Neurogastroenterology …

K K Jain MD†

General Neurology

Updated 10.20.2021
Released 07.12.2000
Expires For CME 10.20.2024

Neurogastroenterology

Author: K K Jain MD†

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Neurogastroenterology

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Introduction

Overview

Neurogastroenterology is a subspecialty of gastroenterology that overlaps with neurology. The enteric nervous system is a collection of neurones that can function independently of the central nervous system (CNS). This article discusses the neurologic manifestations of gastroenterological disorders as well as significant gastroenterological manifestations of neurologic disorders. The CNS plays a role in the pathogenesis of some gastrointestinal disorders. Management depends on the individual disorder. Some general approaches to treatment of various gastrointestinal manifestations of neurologic disease are outlined in this article. Among the specialized procedures in development, transplantation of neural stem cells is a promising therapeutic approach for disorders of the enteric nervous system.

Key points

	• The connection between the gut and the brain is being increasingly recognized.
	• Neurogastroenterology covers primarily the diseases of the intrinsic enteric nervous system of the gastrointestinal tract.
	• Several neurologic disorders have gastroenteric manifestations.
	• Likewise, gastrointestinal disorders can lead to neurologic complications.
	• Knowledge of the pathomechanism and management of neurogastroenterological disorders is important for the practice of neurology.

Historical note and terminology

Neurogastroenterology is defined as neurology of the gastrointestinal tract, liver, gallbladder, and pancreas and encompasses control of digestion through the enteric nervous system, the central nervous system, and integrative centers in sympathetic ganglia (15). Neurogastroenterology has evolved as a subspecialty of gastroenterology. It deals with diseases in which a disordered interaction takes place between the nervous system and the gastrointestinal system. Neurogastroenterology covers primarily diseases of the intrinsic enteric nervous system, "brain of the gut," which is a part of the nervous system and controls motility, endocrine secretions, and microcirculation of the gastrointestinal system. Normal motility and transit through the gastrointestinal system result from a balanced interaction between the enteric nervous system and the extrinsic autonomic nervous system. Disorders of the autonomic nervous system that affect the gastrointestinal system usually manifest as disturbances of motility. Several gastrointestinal disorders including chronic intestinal pseudo-obstruction were once considered functional disorders but are now recognized as organic disorders because the pathology of the enteric nervous system has been identified (40). The term "functional gastrointestinal disorders" is applied to those disorders in which no abnormal metabolic or physical processes that could account for the symptoms can be identified, for example, irritable bowel syndrome (12). Emerging concepts in neurogastroenterology implicate dysfunctions at the levels of the enteric and central nervous systems as underlying causes of the prominent symptoms of many functional gastrointestinal disorders. A consideration of psychological and psychiatric aspects of these disorders is important because they are significant in relation to projections of discomfort and pain in the digestive tract as well as stress-induced gastrointestinal disorders. Neurogastroenterological disorders include gastrointestinal manifestations of well-known neurologic disorders as well as primary disorders of the gastrointestinal system that lead to neurologic manifestations.

The relationship between the brain and the gut has been known for a long time. In the 19th century, Beumont observed that subjects with gastric fistulae who fear and anger and other disturbances of the nervous system suffered suppression of gastric secretions and delay in emptying of the stomach (02). Stress-induced changes in intestinal motility have been recognized since 1902 when Cannon, the discoverer of barium meal technique for studying gastrointestinal motility, noted changes in the flow of intestinal contents in cats confronted by growling dogs (08). Although congenital megacolon was described by Hirschsprung in 1888, the fact that dilatation is secondary to the absence of submucosal Meissner and myenteric Auerbach plexuses was not established until 60 years later. Parkinson described dysphagia and constipation as cardinal features of Parkinson disease (45). Although clinical neurologists in the 19th and 20th century recognized the relationship between the gastrointestinal system and neurologic disorders, there was a paucity of basic research on identifying the basic mechanisms involved in the transfer of information between the gut and the brain. Studies starting in the 1940s and 1950s described neurologic disorders secondary to gastrointestinal disorders. These were mainly nutritional deficiency disorders of the CNS, and the first book on this topic was published in 1974 (44).

A landmark study in 1977 showed that intracerebroventricular injection of a hypothalamic peptide, thyrotropin releasing hormone, stimulates colonic motility in the anesthetized rabbit (57). Several brain structures regulating gastrointestinal function were identified by electrophysiological techniques in the 1980s. The nucleus tractus solitarius was found to be the major projection target of vagal afferent fibers and, in turn, projected to the dorsal motor nucleus of the vagus, a major origin of efferent vagal fibers. Vagal afferent stimulation-evoked gastric secretion was shown to be suppressed by paraventricular hypothalamic nucleus lesion (52).

The enteric nervous system is sometimes called the “second brain” because of the diversity of neuronal cell types and complex, integrated circuits that permit it to autonomously regulate many processes in the bowel (01). The gut and the brain are highly integrated. Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom-attentive behavior or hypervigilance, and pain.

