Autonomic Nervous System and Gastrointestinal Manifestations with an Emphasis on Gastric Dysfunction

Abstract

Gastrointestinal (GI) symptoms are frequent in disorders that involve the autonomic nervous system (ANS) or the enteric neuromuscular apparatus. Although dysfunction may occur anywhere along the alimentary tract, gastric manifestations are often the most clinically visible ‘end-organ’ expression of autonomic disease because they drive nausea, vomiting, early satiety, postprandial distress, malnutrition risk, and impaired drug absorption.

In this invited review, we summarize the organization of the GI neuromuscular apparatus, emphasizing how intrinsic (enteric) circuitry and extrinsic sympathetic and parasympathetic pathways cooperate to regulate gastrointestinal functions. We then link common symptom clusters (dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence) to likely neuroanatomic levels and review autonomic test batteries and motility studies that help characterize dysfunction. Finally, we discuss neurologic and systemic diseases in which autonomic and enteric involvement produce prominent gastric and broader GI phenotypes. These include cerebrovascular and cortical neurodegenerative disorders, Parkinson disease, structural and inflammatory brainstem syndromes, primary autonomic failure and hereditary dysautonomia, postural orthostatic tachycardia syndrome, spinal cord disorders (including multiple sclerosis), peripheral neuropathies such as diabetes mellitus and amyloidosis, paraneoplastic and autoimmune autonomic neuropathies, and selected neuromuscular and myopathic conditions.

Introduction

The gastrointestinal tract is one of the largest effector systems of the autonomic nervous system. Propulsion, mixing, storage, secretion, and visceral sensation are coordinated through dense enteric neural networks that are continuously modulated by extrinsic parasympathetic and sympathetic pathways. When these circuits are disrupted by neurologic or systemic disease, symptoms commonly cluster around motor dysfunction (dysphagia, impaired gastric emptying, pseudo-obstruction, constipation, or incontinence) rather than occurring as isolated sensory or secretory complaints.

For both neurologists and gastroenterologists, gastric symptoms deserve special attention. Autonomic dysfunction may become clinically apparent through early satiety, nausea, vomiting, and postprandial distress, and gastric motor dysfunction can compromise nutritional status and the absorption of oral medications. At the same time, gastric symptoms rarely occur in isolation; the same disease processes often affect esophageal, bowel, and anorectal function and may coexist with orthostatic intolerance, sweating abnormalities, urinary dysfunction, or neuropathic pain.

This review provides a practical framework for recognizing and evaluating suspected neurogenic gastrointestinal dysmotility. We first outline key features of the GI neuromuscular apparatus and its intrinsic and extrinsic control. We then summarize common symptom syndromes and the autonomic and motility tests most useful for localization and characterization of the neural mechanisms. Finally, we review major neurologic and systemic conditions that produce characteristic patterns of gastric and pan-gut dysfunction, with emphasis on how symptom pattern recognition and targeted testing can guide management.

The Gastrointestinal Neuromuscular Apparatus

Coordinated GI motor function requires a tightly coupled ‘neuro-glial-pacemaker-smooth muscle’ unit. Enteric neurons and glia provide local integration, specialized pacemaker cells generate rhythmic electrical activity, and smooth muscle acts as the final common effector (Fig. 1). Neurologic diseases can disrupt any of these components, and mixed mechanisms (neuropathy plus myopathy or pacemaker cell loss) are common in clinical practice.

Figure 1.

Control of gut motility: integration of extrinsic autonomic pathways, the enteric nervous system, pacemaker cells, and smooth muscle effectors.

Left: schematic of extrinsic control via vagal and sacral parasympathetic outflow (blue) and sympathetic pathways (red) arising from approximately T5–L2. Right (upper): organization of the submucosal and myenteric plexuses, and pacemaker cell types (interstitial cells of Cajal and PDGFRα-positive fibroblast-like cells) that help translate neural input into coordinated motor and secretory activity.

The digestive tract’s intrinsic and extrinsic neural control

The enteric nervous system (ENS) is an extensive network embedded within the gut wall, organized primarily within the myenteric (Auerbach) and submucosal (Meissner) plexuses. Through sensory neurons, interneurons, and motor/secretomotor neurons, the ENS can generate patterned behaviors such as peristalsis and the migrating motor complex with a high degree of autonomy. Thus, such patterns of motor function are largely independent of extrinsic neural control.

Autonomic efferents predominantly synapse on enteric neurons, allowing central autonomic nuclei to modulate the vast intrinsic network. Extrinsic parasympathetic innervation reaches the upper gastrointestinal tract mainly through the vagus nerve, while sacral outflow supplies the distal colon and anorectum, generally with excitatory effects on non-sphincteric muscle and propulsion. Sympathetic control arises from thoracolumbar segments via prevertebral ganglia; in most regions it inhibits propulsive smooth muscle activity and enhances sphincter tone, acting as a functional ‘brake’ on transit.

Afferent information from the gut reaches the central nervous system via vagal pathways (to the nucleus tractus solitarii) and spinal pathways (via dorsal root ganglia and the dorsal horn). Prevertebral ganglia integrate visceral afferent information and participate in local reflex arcs, including inhibitory enteroenteric reflexes that coordinate activity across segments (Kreulen et al., 1979; Langley et al., 1895; Szurszewski et al., 1984) (Fig. 2). Table 1 summarizes the wiring and functional roles of extrinsic neural control of the digestive tract (Camilleri, 1997).

Figure 2.

Components of the peristaltic reflex.

Bolus-induced distension activates intrinsic primary afferent neurons, which recruit interneuronal circuits to generate ascending excitation (proximal contraction) and descending inhibition (distal relaxation). Excitatory transmission involves acetylcholine and tachykinins (e.g., substance P), whereas inhibitory transmission involves mediators such as nitric oxide and vasoactive intestinal peptide.

Table 1.

Wiring and functions of extrinsic neural control. Adapted with permission from ref., Camilleri, M. Autonomic regulation of gastrointestinal motility. In Low PA, Ed. Clinical Autonomic Disorders: Evaluation and Management, 2nd ed. Philadelphia: Lippincott-Raven Publishers, 1997, pp. 135–145.

