The sympathetic neurons in the gut: Perspectives on metabolic and immune health and diseases

Purpose of review: The sympathetic nervous system (SNS), a crucial regulator of systemic homeostasis, connects the brain and peripheral organs through complex neural circuits. Often termed the “second brain,” the gut responds to sympathetic innervation to coordinate physiological processes such as digestive motility, nutrient absorption, and immune surveillance, unveiling fundamental and potentially translational significance. Therefore, timely exploration of sympathetic-gut communication is essential. Recent findings: Previous studies have revealed that sympathetic signaling inhibits intestinal peristalsis and blood flow while enhancing nutrient assimilation during feeding. Emerging evidence further identifies a neuro-metabolic axis in which sympathetic activity suppresses enteroendocrine hormone secretion, thereby linking systemic energy balance to central nervous system function. Additionally, bidirectional SNS-immune interactions have been uncovered; these pathways govern antimicrobial defense yet paradoxically exacerbate inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and colorectal cancer (CRC). Summary: This review briefly summarizes anatomical insights into sympathetic-gut projections, highlights their dual roles in metabolic homeostasis and immune modulation, and explores therapeutic opportunities targeting sympathetic pathways for gut-related disorders.