Clinical manifestations

Presentation and course

	• Common manifestations of neurogastroenterological disorders are: nausea and vomiting, dysphagia, and gastroesophageal reflux disorder.
	• These can be associated with neurologic disorders.
	• Nausea and vomiting. Nausea and vomiting are commonly associated with disorders of gastric motility such as gastroparesis.
	• Dysphagia. This term is used for describing difficulty in swallowing. Transfer dysphagia is difficulty in propelling the food from the mouth to the esophagus or initiation of the act of swallowing (see MedLink Neurology article Dysphagia).
	• Gastroesophageal reflux disorder. This term is used for a condition that develops when the reflux of stomach contents causes troublesome symptoms or sequelae. Reflux occurs predominantly during transient lower esophageal sphincter relaxations in which laxity of the diaphragmatic hiatus is an important factor. Gastroesophageal reflux disorder may occur in several neurologic disorders and may produce neurologic sequelae mainly related to sleep disturbances. Most of the reported studies show no connection between obstructive sleep apnea syndrome and reflux disease.

Gastroesophageal reflux disorder may be associated with sleep disorders without symptoms of reflux. A subset of individuals with complaints of disturbed sleep have significant gastroesophageal reflux without heartburn.

	• Gastroparesis. Gastroparesis is a motor disorder of the stomach resulting in delayed gastric emptying. The stomach is distended, leading to a sense of bloating. It is manifested as anorexia, postprandial abdominal discomfort, nausea, and vomiting.
	• Chronic intestinal pseudo-obstruction. Chronic intestinal pseudo-obstruction syndrome is characterized by nausea, vomiting, early satiety, and abdominal discomfort, suggesting intestinal obstruction in the absence of a mechanical cause. The acute form of intestinal pseudo-obstruction is known as paralytic ileus.
	• Constipation. Constipation is perceived as an infrequent or incomplete evacuation of stools. There may be a lack of rectal sensation of stools with an absence of urge to defecate. Dyssynergic defecation due to failure of recto-anal coordination frequently affects patients with chronic constipation and overlaps with slow transit constipation.
	• Fecal incontinence. This is usually associated with a lack of formed stools and neuromuscular damage to the pelvic floor. It may occur during sneezing and coughing or during sleep.
	• Visceral pain. Spinal afferents play a role in the discrimination of pain, whereas vagal input affects the emotional and autonomic reactions to visceral pain. Targeting of these pathways could determine the selection of therapy for patients with chronic visceral pain syndromes. Visceral hypersensitivity and an increased response to stress are both manifestations of irritable bowel syndrome, which may respond to gabapentin as shown in animal models (43).
	• Disturbances of body weight. The balance between anorexigenic and orexigenic factors originating from gastrointestinal tract and mediated by the nervous system plays a role in short-term regulation of food intake and growth hormone release. An impairment of this balance may result in obesity or cachexia.

Neurologic manifestations of gastroenterological disorders are listed in Table 1.

Table 1. Neurologic Manifestations of Gastroenterological Disorders

Gastroenterological disorders	Neurologic manifestations
Celiac disease	• Cerebellar syndrome • Peripheral neuropathy • Cerebral vasculitis • Encephalopathy • Myelopathy • Myopathy • Migraine
Familial adenomatous polyposis coli	• Brain tumor in patients with Turcot syndrome
Gastroesophageal reflux disorder	• Sleep disorders: insomnia and excessive daytime sleepiness
Gastrointestinal motility disorders	• Enteric neuropathies
Inflammatory bowel disease (eg, Crohn disease)	• Peripheral neuropathy • Cranial neuropathies • Encephalopathy • Seizures • Demyelinating disease • Myopathy • Myelopathy • Cerebrovascular: stroke, vasculitis • Migraine
Sequelae of gastric resection and restriction surgery	• Peripheral neuropathy • Myopathy • Myelopathy

Gastrointestinal disorders and migraine. Migraine may be associated with gastroparesis, colic, irritable bowel syndrome, inflammatory bowel syndrome, and celiac disease (64). Gastroparesis may occur during migraine attacks, and children with colic are likely to suffer from migraine. Migraine is more frequent in the rest of the conditions mentioned earlier, and its frequency may diminish with treatment of the primary gastrointestinal disorder.

Gut microbiota and neuroinflammation. Microbes living in the gut may remotely influence the activity of cells in the brain that are involved in controlling inflammation and neurodegeneration. Interferon signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR). In multiple sclerosis, the circulating levels of AHR agonists are decreased. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that act on astrocytes to limit CNS inflammation (53).

Neurologic manifestations of celiac disease. Celiac disease or gluten-sensitive enteropathy is a gluten-related systemic autoimmune disease characterized by abnormal immunological response to ingested gluten in genetically susceptible individuals. Laboratory investigations should include intestinal biopsy and immunological tests. Extraintestinal neurologic manifestations in order of frequency are headache/migraine, attention-deficit hyperactivity disorder, epileptic seizures, mental retardation, cerebellar ataxia, and behavior disorders (10). Celiac crisis has been reported to present with status epilepticus and encephalopathy in the absence of profound gastrointestinal symptoms (20). Among all those reported, confirmed neuropsychiatric manifestations of celiac disease are loss of short-term memory, anxiety and depression, psychosis, ataxia, seizures, irritability, and chronic headache (29). A case report shows that psychosis may also be a manifestation of nonceliac gluten sensitivity and should be considered in the differential diagnosis (30).

Certain dietary nutrients, such as choline, which is contained in meat and eggs, are processed specifically by the gut microbiota to produce trimethylamine (TMA), which is absorbed in the gut and converted in the liver to TMA-N-oxide by hepatic flavin-containing monooxygenases. Increased levels of TMA oxide have been associated with an increased risk of stroke by increasing the accumulation of macrophage-specific cholesterol and the formation of foam cells and reducing net reverse cholesterol transport (62).