	Parasympathetic		Sympathetic		Central mechanism
Region	Wiring	Function	Wiring	Function
Esophagus
Cervical esophagus	Vagus nerve; recurrent laryngeal branch	Peristalsis in response to burst of spike activity	Superior cervical and stellate ganglia	Stimulation of UES tone	Motor: nucleus ambiguus, corticobulbar pathways
	Glossopharyngeal and vagus nerve	Sensation			Sensory: NTS
Thoracic and abdominal esophagus	Vagus nerve	Peristalsis by successive firing of vagal fibers	Celiac, stellate and thoracic vertebral ganglia T6–9 spinal cord	Stimulation of LES tone	Motor: DMV, Corticobulbar pathways Swallowing: afferent modulation of central program
	Vagus nodose ganglia	Sensation			Sensory: NTS
			Stomach
Gastric Contraction	Vagus nerve	Peristalsis (cholinergic), Inhibitory (non-adrenergic) for relaxation	Celiac and thoracic ganglia; T6–9 spinal cord	Inhibition and relaxation (e.g., antrofundal reflex)	Motor: DMV; nucleus ambiguus Sensory: NTS; thoracic spinal cord;
Gastric Accommodation	Vagus nerve	Stretch and chemosensation (non-adrenergic, VIP, NO)	Spinal root and thoracic ganglia T7–11	Mechano-sensation (e.g. distention reflexes)
Small and large intestines
Small and large intestines	Vagus nerve	Small bowel and proximal colon peristalsis and sensation	Celiac ganglion (duodenum); superior MG (splanchnic N. to small bowel); T5–10 spinal cord	Motor inhibition; distention reflexes	Sensory: NTS, Sensory and motor: DMV and : thoracic spinal cord; motor; para-sympathetic spinal nucleus
	Sacral S2–4	Distal colon peristalsis and sensation	Inferior MG (lumbar colonic N.) and pelvic ganglia; T9–10 spinal cord
Ileocecal sphincter	Vagus nerve	Sphincter contraction	Splanchnic and lumbar colonic nerves	Sphincter contraction (α effect)	Motor: T9–10 spinal cord;? vagal nucleus
Anal sphincter
Internal	Sacral S2–4	Sphincter relaxation	Lumbar splanchnic nerves; inferior MG via hypogastric nerves; pelvic ganglia	Sphincter contraction (α effect); RAIR and vesico-anal reflex	T12-L2 spinal cord; spinal cord base of dorsal horn
External	S2–4 via pudendal nerves	Voluntary control; sensation			Motor and sensory: Onufs nucleus, Lateral part of ventral horn of spinal cord

T, thoracic; S, sacral; UES, upper esophageal sphincter; LES, lower esophageal sphincter; MG, mesenteric ganglia; RAIR, rectoanal inhibitory reflex

Muscular and pacemaker components involved in motility

The muscularis propria typically consists of an inner circular and an outer longitudinal smooth muscle layer; the stomach also contains an oblique layer that contributes to trituration. Smooth muscle cells are electrically coupled via gap junctions and respond to excitatory (e.g., acetylcholine, tachykinins) and inhibitory (e.g., nitric oxide, vasoactive intestinal peptide) neurotransmission.

Pacemaker and intermediary cells help translate neural input into coordinated motor activity. Interstitial cells of Cajal (ICC) contribute to slow-wave generation and propagation, while PDGFRα-positive fibroblast-like cells participate in inhibitory neurotransmission. Loss or dysfunction of these cells, together with enteric neuropathy or myopathy, can produce gastric dysrhythmias, impaired accommodation, pyloric dysfunction, and delayed or rapid emptying.

Functionally, gastric motor behavior depends on integration of (i) fundic accommodation and receptive relaxation, (ii) antral peristalsis and mixing, and (iii) pyloric resistance and relaxation. Disruption of vagal circuits, enteric inhibitory pathways, or pyloric control can therefore present with similar symptoms despite distinct mechanisms.

Common gastrointestinal symptoms and syndromes in neurologic disorders

Patients with autonomic or neurologic disease often present with symptom clusters that reflect dysfunction at specific neuroanatomic levels. Table 2 provides a practical overview of frequent GI symptoms/syndromes and commonly used investigations. Oropharyngeal dysphagia is a high-stakes symptom because it increases aspiration risk and can limit nutrition and hydration. Etiologies include suprabulbar dysfunction, lower motor neuron disease, neuromuscular junction disorders, and primary myopathies. Esophageal dysphagia and reflux symptoms may reflect vagal dysfunction, esophageal myopathy, or primary esophageal motor disorders and warrant endoscopic and high-resolution manometric evaluation.

Table 2.

Common Gastrointestinal Symptoms and Syndromes in Neurologic Disorders

GI Symptom	Neurological mechanism	Diagnosis/evaluation	Management
Oropharyngeal Dysphagia	pharyngeal skeletal muscles, lower motor neuron (e.g., bulbar polio or pseudo-bulbar palsy) or muscular (e.g., ALS, myasthenia gravis)	Physical exam: dentition, movement of the uvula (IX and X cranial nerves), jaw jerk; video-fluoroscopy; HR manometry	Nutritional support and prevention of pulmonary aspiration
Thoracic Dysphagia, GERD	Vagal denervation or smooth muscle disease	Videofluoroscopy, HR manometry, EGD	Acid suppression; avoid fundoplication to prevent dysphagia
Gastroparesis	Vagal, myenteric denervation; iatrogenic (narcotics, GLP-1 agonists)	EGD to exclude obstruction; gastric emptying (scintigraphy/GEBT); autonomic test; gastroduodenal (GD) manometry, pylorus test	Support hydration and nutrition; prokinetics and antiemetics; In refractory patients,? endoscopic pyloromyotomy or PEJ feeding
Chronic Intestinal Pseudo-Obstruction	Vagal, myenteric denervation; iatrogenic (narcotics, GLP-1 agonists)	Physical exam: associated neuropathy elsewhere, CT enterography to exclude obstruction; gastric emptying (scintigraphy/GEBT); autonomic tests; GD manometry: myopathy/neuropathy	For gastroparesis + enteral or parenteral nutrition; with myopathic disease treatment for small bowel bacterial overgrowth;? small bowel transplantation
Constipation and evacuation disorders	Vagal, sacral parasympathetic or myenteric denervation	Physical exam: DRE; associated neuropathy or spinal disease, plain x-ray (diameter; stool and gas distribution); Colonic transit; HR ARM + balloon expulsion	Bulk, osmotic, secretory laxatives or prokinetics; pelvic floor training if sensation preserved; rarely colectomy or -ostomy
Fecal Incontinence	Pelvic nerves, sacral roots, cauda equina, and spinal cord denervation of pelvic floor and anal sphincters	Physical exam: DRE; HR ARM + balloon expulsion	Pelvic floor training if sensation preserved; skin care; bowel regimen; rarely - ostomy

