Fragile Guts Make\nFragile Brains: Intestinal Epithelial <i>Nrf2</i> Deficiency\nExacerbates Neurotoxicity Induced by Polystyrene\nNanoplastics

Oral ingestion is the primary route for human exposure\nto nanoplastics,\nmaking the gastrointestinal tract one of the first and most impacted\norgans. Given the presence of the gut–brain axis, a crucial\nconcern arises regarding the potential impact of intestinal damage\non the neurotoxic effects of nanoplastics (NPs). The intricate mechanisms\nunderlying NP-induced neurotoxicity through the microbiome–gut–brain\naxis necessitate further investigation. To address this, we used mice\nspecifically engineered with nuclear factor erythroid-derived 2-related\nfactor 2 (<i>Nrf2</i>) deficiency in their intestines, a\nstrain whose intestines are particularly susceptible to polystyrene\nNPs (PS-NPs). We conducted a 28-day repeated-dose oral toxicity study\nwith 2.5 and 250 mg/kg of 50 nm PS-NPs in these mice. Our study delineated\nhow PS-NP exposure caused gut microbiota dysbiosis, characterized\nby <i>Mycoplasma</i> and <i>Coriobacteriaceae</i> proliferation, resulting in increased levels of interleukin 17C\n(IL-17C) production in the intestines. The surplus IL-17C permeated\nthe brain via the bloodstream, triggering inflammation and brain damage.\nOur investigation elucidated a direct correlation between intestinal\nhealth and neurological outcomes in the context of PS-NP exposure.\nSusceptible mice with fragile guts exhibited heightened neurotoxicity\ninduced by PS-NPs. This phenomenon was attributed to the elevated\nabundance of microbiota associated with IL-17C production in the intestines\nof these mice, such as <i>Mesorhizobium</i> and <i>Lwoffii</i>, provoked by PS-NPs. Neurotoxicity was alleviated\nby <i>in vivo</i> treatment with anti-IL-17C-neutralizing\nantibodies or antibiotics. These findings advanced our comprehension\nof the regulatory mechanisms governing the gut–brain axis in\nPS-NP-induced neurotoxicity and underscored the critical importance\nof maintaining intestinal health to mitigate the neurotoxic effects\nof PS-NPs.