Gastrointestinal beriberi and Wernicke encephalopathy. There is a case report of a patient with gastrointestinal disturbances such as anorexia, nausea, and vomiting resulting in thiamine deficiency who presented with neurologic symptoms fulfilling the criteria of Wernicke encephalopathy (48). This patient responded only to intravenous thiamine.

Enteric neuropathies. The complexity of the enteric nervous system renders it susceptible to develop enteric neuropathies with poorly characterized pathophysiology and outcomes (46).

Prognosis and complications

Not relevant as the article is an overview of a subspecialty and not a single disease entity.

Biological basis

	• The enteric nervous system is related to the central and autonomic nervous systems.
	• The microbiota-gut-brain axis is a bidirectional pathway through which the gastrointestinal tract exerts an influence on cerebral nutrition and function.
	• Gut microbiota changes have an impact on several neurologic disorders.

Etiology and pathogenesis

The enteric nervous system. Establishing the relationship of the enteric nervous system (ENS) to the central and autonomic nervous systems is helpful in understanding the pathophysiology of various neurogastroenterological disorders.

Enteric, central, and autonomic nervous systems

This diagram shows the relationship of the enteric nervous system to the central and autonomic nervous systems. (Contributed by Dr. K K Jain.)

The ENS of humans contains approximately 500 million neurons and is the largest nervous system outside the brain. Its neurons are distributed in thousands of small ganglia, most of which are found in two plexuses, the myenteric and submucosal plexuses. Previously, three types of sensory neurons were recognized in the gastrointestinal tract: dorsal root ganglia, nodose or jugular ganglia, and intrinsic primary afferent neurons. Current research indicates that there are at least 8, and at most 20, different types of neurons in the ENS. There is bidirectional flow of information between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia, but the relative roles of the ENS and CNS differ considerably along the digestive tract. For example, CNS plays a major role in controlling contractile activity as well as acid secretion of the stomach whereas ENS in the small intestine and colon controls muscle activity, local blood flow, and several other functions (16). A high-resolution neuronal imaging method with electrophysiology has revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that generates rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the gastrointestinal tract (59). Monoamines play a role in the physiology of the gastrointestinal tract, and examples include the following (42):

	• Noradrenaline, the primary transmitter of postganglionic sympathetic neurons, is involved in motility and secretory reflexes and controls arterial perfusion as well as immune functions.
	• Dopamine, produced by a subpopulation of enteric neurons, is used as a transmitter.
	• Serotonin, produced by enterochromaffin cells, affects gut motility and enteric neuron development and is involved in immunomodulation.

Neuroimmune regulation. Sensory neurons communicate with the immune system to modulate tissue inflammation. This neuroimmune regulation is carried out via ion channels and sensory neuropeptides, such as substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide (28). Sensory neurons also play a role in regulating host defense against enteric bacterial pathogens.

Role of the vagus nerve in gut to brain communication. The vagus nerve is the main channel of communication between the gastrointestinal tract and the brain. In experimental studies, sensory signals from the gut facilitate the hippocampal-dependent learning and memory function in rats, which is severely impaired following disconnection of this pathway (60). These findings have clinical implications (eg, bariatric surgery such as vertical sleeve gastrectomy for obesity or vBloc that involve disruptive manipulation of the vagus nerve) and may have memory impairment as a side effect. On the other hand, transcutaneous stimulation of the vagus nerve has led to memory improvement in patients with Alzheimer disease (22).

Etiology. Neurologic causes of various gastroenterological disorders are listed in Table 2; gastroenterological manifestations of neurologic disorders are shown in Table 3.

Table 2. Causes of Neurogastroenterological Disorders

Neurogastroenterological disorders	Causes
Achalasia cardia	• Loss of myenteric neurons • Chagas disease
Chronic intestinal pseudo-obstruction	• Brain stem tumors • Diabetes mellitus • Drug or heavy metal toxicity • Multiple sclerosis • Paraneoplastic syndrome • Parkinson disease • Spinal cord transection • Visceral neuropathy
Constipation	• Anorectal disorders • Cauda equina tumors • Colonic disorders • Depression • Diabetic neuropathy • Drug-induced (eg, anticholinergics, anticonvulsants) • Hirschsprung disease • Multiple sclerosis • Myotonic dystrophy • Paraplegia • Parkinson disease • Progressive systemic sclerosis • Shy Drager syndrome • Stroke
Diarrhea	• Diabetes with autonomic neuropathy • Irritable bowel syndrome • Bacterial toxins (eg, cholera) • Vagal nerve stimulation
Dysphagia	• Disorders of pharyngeal and esophageal muscles • Lesions involving the swallowing center • Mechanical: intrinsic obstruction and external compression, eg, cervical spine osteophytes • Myotonic dystrophy • Neurologic disorders affecting the cranial nerves IX and X • Paralysis of the tongue • Parkinson disease • Scleroderma • Retropharyngeal pseudomeningocele after atlantooccipital dislocation • Wilson disease
Fecal incontinence	• Aging • Cauda equina syndrome • CNS injury • CNS neoplasms • Congenital anomalies (eg, myelomeningocele) • Damage to nerves of the pelvic floor muscles • Dementia • Multiple sclerosis • Shy Drager syndrome • Sphincter dysfunction due to diabetic autonomic neuropathy
Gastroparesis	• Autonomic neuropathy of diabetes mellitus
Gastroesophageal reflux disorder	• Down syndrome • Familial dysautonomia • Hydrocephalus
Hirschsprung disease (congenital megacolon)	• Congenital aganglionosis of colon
Infantile hypertrophic pyloric stenosis	• Hypertrophy and hyperplasia of pyloric muscle cells is due alterations in interstitial cells of Cajal of the ENS.
Nausea and vomiting	• Various causes are listed in Table 1 of the article on nausea and vomiting