ALS= amyotrophic lateral sclerosis; CT = computerized tomography; DRE= digital rectal examination; EGD = esophagogastroduodenoscopy; GERD= gastroesophageal reflux disease; GEBT= gastric emptying breath test; HR ARM= high resolution anorectal manometry; PEJ = percutaneous endoscopic jejunal; Scint = scintigraphy

Gastric symptoms such as early satiety, postprandial fullness, nausea, and vomiting may reflect delayed emptying (gastroparesis), impaired accommodation, pyloric dysfunction, or, less commonly, accelerated gastric emptying. A key clinical principle is to review medications and metabolic factors (e.g., opioids, anticholinergics, GLP-1 receptor agonists, hyperglycemia) before attributing symptoms to a primary neurologic mechanism.

Constipation and anorectal dysfunction are among the most frequent GI manifestations of neurologic disease. A useful first step is to distinguish slow-transit constipation from evacuation disorders (e.g., pelvic floor dyssynergia), because confirmatory tests and treatment strategies differ (Manabe et al., 2010; Metcalf et al., 1987). Chronic intestinal pseudo-obstruction occupies an important middle ground between focal and diffuse neuromuscular disease: patients appear obstructed clinically and radiographically, but mechanical causes are absent and the underlying mechanism may be neuropathic, myopathic, or mixed.

Autonomic and GI motility testing in patients with suspected neurogenic GI disorders

Autonomic testing can complement endoscopic and radiographic evaluation when clinical features raise concern for neuropathic GI dysmotility. This is particularly helpful when GI symptoms are accompanied by orthostatic intolerance, abnormal sweating, urinary or sexual dysfunction, pupillary abnormalities, or distal sensory/motor neuropathic symptoms.

Standard autonomic laboratories assess cardiovagal function (e.g., heart rate variability to deep breathing and the Valsalva maneuver), adrenergic function (blood pressure responses to tilt and Valsalva), and sudomotor function (quantitative sudomotor axon reflex testing and/or thermoregulatory sweat testing). This system-based approach allows for the assessment of distribution and severity of autonomic failure, can help localize dysfunction to preganglionic versus postganglionic pathways, and can support broader diagnostic evaluation when autonomic impairment is widespread.

More specific to abdominal vagal integrity is the pancreatic polypeptide response to modified sham feeding, where a robust rise above baseline supports intact vagal efferent pathways (Camilleri et al., 1994; Prather et al., 1997). Tables 3 and 4 summarize autonomic function tests commonly used to infer parasympathetic and sympathetic impairment relevant to GI function.

Table 3.

Tests performed to assess parasympathetic control of viscera, normal values and direct or indirect inference of gastrointestinal autonomic denervation.

Test	Function Tested	Rationale	Normal Values	Comments/Pitfalls
Cardiovascular
1. Heart rate variation with deep breathing	Parasympathetic	Vagal afferents stimulated by lung stretch	Age related, 6-18 beats/min	Best cardiovagal test available, but not a test of abdominal vagus
2. Supine/erect heart rate	Parasympathetic	Vagal stimulation by Δ in central blood volume		Abnormal cardiovagal tests imply abdominal vagal denervation in length-dependent neuropathies; false negative if vagus injury at or below diaphragm
3. Valsalva ratio (heart rate, max./min.)	Parasympathetic		>1.5
Abdominal Vagus: Pancreatic Polypeptide Response to
4. Modified sham feeding	Parasympathetic	Stimulation of vagal nuclei by sham feeding	>25pg/mL peak over baseline	Critically dependent on avoidance of swallowing food during test
Pupil Responses to
5. Light	Parasympathetic	Reflex involving oculomotor nerve	Latency 0.2-0.3sec Constriction 2-4 mm
6. Pharmacology 0.125% pilocarpine 0.1% epinephrine 5% cocaine	Denervation hypersensitivity	Parasympathetic Sympathetic	<0.5 mm constriction No change >1.5 mm dilation
Penis and Urinary Bladder
7. Nocturnal penile tumescence	Pelvic parasympathetic	Integrity of S2–4		Plethysmographic technique requiring special facilities
8. Cystometro-graphic response to cholinergic agonist	Pelvic parasympathetic	Increased intravesical pressure in denervation supersensitivity		Tests parasympathetic supply to bladder, not bowel

Adapted from ref., Camilleri M, Ford MJ. Functional gastrointestinal disease and the autonomic nervous system: a way ahead? Gastroenterology 1994; 106(4):1114–1118 (Table 1 there). Copyright 1994 Elsevier, and from ref., Prather, C. M. and Camilleri, M. (1997). Gastrointestinal dysfunction: approach to management. In Low, P. A. (ed.) Clinical Autonomic Disorders: Evaluation and Management. 2nd ed, pp 597–612 (Table 5 there). Philadelphia: Lippincott-Raven Publishers

Table 4.

Tests performed to assess sympathetic control of viscera, normal values and direct or indirect inference of gastrointestinal autonomic denervation.

