Celiac disease as a model of gut–brain autoimmunity: from gluten exposure to neuropsychiatric manifestations

Background: Celiac disease (CeD) is a systemic immune-mediated disorder triggered by gluten ingestion in genetically predisposed individuals. Further to the gastrointestinal involvement, growing evidence highlights a wide spectrum of neurological and psychiatric manifestations, with still partly understood pathophysiology and clinical relevance. Aims: This narrative review provides an updated appraisal of neuropsychiatric conditions associated with CeD, discussing their underlying mechanisms, clinical implications, and therapeutic perspectives, with particular attention to differences between paediatric and adult populations. Methods: A comprehensive literature review was conducted focusing on neurological and psychiatric complications of CD, proposed pathogenetic pathways, and outcomes following a gluten-free diet (GFD). Results: Neurological features include cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive dysfunction, and sleep disorders; psychiatric manifestations encompass depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and schizophrenia. Possible underlying mechanisms involve autoimmune responses (anti-transglutaminase 6 antibodies), blood-brain barrier dysfunction, gut dysbiosis, neuroinflammation, micronutrient deficiencies, serotonergic dysregulation, and cerebral perfusion abnormalities. Clinical outcomes vary as some patients improve on a GFD, while others experience persistent symptoms despite strict dietary adherence. Paediatric patients usually exhibit lower prevalence and milder neurological involvement, likely due to early diagnosis and better compliance. Conclusions: Neuropsychiatric manifestations are clinically significant yet frequently underrecognized components of CeD. In some patients, they are directly evoked by gluten exposure; in others, gluten acts as a trigger of self-perpetuating neuroimmune or neuroinflammatory cascades. Early identification, multidisciplinary management, and strict dietary monitoring are essential to prevent irreversible neurological damage and optimize long-term outcomes.