Table 3. Significant Gastroenterological Manifestations of Neurologic Disorders

Neurologic disorders	Gastroenterological manifestations
Amyotrophic lateral sclerosis	• Dysphagia • Gastroparesis • Chronic intestinal pseudo-obstruction
Autonomic neuropathies associated with diabetes, paraneoplastic syndromes, amyloid disease, HIV-1, etc.	• Abdominal pain • Constipation • Diarrhea • Dysphagia • Nausea and vomiting
Mitochondrial neurogastrointestinal encephalopathy caused by multiple deletions of mitochondrial DNA	• Peripheral neuropathy • Ophthalmoplegia • Deafness • Leukoencephalopathy • Gastrointestinal symptoms due to visceral neuropathy
Cerebrovascular ischemic syndromes	• Dysphagia due to involvement of the lower cranial nerve nuclei • Chronic intestinal pseudo-obstruction • Stress ulcers
Multiple sclerosis	• Fecal incontinence • Constipation
Myotonic dystrophy	• Abdominal pain • Constipation • Dysphagia
Shy Drager syndrome	• Constipation • Dysphagia • Fecal incontinence
Parkinson disease	• Dysphagia • Gastroparesis • Constipation
Spinal cord injury	• Fecal incontinence • Constipation • Delayed gastric emptying
Wernicke encephalopathy	• Abdominal pain • Anorexia • Nausea and vomiting

Pathogenesis

Disturbances of the myenteric nervous system. Gastrointestinal motor dysfunction can result from disturbances at all levels of extrinsic neural control. The enteric nervous system, consisting of intrinsic afferent neurons, interneurons (interstitial cells), and motor neurons, may be affected primarily or as a part of other disorders. Interstitial cells of Cajal are the pacemakers in gastrointestinal muscles, and these cells also mediate or transduce inputs from the enteric nervous system and generate as well as propagate slow waves in gastrointestinal muscles. Alterations of these cells occur in various disorders of gastrointestinal motility, such as Hirschsprung disease.

Two major neural plexuses that comprise the enteric nervous system are the myenteric Auerbach plexus and the submucous Meissner plexus, which have the capability to maintain basic intestinal function even in the absence of control by the external autonomic nervous system. Injury or alterations in the myenteric plexus can lead to severe disturbances of the motility of the intestine. In Chagas disease, the parasite Trypanosoma cruzi destroys enteric neurons, which leads to achalasia of the lower esophageal sphincter (achalasia cardia). In longstanding diabetes, degeneration and reduction in the number of myenteric neurons can lead to gastroparesis. Myenteric plexus is subject to damage by drugs such as vincristine because it is not protected by a blood-nerve barrier. In congenital megacolon (Hirschsprung disease), portions of the colon are aganglionic, and sustained contraction of a variable length of the preceding colon produces enlargement of the colon.

The term "enteric neuropathies" is used for various conditions affecting motor function of the human gastrointestinal tract. The pathology of motility disorders such as achalasia, gastroparesis, intestinal pseudo-obstruction, colonic inertia, and megacolon cannot be easily correlated with clinical features. Combined clinical and histopathological studies may facilitate the application of basic sciences to the clinical management of patients with enteric neuropathies.

There is a neurogenesis program in the adult gut outside of the CNS, indicating the vulnerability of the enteric nervous system to exogenous influences. Neurogenesis can occur in the adult due to the presence of enteric neural precursor cells (ENPC); acquired diseases of the enteric nervous system, such as achalasia, may result from a loss of ENPCs like congenital disorders such as Hirschsprung disease (27). The ability to identify the adult ENPCs will enable an understanding of the pathogenesis of enteric neuromuscular diseases as well as the development of novel regenerative therapies.

The enteroendocrine system. This is the primary sensor of ingested nutrients and is involved in secretion of gut hormones, which modulates multiple physiological responses including gastrointestinal motility and secretion, glucose homeostasis, and appetite (49). A study of the molecular mechanisms underlying enteroendocrine system contributes to our current understanding of the regulation of gut hormone secretion, including the interaction between the enteroendocrine system and the enteric nervous system. Further insight into how these systems collectively regulate postprandial physiology will further facilitate the development of novel therapeutic strategies for disorders of enteroendocrine system.

Microbiome of the gut and effect on the brain. Commensal microorganisms that inhabit the gut are called the “gut microbiome.” They are beneficial for human health. Bacteria in the gut can produce neurotransmitters such as GABA, serotonin, and norepinephrine, which can directly and indirectly regulate activity in the enteric nervous system and vagus nerve. A study in healthy women has shown that consumption of a fermented milk product with probiotic affects activity of brain regions that control central processing of emotion and sensation (63). However, gut microbes can make proteins or stretches of peptides with sequences like those of humans. This molecular mimicry is usually harmless, except when it causes immune cells to react against native human proteins, which can lead to several autoimmune disorders.