Test	Function Tested	Rationale	Normal Values	Comments/Pitfalls
Sweat tests
1. Thermoregulatory sweat test (% surface area of anhidrosis)	Preganglionic and postganglionic cholinergic	Stimulation of hypothalamic temperature control centers	% surface area of anhidrosis: M: 0%; F: <3%	Cumbersome, whole body test
2. Quantitative sudomotor axon reflex test (sweat output, latency)	Postganglionic cholinergic	Antidromic stimulation of peripheral (postganglionic sympathetic fiber) by axonal reflex	Sweat output (μl/cm3) Forearm: M: 0.76-5.51; F: 0.34–1.33 Foot: M: 0.92–5.73; F: 0.25–1.95 Latency (min) Forearm: M: 1–2.4; F: 0.9–1.9 Foot M: 1–2.7; F: 1–2.8	Needs specialized facilities
Cardiovascular tests
3. Heart rate and BP responses to orthostatic tilt	Adrenergic	Baroreceptor reflex	Response to 80° tilt: systolic BP <25 mmHg; diastolic BP <15 mmHg	Impaired if intra-vascular volume is reduced
Plasma norepinephrine:
A. Response to postural changes	Postganglionic adrenergic	Baroreceptor stimulation	Supine: 70–750 pg/mL Standing: 200–1700 pg/mL	Moderate sensitivity, impaired if intravascular volume reduced
B. Response to i.v. edrophonium (anticholinesterase)	Postganglionic adrenergic	Drug “stimulates” postganglionic fiber at prevertebral ganglia	>35% increase above baseline within 2–8 minutes	False negatives by contributions to plasma norepinephrine from many organs

Adapted from ref., Camilleri M, Ford MJ. Functional gastrointestinal disease and the autonomic nervous system: a way ahead? Gastroenterology 1994; 106(4):1114–1118 (Table 1 there). Copyright 1994 Elsevier, and from ref., Prather, C. M. and Camilleri, M. (1997). Gastrointestinal dysfunction: approach to management. In Low, P. A. (ed.) Clinical Autonomic Disorders: Evaluation and Management. 2nd ed, pp 597–612 (Table 5 there). Philadelphia: Lippincott-Raven Publishers

GI motility testing should be selected based on symptoms and suspected localization. Options include gastric emptying scintigraphy or breath testing, antroduodenal or colonic manometry, radiopaque marker, radionuclide or capsule-based colonic transit testing, and anorectal manometry with balloon expulsion and defecography. In clinical practice, integrating segmental motility measurements with autonomic testing can clarify whether symptoms reflect isolated enteric disease, extrinsic autonomic denervation, or combined neuromuscular pathology.

Extrinsic neurologic disorders causing gastric dysmotility

GI complaints are common in the general population and most often arise from primary GI disorders rather than neurologic disease. Nevertheless, the presence of established neurologic diagnoses (e.g., Parkinson disease, stroke, demyelinating disorders, peripheral neuropathy) or systemic conditions that commonly involve the autonomic nervous system should prompt targeted questions about GI motor and autonomic symptoms and should raise the possibility of neuropathic or myopathic GI dysmotility.

In the sections below we summarize disorders in which gastric and pan-gut manifestations are clinically important. The goal is not to provide exhaustive disease reviews, but rather to highlight high-yield clinical patterns, relevant mechanisms, and pragmatic diagnostic and treatment considerations.

Brain diseases

Cerebrovascular disease

Swallowing impairment is a well-recognized complication of acute stroke and contributes to aspiration pneumonia and poor nutritional status. Early screening and structured dysphagia management improve outcomes (Arnold et al., 2016; Martino et al., 2005), and enteral feeding strategies may be needed when aspiration risk is high (Duncan et al., 2020; Geeganage et al., 2012).

Beyond dysphagia, stroke survivors frequently experience bowel dysfunction. Constipation after stroke is common and is driven by a combination of reduced mobility, impaired cortical control of defecatory reflexes, medication effects, and autonomic imbalance (Cheng et al., 2020; Li et al., 2017; Yi et al., 2011). Acute colonic pseudo-obstruction has also been described in the setting of stroke (Reynolds et al., 1977).

Dementia and cortical neurodegeneration

In dementia syndromes, GI symptoms may arise from impaired feeding behaviors, dysphagia, reduced mobility, and adverse drug effects. In Alzheimer disease, large cohort data have identified increased rates of GI events (Wu et al., 2011). Cholinesterase inhibitors can contribute to nausea, vomiting, diarrhea, and weight loss, and several studies have specifically documented increased GI adverse events with these agents (Darreh-Shori et al., 2010; Farlow et al., 2011). More widespread autonomic dysfunction is common in dementia with Lewy bodies adding another cause for GI symptoms akin to those discussed in more detail in the following section on Parkinson’s disease, another synucleinopathy (Thaisetthawatkul et al., 2004).

Parkinson disease

Parkinson disease (PD) is a prototypical neurologic disorder in which autonomic and enteric pathology contributes substantially to morbidity. GI symptoms may predate motor features by years, consistent with the concept that α-synuclein pathology can involve the ENS and vagal/brainstem autonomic nuclei early in disease (Rietdijk et al., 2017; Travagli et al., 2020). Large epidemiologic studies also suggest that truncal vagotomy is associated with a reduced risk of subsequent PD, supporting a potential gut–brain contribution to pathogenesis (Liu et al., 2017).

Clinically, PD-associated GI manifestations span from sialorrhea (often due to impaired spontaneous swallowing) to dysphagia, esophageal dysmotility, altered gastric emptying, and constipation (Cersosimo et al., 2013; Cersosimo et al., 2009; Edwards et al., 1993a; Edwards et al., 1991; Fasano et al., 2015; Hinkle et al., 2018; Ioannou et al., 2024; Khoshbin et al., 2021; Sakakibara et al., 2003; Sakakibara et al., 2004). Objective measures of GI autonomic involvement have been correlated with central dopaminergic markers early in disease (Hinkle et al., 2018), and GI symptoms often occur prior to motor diagnosis (Cersosimo et al., 2013; Fasano et al., 2015).

Management requires attention to both symptom relief and effects on dopaminergic therapy. Dysphagia interventions include behavioral and rehabilitative strategies (Manor et al., 2013; van Hooren et al., 2014). Sialorrhea can be managed pharmacologically with anticholinergics such as glycopyrrolate or scopolamine, although these medications can have negative effects on other aspects of gastrointestinal function; alternatively, botulinum toxin injections can be very effective and are less likely to have negative systemic effects (Seppi et al., 2011). Gastric motor dysfunction can impair levodopa pharmacokinetics and contribute to motor fluctuations (Pfeiffer et al., 2020); systematic reviews support the association between PD and gastroparesis (Heetun et al., 2012). Small studies also suggest that transcutaneous vagal nerve stimulation may improve gastroenteric symptoms (Kaut et al., 2019).

