Immunocompetent cell targeting by food-additive titanium dioxide

John W. Wills (), Alicja Dabrowska, Jack Robertson, Michelle Miniter, Sebastian Riedle, Huw D. Summers, Rachel E. Hewitt, Adeeba Fathima, Alessandra Barreto 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 and Jonathan J. Powell ()
Additional contact information
John W. Wills: University of Cambridge
Alicja Dabrowska: University of Cambridge
Jack Robertson: University of Cambridge
Michelle Miniter: University of Cambridge
Sebastian Riedle: Massey University
Huw D. Summers: Swansea University
Rachel E. Hewitt: University of Cambridge
Adeeba Fathima: University of Cambridge
Alessandra Barreto Silva: University of Cambridge
Carlos A. P. Bastos: University of Cambridge
Stuart Micklethwaite: University of Leeds
Åsa V. Keita: Linköping University
Johan D. Söderholm: Linköping University
Nicole C. Roy: Massey University
Don Otter: Auckland University of Technology
Ravin Jugdaohsingh: University of Cambridge
Pietro Mastroeni: University of Cambridge
Andy P. Brown: University of Leeds
Paul Rees: Swansea University
Jonathan J. Powell: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-60248-9

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