The microbiota communicates with the brain through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve can sense the microbiota metabolites through its afferents and transfers the gut information to the central nervous system where it is integrated in the central autonomic network, where it generates either an adapted or an inappropriate response (03). A cholinergic antiinflammatory pathway in vagal nerve fibers can dampen peripheral inflammation and decreases intestinal permeability, thus, very probably modulating microbiota composition. A low vagal tone has been described in patients with inflammatory bowel disease indicating peripheral inflammation, and vagal nerve stimulation has the potential to restore homeostasis in the microbiota-gut-brain axis.

Gut microbiota changes have an impact on several neurologic disorders, including neurodevelopmental disorders such as autism spectrum disorder, psychiatric disorders (eg, major depressive disorder, anxiety, and schizophrenia), and neurodegenerative disorders (41). An imbalance in the microbiome may cause other disorders as well. Patients with Alzheimer disease have a proinflammatory state in the blood and proinflammatory bacteria in their gut. Toxic proteins that have been identified in familial Alzheimer disease and other familial dementias (amyloid, tau, alpha-synuclein, and others) are the culprits, but it is not known why they deposit in the sporadic cases. Types of bacteria living in the gut could influence the development of Alzheimer disease symptoms in mice. An experimental study has shown that by altering the gut microbiome, long-term antibiotic treatment reduces inflammation and slows the growth of amyloid plaques in the brains of male mice, but the same treatment was found to have no effect on female animals (11). Mucus is integral to gut health and its properties may be affected in neurologic disease. Factors that influence the nervous system may also affect the volume, viscosity, porosity of mucus composition, and subsequently, gastrointestinal microbial populations. Reduced gut mucus protection may make patients with neurologic diseases more susceptible to gastrointestinal problems (19).

Microbial molecule, capsular polysaccharide A from Bacteroides fragilis, promotes a protective, antiinflammatory response during viral infection and a mouse study has shown that Bacteroides fragilis polysaccharide A can temper the immune system so that infection does not result in an uncontrolled, potentially fatal inflammatory response in the brain (50). The investigators found that mice pretreated with the candidate probiotic Bacteroides fragilis or polysaccharide A survived a lethal herpes simplex virus infection whereas mice pretreated with a placebo did not survive despite the fact that both groups were given acyclovir, an antiviral that is the standard of care for herpes simplex virus encephalitis.

Experimental data indicate that the chemotherapeutic paclitaxel concurrently affects the gut microbiome, colonic tissue integrity, microglia activation, and fatigue in female mice, thus, identifying a novel relationship between colonic tissue integrity and behavioral responses that is not often assessed in studies of the brain-gut-microbiota axis (33). If similar findings can be confirmed clinically, dietary strategies such as probiotics or prebiotics or possibly fecal transplantation may be used to promote gut bacterial populations and conditions that protect the brain from inflammation and reduce chemobrain symptoms.

A small open-label clinical trial has evaluated the impact of microbiota transfer therapy (MTT) on gut microbiota composition and symptoms in children diagnosed with autism spectrum disorder. In addition to relief of gastrointestinal symptoms at the end of treatment, behavioral symptoms of autism spectrum disorder improved significantly, and the improvement was maintained at 8 weeks after cessation of treatment (23). The investigators urged caution against overinterpretation of results and families attempting to replicate the treatment on their own. Results of a systematic review of literature were inadequate to confirm a global microbiome change in children with autism spectrum disorder and causality could not be inferred to explain the etiology of the behaviors associated with autism spectrum disorder (21). Mechanistic studies of pathomechanism are needed to elucidate the specific role of the gut microbiome in the pathogenesis of autism spectrum disorder.

The first demonstration of a sensitive and specific diagnostic microbiome in a human cerebrovascular disease is that combinations of microbiome signatures and plasma inflammatory biomarkers show associations with disease severity and hemorrhage of cavernous hemangiomas (47).

Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. An experimental study has found reduced lactobacillus and increased circulating kynurenine levels as the most prominent changes in chronically stressed mice (38). Ongoing studies are investigating the activity of kynurenine, a major biomarker for depression, in the human brain and potential of lactobacillus probiotic as a dietary supplement to help patients with depression.

Gut microbiota represents a feasible target for modulating kynurenine pathway metabolism, and further development of this approach will improve our understanding of how the gut microbiota shapes brain and behavior (24). It will facilitate successful translation of microbiota-gut-brain axis research from bench to bedside.

A genome-wide association study has traced the connections between genetics, the gut microbiome, and memory in a mouse model bred to resemble the diversity of human population (36). The authors identified single-nucleotide polymorphisms that were significantly associated with short-term memory and learning. Further work is needed to show if Lactobacillus can improve memory in humans. In the future, it may be possible to use probiotics to improve memory in targeted populations, such as those with learning disabilities and neurodegenerative disorders.

Because foods containing nitrates are alleged to trigger migraines, the relation between food and microbiomes has been studied in those suffering from migraines. Oral samples collected by the American Gut Project were subjected to 16S rRNA sequencing, which confirmed that those with migraines had much higher levels of nitrate-reducing bacteria in their mouths (18).

Autoimmune gastrointestinal dysmotility. This is a manifestation of autoimmune dysautonomia and can occur as an idiopathic phenomenon, eg, idiopathic gastrointestinal dysmotility. It may or may not be accompanied by autoimmune neurologic disorder. Gastrointestinal dysmotility may be due to underlying cancer. This has been reported to be associated with paraneoplastic type 1 antineuronal nuclear antibodies and neuronal acetylcholine receptor antibodies in a case of small cell lung cancer (31).