Constipation management is foundational and includes dietary measures, osmotic laxatives, and secretagogues. Randomized controlled trials have demonstrated benefit of polyethylene glycol 3350 (Zangaglia et al., 2007) and lubiprostone (Ondo et al., 2012) in PD-related constipation, and dopaminergic agents such as apomorphine can influence defecatory function (Edwards et al., 1993b). The gastrointestinal tract is also increasingly viewed as a therapeutic target in PD, including approaches that aim to modulate enteric neuronal signaling (Hauser et al., 2019).

Motor neuron disease and bulbar syndromes

In amyotrophic lateral sclerosis (ALS), dysphagia and impaired airway protection are major drivers of aspiration and malnutrition. Multiple studies have characterized swallowing impairment in ALS and emphasize the importance of early recognition and multidisciplinary management (Chapin et al., 2020; Elbe et al., 2020; Toepfer et al., 1999; Toepfer et al., 1997). Gastric emptying abnormalities are not central features, but reduced mobility, respiratory compromise, and medication effects can contribute to constipation and feeding difficulties.

Bulbar dysfunction and dysphagia have also been described in post-polio syndromes, where chronic neuromuscular weakness and impaired coordination can compromise safe swallowing and nutrition (Kay et al., 2018; Oluwasanmi et al., 2019).

Brainstem and posterior cranial fossa disorders

The brainstem contains key integrative circuits for autonomic regulation of the stomach and upper gut. Lesions and impaired circuits in the brainstem can alter gastric motor function by interrupting parasympathetic pathways, including vagal afferent fibers, neurons in the nucleus tractus solitarii (NTS), and preganglionic efferents arising from the dorsal motor nucleus of the vagus (DMV) (Travagli et al., 2006).

Clinically, brainstem pathology may present with isolated vomiting or severe nausea due to involvement of the vomiting center in the floor of the fourth ventricle (Wood et al., 1985). Importantly, such symptoms can occur even without elevated intracranial pressure (Mann et al., 1998). Structural compression of the brainstem and lower cranial nerves, including in Arnold–Chiari malformation, can also cause neurogenic dysphagia (Elta et al., 1996).

Inflammatory demyelinating syndromes can produce distinctive brainstem presentations. In neuromyelitis optica spectrum disorder, persistent nausea and vomiting due to area postrema involvement is a well-described ‘area postrema syndrome’ and should prompt neurologic evaluation in appropriate contexts (Popescu et al., 2011).

When brainstem symptoms are accompanied by more widespread autonomic deficits, particularly combined vagal and preganglionic sympathetic involvement suggested by anhidrosis on thermoregulatory sweat testing with preserved postganglionic responses on quantitative sudomotor axon reflex testing (QSART), neuroimaging and broader evaluation for central nervous system lesions are warranted (Tables 3 and 4).

Autonomic system degenerations, generalized dysautonomia, and disorders of autonomic dysregulation

Multiple system atrophy and primary autonomic failure

In primary autonomic failure syndromes, gastrointestinal dysmotility can be prominent and may reflect diffuse autonomic and enteric involvement. Classic descriptions of Shy-Drager syndrome (now encompassed within multiple system atrophy, MSA) include constipation, gastroparesis, and, in severe cases, intestinal pseudo-obstruction (Shy et al., 1960).

Pure autonomic failure (PAF) is a chronic neurogenic autonomic disorder in which gastrointestinal involvement may include constipation and other manifestations of dysmotility (Sakakibara et al., 2000; Thatcher et al., 1987; Yamanaka et al., 2006). Neuropathologic overlap with Lewy body disorders and multiple system atrophy has been described, supporting close longitudinal clinical surveillance (Hague et al., 1997; Singer et al., 2021). Recognition of associated GI symptoms can aid comprehensive management and anticipatory guidance.

Pandysautonomia and acute autonomic neuropathies

Pandysautonomia refers to widespread sympathetic and parasympathetic failure due to lesions at preganglionic, ganglionic, or postganglionic levels. Gastrointestinal involvement (vomiting, paralytic ileus, constipation, and chronic pseudo-obstruction) has been reported in acute, subacute, and congenital forms (Camilleri, 1990; Suarez et al., 1994).

Several post-infectious syndromes have been described, including selective cholinergic dysautonomia with GI dysmotility after infectious mononucleosis (Epstein-Barr virus) or influenza A (Lukkarinen et al., 2010; Vassallo et al., 1991). Autoantibodies to muscarinic M3 receptors have been reported in selective dysautonomia (Palma et al., 2020), and cytomegalovirus infection of the myenteric plexus can produce chronic intestinal pseudo-obstruction (Sonsino et al., 1984). Ganglionic acetylcholine receptor (G-AChR) antibodies are implicated in autoimmune autonomic ganglionopathy, an acute pandysautonomia with characteristically severe gastrointestinal involvement. Response to immunosuppressive and immunomodulatory therapies underlines the importance of recognizing this rare syndrome (Vernino et al., 2009). There is overlap of the autonomic neuropathies with the section on neuropathies, please see below.

Familial dysautonomia

Familial dysautonomia is a hereditary sensory and autonomic neuropathy in which feeding and GI motor problems are often present from infancy (Rubin et al., 2017). Common features include oropharyngeal incoordination, poor suck, excessive drooling, gastroesophageal reflux, and episodic vomiting that is often triggered by physical or emotional stress (Krausz et al., 1994).

Esophageal and gastric transit may be delayed, which can contribute to recurrent aspiration pneumonia (Krausz et al., 1994). Structural and functional abnormalities include reduced neuronal density in the myenteric plexus (Bar-Shai et al., 2004) and severe esophageal dysmotility with dilatation and fluid stasis in some patients (Palma et al., 2018).

Vomiting episodes may be accompanied by biochemical and autonomic signatures, including increased circulating dopamine that likely activates dopamine receptors in the chemoreceptor trigger zone (Norcliffe-Kaufmann et al., 2013b). Carbidopa, which reduces peripheral dopamine synthesis, has been reported to lessen the frequency and intensity of vomiting attacks (Norcliffe-Kaufmann et al., 2013a).

