The Role of Gut-Derived Neurotransmitters in the Pathogenesis of Autoimmune Neurological Disorders

Abstract

Autoimmune neurological disorders such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders (NMOSD), and stiff‐person syndrome (SPS) result from dysregulated immune responses targeting central nervous system (CNS) components. Emerging evidence highlights the gut–brain axis as a key modulator of neuroimmunological health, with gut‐derived neurotransmitters acting as critical mediators linking the gut microbiome, mucosal immunity, and CNS autoimmunity. In this review, we explore current knowledge on how gut‐derived serotonin (5‐HT), γ‑aminobutyric acid (GABA), dopamine, acetylcholine, and related metabolites influence immune cell function and contribute to the pathogenesis of autoimmune neurological diseases. We discuss the mechanisms by which microbial communities regulate neurotransmitters production, the pathways through which these neurotransmitter modulate peripheral and central immune responses, and how dysbiosis or altered neurotransmitter signaling may promote neuroinflammation and autoimmunity. Specifically, we examine the roles of 5‑HT in suppressing Th17 responses in multiple sclerosis, GABA in T cell regulation, dopamine in modulating IL‑17 and microglial activation, and cholinergic signaling in gut immune homeostasis. We also explore the contribution of microbial metabolites short‐chain fatty acids and bile acids that influence neurotransmitter release and immune tolerance. Finally, we highlight potential translational avenues, including neurotransmitter modulating probiotics, dietary interventions, and pharmacotherapies targeting gut neurotransmission. Understanding these pathways may open preventive and therapeutic strategies in autoimmune neurological disorders by harnessing gut‐CNS immunomodulation.