Mouse models of experimental autoimmune encephalomyelitis show features of gastrointestinal dysmotility that persist in the absence of extrinsic innervation, suggesting direct involvement of ENS. The absence of gastrointestinal dysmotility together with experimental autoimmune encephalomyelitis and serum immunoreactivity in multiple sclerosis against ENS targets suggest that multiple sclerosis could be classified among other diseases known to induce autoimmune gastrointestinal dysmotility (58).

Role of aging. Some of the changes in the function of gastrointestinal system with aging are due to age-related neurodegenerative changes in the enteric nervous system. There is loss of enteric neurones in both submucosal and myenteric plexuses with selective preservation of nitrergic, but not cholinergic, neurones. These findings may lead to the discovery of therapeutic approaches that may help ameliorate deterioration of bowel function in advanced age. Animal experimental evidence indicates that reactive oxygen species are elevated in aging enteric neurons, which may be reduced by neurotrophic factors. Further data suggest that glial cell-line derived neurotrophic factor may play a protective role in the gut throughout life, and that dysregulation of neurotrophic factor support could contribute to neuronal ageing in the gut (26).

Gastrointestinal disorders associated with diabetes mellitus. Diabetes is associated with several disturbances of gastrointestinal motility through changes in intestinal smooth muscle or alterations in extrinsic neuronal control. The multifactorial pathogenesis includes disturbances of the enteric nervous system. Diabetic enteric neuropathy can cause changes in gastric emptying, diarrhea, or constipation (09). Gastric mucosal biopsy is a safe, practical method for histologic diagnosis of gastric autonomic neuropathy gastroparesis as a complication of type 1 diabetes (55).

Role of the CNS in gastrointestinal disorders. Many peptides and neurotransmitters are involved in CNS regulation of gastrointestinal motility and are found in the enteric nervous system. Peptides, including calcitonin gene-related peptide, cholecystokinin, neuropeptide Y, neurotensin, oxytocin, somatostatin, opioid peptides, and corticotrophic-releasing hormone, affect gastrointestinal motility when injected into the CNS of experimental animals.

Physical stress as well as psychological stress is known to contribute to gastrointestinal disorders. Most of the stressors are known to be associated with the release of corticotrophic-releasing hormone. The action of corticotrophic-releasing hormone on gastrointestinal motor function is mediated by the CNS through the autonomic nervous system independent of the pituitary-adrenal axis. Intestinal motor inhibition induced by surgery involves the release of corticotrophic-releasing hormone from the brain. Neuropeptide Y as well as corticotrophic-releasing hormone in the paraventricular nucleus of the hypothalamus is involved in the CNS regulation of gastrointestinal function.

Several CNS nuclei and neurotransmitters control gastric acid secretion and gastrointestinal motility. Central structures include the hypothalamus, the nucleus ambiguus, the dorsal motor nucleus of the vagus, the cingulate gyrus, the hippocampus, and the amygdala. Neurotransmitters that mediate this CNS control of the enteric nervous system include acetylcholine, norepinephrine, serotonin, and gamma amino butyric acid. The effects are multiple and include control of mucosal function such as secretion and absorption. The role of neurotransmitters in the pathogenesis of intestinal disorders is illustrated by the following example.

Irritable bowel syndrome is a chronic condition characterized by dysregulation of intestinal motor, sensory, and central nervous system functions. Manifestations are abdominal pain, bloating, and symptoms associated with irregular bowel function, such as constipation, diarrhea, or an alternating pattern between the 2. It is likely that serotonin (5-HT) acts as a key sensitizing agent in the etiology of irritable bowel syndrome. Acting mostly at 5-HT3 receptors, it enhances the sensitivity of visceral neurons projecting between the gut and the central nervous system. Its action at 5-HT4 receptors promotes the sensitivity of enteric neurons that react to luminal stimuli. 5-HT4 and 5-HT3 receptors also mediate, respectively, sensitizing and physiological actions of 5-HT (serotonin) on gastrointestinal motor and secretory functions.

GABAergic transmission to dorsal motor nucleus of the vagus and vagal efferent output to the gastrointestinal tract are regulated by variations in the levels of neurotransmitters that act as second messengers on the brainstem neurons that form vagovagal reflex circuits. Disturbances of the brainstem vagal circuits may underlie the pathophysiological changes observed in gastroparesis (05).

Loss of appetite observed during sickness is attributed to the proinflammatory cytokine IL-18, which has been shown in experimental studies in the mouse to decrease food intake by acting on neurons of the bed nucleus of the stria terminalis, a component of extended amygdala, to influence feeding via its projections to the lateral hypothalamus (14). The circuit affected by IL-18 may be a potential drug target for treating loss of appetite.

Pathogenesis of gastrointestinal disturbances in neurologic disorders.

Neurodegenerative disorders. Neurodegenerative disorders not only affect the CNS but also cause gut dysfunctions, suggesting they have an impact on both CNS and gut-innervating neurons. CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other's functions and cause progressive CNS disorder and persistent gut dysfunction (56).

