Immunocompetent cell targeting by food-additive titanium dioxide

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.