A subset of patients experience ‘dysautonomic crises’ characterized by hypertension, tachycardia, diffuse sweating, and behavioral changes. These crises may respond to benzodiazepines as well as to α2-adrenergic agonists (e.g., clonidine or dexmedetomidine) that reduce norepinephrine release (Axelrod et al., 1991). When aspiration or feeding failure is recurrent, surgical strategies such as fundoplication or feeding tube placement may be required (Axelrod et al., 1991).

Postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance that is particularly common in younger women. It is characterized by an exaggerated heart rate rise with upright posture in the absence of orthostatic hypotension (Schondorf et al., 1993). Evaluation should exclude dehydration, medication effects, and other medical conditions that can influence heart rate and blood pressure.

Gastrointestinal complaints are common in POTS. Approximately one-third of patients report nausea, vomiting, bloating, or constipation (Low et al., 1994; Park et al., 2013). POTS may co-occur with hypermobility-type Ehlers–Danlos syndrome, fibromyalgia, chronic fatigue, interstitial cystitis (DiBaise et al., 2018), and functional GI disorders (Tai et al., 2020). Management is directed at the underlying orthostatic intolerance and symptomatic treatment of GI manifestations (Afrin et al., 2017).

Mast cell activation syndrome and overlapping phenotypes

Mast cell activation syndrome has been proposed as a contributor to multisystem symptom complexes that include flushing, orthostatic intolerance, and prominent GI complaints. While mechanistic links remain incompletely defined, recognition of this phenotype can be relevant in patients with unexplained GI symptoms and dysautonomia-like features (Afrin et al., 2017).

Spinal cord disorders

Spinal cord injury

Acute spinal cord injury can be accompanied by transient disturbances of upper gastrointestinal motility, including dysphagia; ileus and acalculous cholecystitis have also been described, particularly after acute cervical injury (Wolf et al., 2003). Importantly, “acute abdomen” in this population may present atypically: instead of guarding or absent bowel sounds, patients may exhibit vague or poorly localized abdominal pain, vomiting, or agitation, and only about half develop objective signs such as focal tenderness, fever, or leukocytosis (Ebert, 2012). Delayed recognition of an intra-abdominal emergency in this setting can contribute to excess mortality.

By contrast, chronic neurogenic bowel dysfunction is common, reported in roughly 27%–62% of individuals following spinal cord injury, and most often manifests as constipation, bloating, abdominal discomfort, rectal bleeding, hemorrhoids, fecal incontinence, and episodes of autonomic hyperreflexia; gallstones are also frequent (17%–31%) (Ebert, 2012). Persistent upper gastrointestinal motility problems are relatively uncommon in the chronic phase, whereas colonic and anorectal dysfunction predominate, reflecting loss of supraspinal modulation of sacral parasympathetic outflow and impaired postprandial colonic motor responses (Bruninga et al., 1997). Disruption of coordinated pelvic floor and anal sphincter function further contributes to defecatory disorders and incontinence.

Management typically relies on structured bowel programs using reflex-evoked rectal stimulation and combinations of stool softeners or laxatives, bulking agents, digital/anal maneuvers, and scheduled enemas or transanal irrigation (Krassioukov et al., 2010) that may be facilitated with a device that incorporates an inflatable balloon that enhances irrigation in patients with neurogenic bowel dysfunction who suffer from fecal incontinence. Pharmacologic augmentation of cholinergic activity with neostigmine, administered with glycopyrrolate to mitigate systemic adverse effects, has demonstrated efficacy in randomized, double-blind trials (Krassioukov et al., 2010). In selected patients, computerized stimulation of the sacral anterior roots may improve pelvic colonic and anorectal sphincter function, generally in conjunction with S2–S4 posterior sacral rhizotomy to reduce the risk of autonomic dysreflexia (Rasmussen et al., 2015; Valles et al., 2009). For refractory cases with severe constipation despite optimized conservative therapy, diverting colostomy can shorten bowel-care time and facilitate healing of pressure ulcers.

Multiple sclerosis

Multiple sclerosis (MS) is frequently accompanied by autonomic dysregulation, and bowel symptoms are common across disease phenotypes. Constipation, fecal incontinence, and evacuation disorders often co-occur with bladder dysfunction and can significantly impair quality of life (Almeida et al., 2019; Hinds et al., 1989; Lin et al., 2019).

Physiologically, demyelinating lesions involving spinal long tracts and autonomic centers can disrupt colonic propulsion, anorectal sensation, and pelvic floor coordination. Objective studies using anorectal manometry, transit testing, and validated symptom instruments demonstrate that both slow transit and defecatory dyssynergia contribute to symptoms in MS, with severity often tracking neurologic disability (Almeida et al., 2019; Lin et al., 2019; Marola et al., 2016; Preziosi et al., 2014; Weber et al., 1987; Wiesel et al., 2000).

Upper GI involvement in MS has been less systematically characterized than bowel dysfunction, but available data suggest that gastric motor abnormalities can occur. In a scintigraphic study, MS patients demonstrated delayed gastric emptying compared with controls (el-Maghraby et al., 2005). In a single-center retrospective cohort of 166 MS patients evaluated for GI motility symptoms over a 25-year interval, delayed gastric emptying (16%) and accelerated emptying (22%) were both reported, highlighting phenotypic heterogeneity and the influence of comorbidities and medications (Khanna et al., 2022).

Management is individualized and typically requires collaboration between neurology and gastroenterology. For bowel dysfunction, structured bowel programs, osmotic laxatives, secretagogues, pelvic floor biofeedback, and transanal irrigation may be used alongside optimization of mobility and medication review. For prominent gastric symptoms, standard approaches to functional dyspepsia and gastroparesis apply, with attention to autonomic comorbidities and the impact of neurologic disability on nutrition and aspiration risk.

Peripheral neuropathy and systemic disorders

General considerations

Chronic peripheral neuropathy is the most prevalent neurologic substrate for GI motor dysfunction. Depending on the disorder, pathology may involve vagal fibers, sympathetic pathways, and enteric neurons, along with pathology affecting interstitial cells of Cajal and smooth muscle. Clinicians should maintain a high index of suspicion for neuropathic GI dysmotility when typical GI symptoms are accompanied by orthostatic hypotension, anhidrosis, neuropathic pain, or objective sensorimotor deficits.