Parkinson disease. The pathogenesis of various gastrointestinal disturbances in Parkinson disease is uncertain. Some of these problems, such as dysphagia and constipation, may be secondary to abnormalities in skeletal muscle function or side effects of antiparkinsonian medications. The pathological process in Parkinson disease may involve the enteric nervous system as well. Lewy bodies, like those in the CNS, have been demonstrated in the enteric nervous system as well as the autonomic ganglia. A depletion of dopaminergic neurons takes place in the colon of patients with Parkinson disease who suffer from constipation and megacolon. Constipation is a minor symptom in most patients with Parkinson disease; severe constipation, however, is associated with time since diagnosis and severity of disease.

Autonomic nervous system dysfunction is also common in patients with Parkinson disease and includes sexual dysfunction, swallowing and gastrointestinal disorders, bowel and bladder abnormalities, sleep disturbances, and derangements of cardiovascular regulation. These disorders may be caused by an underlying degenerative process that affects the autonomic ganglia, brainstem nuclei, and hypothalamic nuclei. In addition to loss of mesencephalic dopamine-containing neurons, the dorsal motor nucleus of the vagus nerve and central noradrenergic nuclei are also affected in Parkinson disease. Patients with Parkinson disease experienced higher frequency of dysphagia and constipation, which is associated with slow colonic transit, decreased phasic rectal contraction, and paradoxical sphincter contraction on defecation. The hypothesis that alpha-synuclein pathology could spread from the gut to brain via the vagus nerve was tested by assessing alpha-synucleinopathy in the brain in a novel gut-to-brain alpha-synuclein transmission mouse model, and the findings were as follows (25):

	• Gut-to-brain propagation of pathologic alpha-synuclein via the vagus nerve causes Parkinson disease.
	• Dopamine neurons degenerate in this model.
	• Injection of alpha-synuclein into the gut causes Parkinson disease–like symptoms. These findings will help to test potential therapeutic interventions to mitigate the risk of developing sporadic Parkinson disease.

Analysis of data on vagotomized patients for various indications from nationwide Swedish registers with follow-up for 5 years, has revealed suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against development of Parkinson disease (32). The results, along with gastrointestinal symptoms, which can manifest years before the diagnosis of Parkinson disease, provide preliminary evidence that the disease may start in the gut.

Wilson disease. Dysphagia is a common symptom of patients with Wilson disease, and they may die of aspiration pneumonia. Wilson disease may present with objective swallowing dysfunction, even in the absence of neurologic manifestations. Genotyping studies have revealed several mutations in Wilson disease, eg, an association between 3402delC and dysphagia.

Down syndrome. Gastroesophageal reflux and dysphagia occur in subjects with Down syndrome, but the precise pathomechanism is not established.

Shy Drager syndrome. In this form of primary autonomic failure, gastrointestinal abnormalities manifest at an early stage of the disease. These are attributed to atrophy, and loss is seen in various brain stem nuclei including those of the vagus and the intermediolateral cell mass in the thoracic and lumbar spinal cord. No pathological changes have been reported in the enteric nervous system. Constipation and dysphagia are common. Postprandial hypotension in these patients is due to combined disturbances of the gastrointestinal, cardiovascular, and autonomic nervous systems.

Autonomic neuropathy. Gastrointestinal manifestations of autonomic neuropathies are varied and complex because of numerous associated disorders. Diabetic neuropathy is the best-known example, but the pathogenesis is poorly understood. The neuropathy itself induces motility disorders, which produce further complications such as gastroparesis.

Cerebrovascular disease. Dysphagia is the most frequent gastrointestinal complication of stroke and is due to involvement of lower cranial nerve nuclei in brain stem syndromes. Stress ulcers have been considered as a complication of stroke where an interaction between the CNS, gastric circulation, gastric mucosa, and intraluminal contents plays a role. Cerebrovascular disorders are often accompanied by gastrointestinal mucosal damages. The pathophysiologic investigation of stress-related gastroduodenal mucosal damages has suggested that increased activity of the autonomic nervous system plays an important role in the development of these lesions.

Multiple sclerosis. The pathophysiology of gastrointestinal dysfunctions in multiple sclerosis is not as well explained as bladder dysfunction in patients with spinal cord involvement. Constipation may be due to slow colonic transit and abnormal rectal function. Fecal incontinence may be due to impaired sense of filling of the rectum and poor voluntary contraction of the anal sphincter.

Spinal cord injury. Autonomic function of the gastrointestinal system is impaired significantly following spinal cord injury. The term "neurogenic bowel" is usually applied to impairment of bowel function resulting from spinal cord injury but may also result from involvement of spinal cord in multiple sclerosis. Two patterns of neurogenic bowel exist: (1) the upper motor neuron bowel is due to spinal cord lesions above the sacral level, and (2) the lower motor neuron bowel results from lesions of the sacral spinal cord, nerve roots, or peripheral nerve innervation of the colon.

Upper gastrointestinal transit is prolonged in patients with spinal cord injury not only in those with cervical lesions but also in those with cauda equina lesions, which is secondary to colonic dysfunction and constipation (17).

Diagnostic workup

• The diagnostic workup of patients with neurogastroenterological disorders is a combination of those used for neurologic and gastroenterological disorders included in this category.

Basic laboratory tests include blood counts, blood chemistry, and stool examination. Blood glucose analysis is ordered in the case of suspected diabetic neuropathy.

