Enteric Nervous System Damage by Food Contaminants: A Pathway to Neurodegeneration?

The enteric nervous system (ENS), a key component of the gut-brain axis, has emerged as a critical player in the pathogenesis of Parkinson's disease (PD). It is the first neural system exposed to food contaminants (FCs)-a diverse group of ubiquitous toxic compounds fortuitously present in food derived from production, processing, storage, or environmental contamination. Emerging evidence suggests that FCs may initiate or amplify neurodegenerative processes, yet their effects on the ENS and their impact in gut-to-brain communication remain insufficiently characterized. This systematic review synthesizes current evidence on FCs-induced effects on the ENS and its involvement in mediating neurotoxicity from dietary toxicants exposure. Following PRISMA guidelines, 67 studies were included pertaining to cellular or mammalian experimental models exposed to FCs via enteral routes, reporting ENS-related outcomes or studying vagal involvement in modulating FC toxicity. The main FCs evaluated were pesticides, toxins, bisphenols, acrylamide, manganese, and micro-/nanoplastics. Across studies, FCs consistently induced neurochemical remodeling of the ENS, activation of enteric glia, often coupled with intestinal alterations. Rotenone, paraquat, and polystyrene micro-/nanoplastics promote α-synuclein aggregation within the ENS and its vagal propagation to the brain. Vagotomy models confirmed that disrupting ENS-CNS communication attenuates FC-related central neurotoxicity, supporting the involvement of food toxicants in gut-to-brain propagation of neurotoxic signals. These findings support the body-first hypothesis of PD and position the ENS as a critical, yet underinvestigated interface in exposome-related neurotoxicology. The review highlights research gaps and the need for improved models and long-term, low-dose studies reflecting realistic FC exposure.