Diabetes mellitus

Population-based studies demonstrate that GI symptoms are more frequent in diabetes mellitus than in age- and sex-matched controls (Ricci et al., 2000). In a community cohort from Olmsted County, Minnesota, constipation (with or without laxative use) was more common in type 1 diabetes than in controls, whereas the association was less clear in type 2 diabetes; concomitant medications and bladder dysfunction were common contributors (Maleki et al., 2000).

Diabetes can affect motility along the entire gut, producing gastroparesis (often with antral hypomotility and pyloric dysfunction), rapid gastric emptying, impaired gastric accommodation, diarrhea, constipation, and fecal incontinence (Camilleri et al., 2018; Chedid et al., 2019). Pathologic correlates include ‘autovagotomy’ (loss of unmyelinated axons) and loss of interstitial cells of Cajal, with emerging evidence that macrophage phenotypes within the gut wall influence susceptibility to oxidative stress (Camilleri et al., 2018).

Therapy requires attention to both glycemic control and iatrogenic influences. Amylin analogs and GLP-1 receptor agonists, particularly short-acting agents, can worsen gastric emptying and should be considered when symptoms arise or deteriorate (Maselli et al., 2021; Vella et al., 2002). Diabetic diarrhea and constipation also require structured evaluation and management (Maleki et al., 1998; Valdovinos et al., 1993).

Amyloidosis

Gastrointestinal dysfunction in amyloidosis may result from mucosal infiltration, neuromuscular infiltration, and/or extrinsic autonomic neuropathy. In a large retrospective series, a minority of patients with systemic amyloidosis had biopsy-proven GI involvement (Cowan et al., 2013).

Clinically, amyloid neuropathy, besides sensorimotor and cardiovascular autonomic deficits, may cause dysphagia, constipation, diarrhea, and steatorrhea. Manometric studies suggest that early disease can manifest with motor incoordination consistent with neural involvement, whereas later stages may show low-amplitude contractions reflecting myopathic infiltration of smooth muscle (Battle et al., 1979; Camilleri et al., 1985; Rubinow et al., 1983). Hereditary transthyretin amyloidosis can also involve small bowel motility (Wixner et al., 2018).

Advanced therapies can improve GI symptoms in selected patients, including stem cell transplantation with cytotoxic therapy in systemic amyloidosis and liver transplantation in transthyretin amyloidosis (Afrough et al., 2015; Wixner et al., 2015). Newer disease-modifying therapies, including antisense oligonucleotides and RNA interference approaches, are increasingly used for hereditary transthyretin amyloidosis (Gertz et al., 2019).

Paraneoplastic and immune-mediated enteric neuropathies

Gastrointestinal dysmotility can occur as a paraneoplastic manifestation, most often in association with small cell lung carcinoma or other neuroendocrine tumors (Tannoury et al., 2021). Patients may present with constipation, gastroparesis, intestinal pseudo-obstruction, and esophageal spasm or achalasia (Chinn et al., 1988).

Circulating IgG autoantibodies such as ANNA-1 (anti-Hu), directed against neuronal nuclear antigens, support an immune attack on the enteric nervous system in paraneoplastic dysmotility (Lennon et al., 1991). Other antibodies, including ganglionic acetylcholine receptor antibodies and CRMP-5 (CV2), have also been associated with enteric dysmotility in paraneoplastic/autoimmune contexts (Blackburn et al., 2019; Vernino et al., 2000), and neuropathologic studies show that some patients have more extensive involvement (Sodhi et al., 1989).

Because chest radiography may be unrevealing, chest computed tomography and/or whole-body fluorodeoxyglucose positron emission tomography (FDG-PET) can aid tumor detection and staging (Koike et al., 2011). Immunomodulatory therapy in conjunction with oncologic treatment may benefit selected patients with paraneoplastic enteric neuropathy.

Porphyrias

Acute hepatic porphyrias can present with severe abdominal pain, nausea, constipation, and autonomic instability. In acute intermittent porphyria, neurovisceral attacks may mimic surgical abdomen and can be accompanied by ileus or pseudo-obstruction, reflecting autonomic neuropathy and visceral motor dysfunction (Berlin et al., 1950; Stein et al., 1970; Stolzel et al., 2019).

Neurofibromatosis type 1

Constipation is frequent in children with neurofibromatosis type 1 (NF1) and can be associated with increased rectal diameter and prolonged colonic transit (Pedersen et al., 2013). Although there are rare reports of motility disorders in NF1 (Bernardis et al., 1999; Garcia Aroca et al., 1994), it is essential to exclude mechanical obstruction and mass lesions.

NF1 patients can develop a range of intra-abdominal tumors, including plexiform neurofibromas, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors related to interstitial cells of Cajal hyperplasia, neuroendocrine tumors, and embryonal tumors such as rhabdomyosarcoma (Dare et al., 2020; Xie et al., 2018).

In a large single-center cohort study of patients with documented NF1, a subset developed clinically significant bowel obstruction or dysmotility. Among those with motility testing, abnormalities included esophageal achalasia/spasm, delayed gastric emptying, slow-transit constipation, and pelvic floor dyssynergia; histopathology suggested enteric neuropathic mechanisms in some cases (Damianos et al., 2025).

Infectious and iatrogenic autonomic neuropathies

Acute autonomic dysfunction can occur in association with infectious and immune triggers. Guillain–Barré syndrome can feature prominent dysautonomia, and there are reports of associations with gastrointestinal infections such as Helicobacter pylori (Dardiotis et al., 2020).

Iatrogenic immune activation can also involve the autonomic nervous system. Neurologic immune-related adverse events from immune checkpoint inhibitors include autonomic neuropathy and can present with severe GI dysmotility (Bertrand et al., 2015). Viral infections such as Zika and SARS-CoV-2 have also been associated with neurologic syndromes that include dysautonomia and GI complaints in some patients (Counotte et al., 2019; Ghannam et al., 2020).

