An intricate communication between the gastrointestinal (GI) tract’s enteric nervous system (ENS) and the central nervous system (CNS) creates a unique dynamic unlike any other peripheral organ system. Together, the GI tract’s intrinsic and extrinsic neurologic inputs influence its movement patterns, blood flow, reflexes, and interactions with the gut immune and endocrine systems [1]. While the GI tract’s intrinsic neural plexuses allow the system a degree of autonomy in executing many of these functions, the CNS plays an integral role in regulating and modulating these in response to external stimuli [1,2].

Extrinsic neuronal communication with the GI tract occurs via vagal, spinal thoracolumbar, and spinal lumbosacral innervation [1,2]. Vagal efferents arising from the dorsal motor nucleus (DMN) consist of both excitatory and inhibitory lower motor neurons (LMNs) as well as preganglionic parasympathetic fibers [3]. Vagal influence on the GI tract is most prominent in the esophagus and stomach, where responsibilities include upper esophageal sphincter (UES) contraction, striated and smooth muscle peristalsis, and regulation of hormonal release [1,3]. Without vagal efferents, the upper and lower esophagus can no longer propel its contents forward [4,5]. Vagal sensory neurons, or afferents, at the level of the esophagus, stomach, and proximal small intestine communicate with the CNS to mediate numerous vasovagal reflexes in addition to sensing satiety [6,7]. Similar to vagal innervation in the upper GI tract, thoracolumbar innervation on the middle GI tract consists of both efferents and afferents. Thoracolumbar preganglionic sympathetic efferents innervate their postganglionic counterparts in the celiac, superior mesenteric, and inferior mesenteric ganglia. In addition to their significant influence on GI tract vasculature, these fibers function in slowing transit times of tract contents directly via sphincter contraction and indirectly via inhibition of myenteric and submucosal ganglia [1,2,8]. Thoracolumbar afferents compromise the majority of thoracolumbar innervation in the GI tract. Although primarily inactive in nonpathological states, sensitization of thoracolumbar afferents via gut inflammation plays a role in pain sensation [1,6]. Lumbosacral input on the GI tract is primarily in the form of parasympathetics which innervate their respective postganglionic cell bodies in the pelvic plexus or act indirectly via the ENS myenteric plexus [2,9]. Similar to vagal parasympathetics in the upper GI tract, lumbosacral parasympathetic efferents provide excitatory and inhibitory innervation to the distal colon to increase or decrease motility, respectively [2,10]. Lumbosacral afferents communicate stretch and pain to the CNS, namely Barrington’s nucleus [2,11,12,13]. Lumbosacral sensory and motor neurons also function in important lower GI reflexes, such as defecation [1,14,15].

Despite the importance of CNS innervation in proper digestive system functioning described above, the ENS gives the GI tract the ability to maintain many of its functions independent of extrinsic support [16,17,18,19]. The ENS consists of approximately 20 neuronal subtypes dispersed in its two major ganglia, the myenteric extending from esophagus to anus and submucosal in the small and large intestines [1]. In the esophagus, nitric oxide producing enteric neurons allow for sphincter relaxation independent of vagal inhibition [1,20]. ENS innervation in the stomach is responsible for gastric acid secretion through its direct innervation of gastrin-releasing G cells [5,20,21]. In the small and large intestines, enteric neurons function in fluid movement and balance; blood flow; nutrient handling; gut-wall integrity; and communicating with local and peripheral neural, endocrine, and immune cells [1,5,22]. Through intrinsic sensory neurons, interneurons, and motor neurons, the ENS is responsible for controlling small intestine motility and propulsion [5,23,24]. Likewise, the migrating motor complex (MMC), a small intestinal phenomenon important for preventing bacterial overgrowth, is dependent entirely on ENS neurons [25,26]. Enteric nociceptive neurons are important for retropulsive reflexes such as vomiting in the small intestine and for propulsive contractions and copious fluid secretion in the colon [5,27,28]. With the support of sympathetic pathways, small intestinal secretomotor neurons regulate fluid movement and electrolyte secretion between the intestinal lumen and body fluid compartments [1,29,30,31,32,33]. In the colon, the ENS is capable of reproducing the defecation reflex with lumbosacral stimulation independent of central command [34].

2. Neurologic Control of the Gut Microbiome

The gut microbiome contains trillions of bacteria, viruses, and fungi that are critical for the health of the organism. The majority of these microbes are symbiotic; however, pathogenic bacteria can invade the gut and lead to diseases such as cancer, autoimmunity, and multiple sclerosis [35]. Thus, tight neuronal control of this system is critical in order to maintain homeostasis and prevent disease. This control is achieved through intrinsic (enteric) and extrinsic innervation of the gut.

2.1. Intrinsic (Enteric) Nervous System