Idiopathic achalasia: unraveling the etiology and pathogenesis of an inflammatory disease.

Idiopathic achalasia is a rare esophageal motility disorder caused by the loss of enteric neurons leading to impaired relaxation of the lower esophageal sphincter and absent peristalsis of the esophageal body. Despite being described over three centuries ago, the precise etiology and molecular pathogenesis of idiopathic achalasia remain unclear. Recent studies indicate that an initial injury to the esophagus, potentially caused by viral infection, may trigger inflammation in genetically predisposed individuals. Ultimately, chronic inflammation causes the destruction of inhibitory myenteric neurons, resulting in clinical symptoms of achalasia-like dysphagia, regurgitation, chest pain, and weight loss. Although extensive research has been conducted on the etiology of achalasia, the majority of these studies have been limited to exploration of the infection and immune factors within the context of genetic susceptibility. In this review, we aim to provide a detailed understanding of the etiology of achalasia. In addition to the genetic factors, viral infection, and autoimmunity, we additionally propose that psychological factors, gut microbiota, and the gut-brain axis play a role in the pathogenesis of achalasia.