Lipomatosis of nerve

In a series of 10 patients with lipomatosis of nerve involving the lumbosacral plexus and/or sciatic nerve, three individuals were noted to have early-onset colonic diverticulosis, raising the possibility of involvement of sacral pathways supplying the sigmoid colon. In one case, postprandial colonic motor activity was reduced, while pharmacologic stimulation with intravenous neostigmine remained intact; myenteric neuronal morphology was reported to be normal. This pattern supports a mechanism consistent with extrinsic (rather than intrinsic enteric) denervation (Marek et al., 2020).

HIV neuropathy

Gastrointestinal complaints in HIV can reflect opportunistic or secondary infections related to immunodeficiency. Chronic diarrhea has also been attributed to autonomic mechanisms, including heightened extrinsic parasympathetic drive to the intestine (Coker et al., 1992) and/or injury to adrenergic fibers within enteric plexuses; additionally, diarrhea may occur as an adverse effect of nelfinavir-containing antiretroviral regimens (Bardsley-Elliot et al., 2000). In a nonblinded randomized crossover study of 12 patients with AIDS-associated chronic diarrhea refractory to loperamide, the enkephalinase inhibitor racecadotril (100–300 mg orally three times daily) outperformed the short-acting somatostatin analogue octreotide (50–150 μg subcutaneously three times daily) over a one-week treatment period, and racecadotril also improved stool output relative to baseline (Beaugerie et al., 1996). By contrast, adsorbent therapy with attapulgite did not demonstrate benefit compared with placebo (Nwachukwu et al., 2008).

Autoimmune gastrointestinal dysmotility

Autoantibodies directed against specific neural antigens (including ion channels and ganglionic acetylcholine receptors) have been associated with esophageal dysmotility, slow-transit constipation, and chronic intestinal pseudo-obstruction. In cohorts of patients with idiopathic, paraneoplastic, or diabetic autonomic neuropathy and in idiopathic GI dysmotility, ganglionic receptor-binding antibody titers have correlated with more severe autonomic dysfunction (Dhamija et al., 2008; Pittock et al., 2011).

Experimental immunization with neuronal nicotinic acetylcholine receptors can reproduce autonomic and GI dysfunction in animal models, supporting a pathogenic role for some antibody-mediated processes (Lennon et al., 2003).

Neuromuscular junction and myopathic disorders

Myasthenia gravis and thymoma-associated syndromes

Although myasthenia gravis (MG) is classically characterized by fatigable skeletal muscle weakness, esophageal dysmotility has been documented with high-resolution manometry in MG (Torres-Barrera et al., 2020). MG can also co-occur with autoimmune autonomic neuropathy (Vernino et al., 2001), and thymoma-associated immune dysregulation has been linked to severe GI syndromes such as intestinal pseudo-obstruction and chronic diarrhea (Anderson et al., 1996; Gupta et al., 1985).

Primary muscle diseases and visceral myopathies

Several primary muscle diseases can affect gastric and intestinal motility through smooth muscle involvement, secondary autonomic dysfunction, or mixed neuromuscular mechanisms. Children with Duchenne and Becker muscular dystrophy show evolution of gastric electrical activity abnormalities and altered gastric emptying over time, consistent with progressive involvement of the gastric neuromuscular apparatus (Borrelli et al., 2005).

Inflammatory myopathies can also involve the gut. Juvenile dermatomyositis has been associated with novel GI tract manifestations (Laskin et al., 1999), and reviews of adult myositis emphasize the spectrum of esophageal and intestinal complications (Ebert, 2010). Familial visceral myopathy, sometimes in association with mitochondrial myopathy, represents an important differential diagnosis for chronic intestinal pseudo-obstruction (Lowsky et al., 1993).

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

MNGIE is a rare mitochondrial disorder characterized by severe GI dysmotility (often pseudo-obstruction), cachexia, peripheral neuropathy, and leukoencephalopathy. Because presentations overlap with more common functional and inflammatory disorders, diagnostic pitfalls are frequent (Filosto et al., 2011). Comprehensive reviews summarize clinical progression and evolving therapeutic strategies (Pacitti et al., 2018).

Case series and mechanistic studies highlight the importance of early recognition, as disease-modifying strategies such as allogeneic stem cell transplantation, liver transplantation, and experimental gene therapy approaches aim to correct thymidine phosphorylase deficiency and may alter trajectory in selected patients (D’Angelo et al., 2020; Filosto et al., 2012; Habibzadeh et al., 2020; Yadak et al., 2018).

Myotonic dystrophy

Gastrointestinal manifestations are common in myotonic dystrophy types 1 and 2, with high reported frequencies of constipation, diarrhea, abdominal pain, and dysphagia (Hilbert et al., 2017). Severe phenotypes include megacolon due to degenerative neuropathy of the myenteric plexus (Yoshida et al., 1988) and pseudo-obstruction, including in pediatric cases with smooth muscle and myenteric pathology (Ho et al., 2019; Pelizzo et al., 2018).

Conclusions

Neurologic and systemic diseases can disrupt gastric and pan-gut motor function through lesions of the brain, brainstem, spinal cord, autonomic nerves, enteric plexuses, pacemaker cells, and smooth muscle. Because GI symptoms are common and nonspecific, identifying a neurogenic mechanism requires careful pattern recognition and attention to accompanying autonomic and neurologic features.

When neurogenic dysmotility is suspected, integration of targeted autonomic testing (Tables 3 and 4) with segmental motility studies can improve diagnostic localization and clarify whether symptoms reflect predominant vagal, sympathetic, enteric, or myopathic mechanisms. Disease-specific patterns, such as prodromal dysmotility in Parkinson disease, area postrema syndromes, diabetic ‘autovagotomy,’ and antibody-mediated enteric neuropathy, provide additional diagnostic clues and may guide treatment. Management is typically multimodal, combining optimization of the underlying neurologic/systemic disorder, medication review, nutritional and rehabilitative strategies, and symptom-directed GI therapies. As immune and inflammatory mechanisms and neuromodulatory interventions evolve, collaborative care between gastroenterologists and neurologists will become increasingly important for patients with autonomic GI disorders.

Figure 3.

Neurologic disorders known to affect gastrointestinal motility.

Conditions may involve sympathetic pathways, craniosacral parasympathetic pathways, and/or primary disorders of enteric neurons or smooth muscle. ENS, enteric nervous system; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy.