The Brain in the Gut: Enteric Nervous System and Its Clinical Relevance

The gastrointestinal tract (GIT) in humans is characterized by a well-defined four-layered architecture: the innermost mucosa, followed by the submucosa, muscularis externa, and the outermost serosa. The GIT is intricately innervated by three major nervous systems: the parasympathetic, sympathetic, and enteric nervous systems (ENSs). The ENS, embedded within the walls of the GIT, represents the biggest and most complex component of the peripheral nervous system (PNS). It consists of two primary networks: the Meissner’s/submucosal and the Auerbach’s/myenteric plexuses, located in the submucosa and muscularis externa, respectively.[1] These plexuses are uniquely capable of functioning independently of central nervous system (CNS) input, owing to their self-sustaining local circuits.[2] Langley’s classification of the ENS as the third branch of the autonomic nervous system (ANS), along with the sympathetic and parasympathetic systems, highlights its functional independence and physiological significance.[3,4] The critical role of the ENS is further highlighted by its association with various health conditions, including developmental disorders, infections, and inflammatory pathologies, which can lead to significant morbidity and mortality. This emphasizes the need for a comprehensive understanding of the ENS’s anatomy and physiology to advance diagnostic and therapeutic strategies. The two primary plexuses of the ENS are distinct histological structures composed of neurons, ganglia, interganglionic fiber tracts, and secondary and tertiary fiber projections, that connect to effector systems, including smooth muscles, glands, and blood vessels. Positioned between the circular muscle layer of submucosa and the mucosa, Meissner’s plexus is most prominent in the intestines (both small and large). In contrast, it is sparsely distributed in the stomach’s submucosa and nearly absent in the esophagus. Notably, in humans, two additional submucosal plexuses–Schabadasch’s plexus and the intermediate plexus have been identified, further enriching the complexity of ENS architecture. Meissner’s plexus primarily innervates the glands of the GIT, regulating their secretory functions.[2] The myenteric/Auerbach’s plexus is situated between the circular and longitudinally oriented smooth muscle fibers along the entire length of the GIT. It plays a critical role in innervating these muscle layers, thereby coordinating gastrointestinal motility.[4] Based on axonal projections, electrophysiological properties, neurotransmitter profiles, and physiological roles, ENS neurons have been classified into distinct subtypes.[5] Furness et al. broadly categorized these neurons into three functional groups: intrinsic primary afferent neurons, motor neurons, and interneurons.[6,7] These categories are further subdivided based on their specific roles and characteristics, as illustrated in Figure 1. In addition, the ENS neurons are supported by enteric glial cells, which are thought to originate from the neural crest and contribute to the maintenance and function of the ENS.[8,9]Figure 1: Different types of neurons based on different features. ENS: Enteric nervous systemThe other important supporting cell is an interstitial cell of Cajal (ICC), referred to as pace make of GIT to initiate slow waves with the GIT. They have an elongated, fusiform body having few processes.[10-12] The neurons within the submucosal and myenteric plexus are interlinked, playing a crucial role in maintaining the functional integrity of both plexuses. The structure, functionality, and neurochemical properties of the ganglia in the ENS show similarities to those in the CNS, yet they differ significantly from the ganglia found in the sympathetic and parasympathetic divisions of the ANS. Unlike the majority of ganglia in the sympathetic or parasympathetic systems, which primarily serve as relay and distribution centers for signals relayed from the brain and spinal cord to peripheral systems, enteric ganglia are interconnected to establish a nervous system that can integrate and process information similarly to the brain and spinal cord. This supports the notion of referring to the ENS as a “minibrain in the gut.” The ENS orchestrates and synchronizes the activities of effector systems–such as smooth muscles, glands, and blood vessels–into a cohesive functional behavior of the entire organ. This coordination is achieved through robust connections between sensory and motor neurons, as well as the integrative networks of interneurons within the ENS. Furthermore, the ENS maintains bidirectional communication with the sympathetic and parasympathetic centers of the CNS, facilitating a dynamic interplay between the two systems.[4,6] The ENS plays a pivotal role in regulating key GIT functions, including secretion, motility, mucosal maintenance, and immunologic responses [Figure 2]. It also contributes to nutrient handling, blood flow regulation, nonpropulsive mixing (segmentation), and the retropulsion of noxious substances.[13-16]Figure 2: Summary of components of enteric nervous system and function. GIT: Gastrointestinal tractThe role of the ENS in GIT disorders highlights the importance of understanding its structure, which is essential for current and future targeted therapies aimed at assisting patients with various gastrointestinal issues. In addition, the ENS has gained attention as a potential framework for creating early diagnostic approaches for some neurological conditions as well.[2] The ENS plays a vital role in regulating numerous gastrointestinal functions, and any structural or functional abnormalities can lead to a range of disorders. These include Hirschsprung’s disease (aganglionosis of both plexus), achalasia, gastroparesis, irritable bowel syndrome, pediatric intestinal pseudo-obstruction, and intestinal neuronal dysplasia type B.[2] In addition, enteric glial cells, which support ENS neurons, are implicated in the pathophysiology of conditions such as diarrhea, Parkinson’s disease, and Creutzfeldt–Jakob disease.[8,9] The ICC, present at the junction of motor neurons and smooth muscle fibers, is critical for coordinating gut motility. The absence or dysfunction of ICCs is associated with several clinical conditions, including Hirschsprung’s disease, inflammatory bowel diseases, short bowel syndrome, chronic intestinal pseudo-obstruction (CIPO), slow transit constipation, postoperative ileus, and mechanical obstruction.[12,17,18] Beyond gastrointestinal disorders, the ENS has also been linked to neurological conditions such as amyotrophic lateral sclerosis, Huntington’s disease, Alzheimer’s disease, autism, frontotemporal dementia, transmissible spongiform encephalopathies, and varicella zoster virus infections.[3,13,19] Recent research shows that intestinal motility can be regulated by the glutamatergic neurons. The ENS plays a role in controlling digestion autonomously and this occurs through complex neural connections located within the gut wall. Enteric neurons that express glutamate were identified by transcriptomic studies as a separate subpopulation, and glutamate was found to affect intestinal motility. Glutamate can induce and alter the strength of intestinal muscle contractions.[20] The involvement of the ENS in both gastrointestinal and neurological disorders underscores the importance of understanding its structure and function. This knowledge is critical for developing targeted therapies to address gastrointestinal pathologies and has also sparked interest in leveraging the ENS as a potential framework for early diagnostic approaches for certain neurological conditions. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.