Autonomic nervous system dysfunction in irritable bowel syndrome: pathophysiology and therapeutic implications

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  FIGURE 1. Model of irritable bowel syndrome pathogenesis, emphasizing brain-gut efferent pathways (e.g., HPA axis, autonomic nervous system) and gut-to-brain afferent pathways (e.g., vagal innervation and enteroendocrine signaling). IBS has a multifactorial pathophysiology and multiple interrelated pathways can influence the manifestation of symptoms. External factors are dominant, but internal factors such as gut microbiome, gastrointestinal immune system and genetic makeup is also likely to be crucial for the development and progression of symptoms. Food and microbial metabolism stimulate the gut’s endocrine cells to release hormones and neurotransmitters, leading to visceral pain and reducing gastrointestinal motility. Bacterial metabolites including short-chain fatty acids modify gut barrier integrity, and modulate brain and behavior via the vagus and/or directly acting brain through circulation, thereby possibly causing psychiatric comorbidities. IBS, irritable bowel syndrome; IBS-M, mixed IBS; IBS-C, constipation predominant IBS; IBS-D, diarrhea predominant IBS; FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; 5-HT, serotonin; CCK, cholecystokinin;…

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  FIGURE 2. Diagram of the ANS anatomy and mode of action. The gut is innervated by extrinsic and intrinsic neurons. Extrinsic afferent neurons of the GI tract send information to the CNS through vagal or spinal afferents. Extrinsic efferent neurons, including sympathetic and parasympathetic motor neurons, project to the gut wall. Intrinsic or enteric neurons are present within the myenteric and submucosa plexus of the gut and form a complex network involved in motility, secretion and vasodilatation. The vagus nerve contains several distinct types of afferent terminals. Intraganglionic laminar endings, situated within the myenteric plexus, function as tension receptors. Intramuscular afferents, located in the muscle layer, act as stretch or length receptors. Vagal villus and crypt afferents terminate near the villus tip adjacent to the epithelium or surround the luminal ends of intestinal crypts, where they serve as chemoreceptors. The efferent vagus nerve projects into the myenteric plexus and releases neurotransmitters to regulate smooth muscle contraction and gastrointestinal motility. CNS, central nervous system; NTS, nucleus of the solitary tract; DMN, dorsal motor nucleus.

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  FIGURE 3. The vagus nerve provides a critical communication pathway between the gut and the brain. This gut-brain axis integrates the enteric nervous system, central nervous system, peripheral gut wall, and the hypothalamic-pituitary-adrenal (HPA) axis. Dysregulation within this network promotes visceral hypersensitivity, abnormal intestinal motility, mucosal immune activation, and alterations in the gut microbiota. Gut microbiota can activate the vagus nerve, which then relays signals from the gastrointestinal tract to the nucleus tractus solitarius (NTS). From the NTS, information is propagated through diverse neuronal pathways of the central autonomic network to produce specific physiological effects. ANS, autonomic nervous system; ENS, enteric nervous system; HPA, hypothalamo-pituitary-adrenal; PFC, prefrontal cortex; vmPFC, ventromedial prefrontal cortex; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

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  FIGURE 4. Communication between the gut and brain occurs via the endocrine system and the vagus nerve. The hypothalamic-pituitary-adrenal (HPA) axis regulates intestinal motility, gut microbiome composition, intestinal permeability, and immune activation through cortisol secretion. Through acetylcholine release and direct connections, the vagus nerve modulates immune function, intestinal permeability, and motility, often in concert with the enteric nervous system (ENS). Microbial metabolites, including short-chain fatty acids (SCFAs), neurotransmitters, and bile acids, directly influence peripheral and central nervous system activity. The microbiota also exerts its effects by modulating enteroendocrine cells, such as enterochromaffin cells. CNS, central nervous system; HPA, hypothalamic-pituitary-adrenal; ANS, autonomic nervous system.