.org/licenses/by/4.0/
title Immunocompetent cell targeting by food-additive titanium dioxide
spellingShingle Immunocompetent cell targeting by food-additive titanium dioxide
Huw Summers
Paul Rees
title_short Immunocompetent cell targeting by food-additive titanium dioxide
title_full Immunocompetent cell targeting by food-additive titanium dioxide
title_fullStr Immunocompetent cell targeting by food-additive titanium dioxide
title_full_unstemmed Immunocompetent cell targeting by food-additive titanium dioxide
title_sort Immunocompetent cell targeting by food-additive titanium dioxide
author_id_str_mv a61c15e220837ebfa52648c143769427
537a2fe031a796a3bde99679ee8c24f5
author_id_fullname_str_mv a61c15e220837ebfa52648c143769427_***_Huw Summers
537a2fe031a796a3bde99679ee8c24f5_***_Paul Rees
author Huw Summers
Paul Rees
author2 John W. Wills
Alicja Dabrowska
Jack Robertson
Michelle Miniter
Sebastian Riedle
Huw Summers
Rachel E. Hewitt
Adeeba Fathima
Alessandra Barreto da Silva
Carlos A. P. Bastos
Stuart Micklethwaite
Åsa V. Keita
Johan D. Söderholm
Nicole C. Roy
Don Otter
Ravin Jugdaohsingh
Pietro Mastroeni
Andy P. Brown
Paul Rees
Jonathan J. Powell
format Journal article
container_title Nature Communications
container_volume 16
container_start_page 6067
publishDate 2025
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-025-60248-9
publisher Springer Nature
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Biomedical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Biomedical Engineering
document_store_str 1
active_str 0
description Food-grade titanium dioxide (fgTiO2) is a bio-persistent particle under intense regulatory scrutiny. Yet paradoxically, the only known cell reservoirs for fgTiO2 are graveyard intestinal pigment cells which are metabolically and immunologically quiescent. Here we identify immunocompetent cell targets of fgTiO2 in humans, most notably in the subepithelial dome region of intestinal Peyer’s patches. Using multimodal microscopies with single-particle detection and per-cell / vesicle image analysis we achieve correlative dosimetry, quantitatively recapitulating human cellular exposures in the ileum of mice fed a fgTiO2-containing diet. Epithelial microfold cells selectively funnel fgTiO2 into LysoMac and LysoDC cells with ensuing accumulation. Notwithstanding, proximity extension analyses for 92 protein targets reveal no measureable perturbation of cell signalling pathways. When chased with oral ΔaroA-Salmonella, pro-inflammatory signalling is confirmed, but no augmentation by fgTiO2 is revealed despite marked same-cell loading. Interestingly, Salmonella causes the fgTiO2-recipient cells to migrate within the patch and, sporadically, to be identified in the lamina propria, thereby fully recreating the intestinal tissue distribution of fgTiO2 in humans. Immunocompetent cells that accumulate fgTiO2 in vivo are now identified and we demonstrate a mouse model that finally enables human-relevant risk assessments of ingested, bio-persistent (nano)particles.
published_date 2025-07-04T05:25:09Z
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