Gastroparesis and the brain-gut axis

Autonomic innervation, including vagus nerve and sympathetic nerves

Afferent and efferent signals are communicated chiefly from the autonomic nervous system which is generally extrinsic to the stomach, ultimately moderating the enteric nervous system which is intrinsic to the stomach . While the stomach does have intrinsic innervation that allows for loco-regional control, the foregut is heavily reliant upon extrinsic signals from the autonomic nervous system; this originates from the caudal brain stem. Autonomic innervation consists of either parasympathetic or sympathetic pathways. Predominantly afferent pathways will be detailed in greater depth in the portion of the chapter dedicated to signaling in the setting of nausea and vomiting ( Fig. 9.2 ).

Parasympathetic innervation, which is responsible for gastric motor function, is largely the domain of the vagus nerve; gastric motor functions are routed through the dorsal motor nerve nucleus. The potency of this vagal control over stomach function has been known for thousands of years up through to the father of gastrointestinal physiology, William Beaumont; there is remarkable conservation of the regulatory mechanisms throughout vertebrate species as well . Over the past several centuries, deliberate perturbation of the vagus nerve has been known to have several consequences. Beaumont himself noted that stress impacted both motor and secretory functions of the stomach (both vagally mediated); severing the vagus nerve dramatically reduces the secretory function of the stomach as well as causes the gastric fundus to inappropriately maintain its tone as well as decreases contractions in the antrum . Regulatory pathways and their actors (such as acetylcholine and nitric oxide) will be discussed as they relate to their end-organ targets as mediated by the enteric nervous system ( Fig. 9.3 ).

The sympathetic nervous system, in contrast, tends to inhibit the secretomotor function of the stomach through a variety of different targets . Input from the sympathetic nervous system arises from fibers in the intermediolateral column of the spinal cord, principally the T6-T9 levels through cholinergic neurons that control post-ganglionic adrenergic neurons within the celiac ganglion, resulting in the sympathetic innervation of the stomach. The sympathetic nervous system influences gastric function through both control of presynaptic vagal input to the nerves of the enteric plexus as well as directly moderating nerves in plexi that control smooth muscle in the stomach ( Fig. 9.4 ).

Intrinsic innervation, including the enteric nervous system

The intrinsic innervation of the stomach/the enteric nervous system integrates divergent autonomic signals in order to transmit their excitatory or inhibitory output as these fibers directly penetrate into the gastric wall . The enteric nervous system is the major actor in terms of secretomotor and sensorimotor function of the stomach. It arises from neural crest cells through a combination of different embryologic events including migration, proliferation, differentiation, and synapse formation. The vast majority of nerves of the enteric nervous system in the foregut reside in the myenteric plexus (compared to the rest of the gastrointestinal tract which has ENS nerves residing in greater populations in the submucosal plexus). Various neuron types arise from these neural crest cells including primary afferent neurons, excitatory/inhibitory circular muscle motor neurons, longitudinal muscle motorneurons, ascending/descending interneurons, and secretomotor/vasomotor neurons comprised of Dogiel cells . Local enteric circuits then promote changes in secretion, vascular perfusion, contraction, and relaxation ( Fig. 9.5 ).

It is only through integrated control of the above structures and nerves that the stomach can undergo appropriate secretomotor and sensorimotor function . It ensures that appropriate parts of the stomach are contracting, relaxing, secreting, are adequately perfused to allow for the complicated process of digestion. It is no surprise, then, that processes such as neuropathy arising from diabetes or loss of ENS cells can provoke the abnormalities and symptoms of gastroparesis. Normal function is accomplished by a more intricate connection of the stomach ENS with brainstem and cranial nerve/spinal structures due to the inability of the ENS to control as precisely through loco-regional mechanisms as compared to other parts of the gastrointestinal tract. Yet, it is important to put in perspective that despite this more controlled function of the ENS that the vast majority of the vagus nerve fibers to the stomach (90%) are afferent and sensory which means that the brain can only control based on input it receives via the vagus from the ENS. Those efferent fibers use acetylcholine to simultaneously stimulate controlled excitatory and inhibitory contractions of the stomach smooth muscle via nicotinic receptors on the post synaptic myenteric neurons. In general, contractile responses are mediated by cholinergic nerves acting upon smooth muscle. Relaxation mediated by the vagus nerve is accomplished by the release of nitric oxide, adenosine triphosphate, and vaso-active intestinal peptide.

Gastric fundus and the stomach reservoir

When food passes from the esophagus into the gastric cardia and fundus, it requires relaxation of the normal vagus-mediated tone to allow for the proximal stomach to perform its chief meal-related duty: gastric accommodation . In addition to providing more room for additional food bolus to pass from the esophagus, gastric accommodation allows for the controlled passage of food into the distal esophagus where the next steps of digestion occur . There have been attempts to manipulate gastric accommodation in experimental models which subtly hint at mechanisms behind aberrant brain-gut modulation of gastric accommodation. For example, in normal healthy subjects, transcutaneous stimulation improves gastric accommodation that is deliberately impaired with a bolus of cold contents . By provoking pain in the form of a clothespin clipped to the ear, this results in impaired post-prandial stomach volumes . In addition to pain and discomfort, psychosocial factors have also been shown to have an impact on gastric accommodation. Those patients suffering from anxiety have both reduced and slower increases in gastric volume . Anorexia nervosa adolescents have been found to have impaired gastric accommodation . Prior sexual abuse/trauma can also provoke changes in gastric accommodation . Pharmacologic therapy exists to address gastric accommodation difficulties, which will be described further as it relates to brain-gut axis modulatory targets.