Vagus nerve stimulation in autoimmune diseases: Mechanisms, therapeutic potential, and clinical applications

Autoimmune diseases characterized by dysregulated immune responses against self-antigens. Current pharmacotherapies are limited by like resistance, side effects, and high costs, highlighting the need for novel interventions. Vagus nerve stimulation (VNS) offers a promising alternative through three forms, including implantable, transcutaneous cervical, and transcutaneous auricular. Increasing clinical evidence demonstrates VNS benefits patients with autoimmune disorders, such as treatment-refractory rheumatoid arthritis, Crohn's disease, and systemic lupus erythematosus. Preclinical studies support that VNS attenuates inflammation primarily via the cholinergic anti-inflammatory pathway (CAP) through α7 nicotinic acetylcholine receptor (α7nAChR) activation. Emerging insights implicate β-adrenergic signaling, hypothalamic-pituitary-adrenal (HPA) axis modulation, and gut microbiome regulation. This review summarizes current clinical and preclinical evidence, synthesizes current mechanistic understanding, and addresses key gaps in clinical validation. Future research priorities include conducting large-scale randomized controlled trials to extend VNS applications to broader autoimmune diseases and advancing the neurostimulation efficacy of non-invasive vagus nerve stimulation devices.