Special diagnostic procedures vary according to whether the upper or lower gastrointestinal system is involved. Barium swallow and gastric emptying test are done in the case of dysphagia and stomach disorders, respectively. Abdominal radiographs and barium follow-through examinations are done in cases of chronic intestinal pseudo-obstruction. Endoscopic studies include gastroscopy and colonoscopy, depending on the part of the gastrointestinal system involved. Special neurogastroenterological tests are done according to the suspected disease:

	• Videofluoroscopy of oropharyngeal swallowing is done in cases of oropharyngeal dysphagia.
	• Colon transit studies may be done using radiopaque markers or radioscintigraphy.
	• Anorectal manometry is done to evaluate constipation and fecal incontinence in patients with pudendal neuropathy and is combined with assessment of the rectal emptying time (ability to expel a balloon) and rectal proctography. EMG of the puborectalis muscle and pudendal nerve studies may be required.
	• Tests of autonomic dysfunction include pharmacological tests, blood pressure studies on tilt table, and sweat tests. Abdominal vagal function is tested by plasma pancreatic polypeptide response to sham feeding.
	• Intraluminal manometry is used to detect motility patterns (groups of phasic pressure waves resulting from contractions of the circular muscle layer of the small bowel that are organized by the enteric nervous system). These studies reveal functional integrity of the small bowel but cannot diagnose a specific disease.
	• Biopsy of the gastrointestinal mucosa and submucosa is usually done along with endoscopy. Adequate amounts of submucosal plexus containing a substantial number of submucosal ganglia and neurons can be obtained, which can be reliably used to perform morphometric and neurochemical analysis.
	• Laparoscopy and exploratory laparotomy are done in cases where diagnosis remains unresolved by other procedures.
	• Studies of the brain to gut pathways are studied using cortical evoked potentials and brain imaging such as positron emission tomography and functional magnetic resonance imaging. The aim of these studies is to discriminate patients who have gut hypersensitivity due to sensitization of primary visceral afferents or spinal cord from those who have aberrant processing of sensation by the brain, as this has therapeutic implications. Such procedures are still being investigated in neurogastroenterology.
	• Brain imaging, particularly fMRI, has been used for the study of functional gastrointestinal disorders. Further improvements in methods and analysis of results are needed.

Management

	• Management depends on the individual disorder.
	• The disorder may be a gastrointestinal manifestation of a neurologic disorder or neurologic manifestation of a gastrointestinal disorder.

Gastrointestinal manifestations of neurologic disease. Some general approaches to treatment of various gastrointestinal manifestations of neurologic disease are outlined here.

Irritable bowel syndrome. Transverse tripolar dorsal column stimulation has been used for irritable bowel syndrome associated with abdominal pain resistant to conservative treatments (51).

Gastroparesis. Prokinetic agents, such as metoclopramide and cisapride, enhance gastric emptying and improve the symptoms of gastroparesis. A severely distended stomach may require decompression through a gastric tube. Rarely, a feeding gastrostomy may be required. Symptomatic treatment for nausea may be adequate if gastric emptying is normal.

Gastric mucosal disturbances. These may occur in acute stroke. The suppression of gastric acid secretion by using H2-receptor antagonists or proton-pump inhibitors is useful for the prevention and management of stroke-induced gastric mucosal damages.

Constipation. In neurologic disorders, such as Parkinson disease, constipation is usually treated with stool softeners, addition of fiber to the diet, prokinetic agents (ie, cisapride), and enemas. Cisapride relieves nausea and facilitates delivery of dopaminergic agents. Cisapride was taken off the market in the United States because of adverse effect of cardiac rhythm disturbances but is available on special request. Linaclotide, which activates chloride secretion through chloride-2 channels and cystic fibrosis transmembrane regulator, is approved for treatment of chronic idiopathic constipation. Various drugs in clinical trials or those used off-label for chronic idiopathic constipation and opioid-induced constipation are described elsewhere (07). Prucalopride, a benzofuran 5-HT4 agonist, accelerated bowel movement in chronic constipation without cardiovascular side effects. It has successfully completed clinical trials and is approved by the European Medicines Agency.

Methylnaltrexone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of opioid-induced constipation in patients receiving palliative care when response to laxative therapy has not been sufficient; however, it is not yet approved for adults with chronic, noncancer visceral pain. Lubiprostone, a bicyclic fatty acid, was approved by the FDA for treatment of opioid-induced constipation in patients with noncancer pain, based on results of clinical trials. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.

Dyssynergic defecation may be treated by using neuromuscular conditioning and biofeedback therapy. A review of published studies showed that test sacral nerve stimulation was successful in 42% to 100% of patients with chronic constipation, and of those who proceeded to implantation of a permanent sacral nerve stimulator, up to 87% showed an improvement in symptoms at a median follow-up of 28 months (61).

Fecal incontinence. Care of the patients with denervation-induced fecal incontinence requires protection of the perianal skin and use of incontinence pads. Biofeedback training may be helpful for patients who have some residual innervation.

Sacral nerve stimulation reduces symptoms in up to 80% of patients with fecal incontinence and because its effects are not limited to the distal colon and the pelvic floor, neuromodulation at spinal or supraspinal levels have been suggested as part of the mode of action.

Management of loss of normal bowel function in neurologic disorders. Loss of normal bowel function caused by injuries to the nervous system, neurologic disease or congenital defects of the nervous system is termed “neurogenic bowel dysfunction” and includes combinations of fecal incontinence, constipation, abdominal pain, and bloating. If medical treatment of gastrointestinal disorders fails, surgical procedures may be needed. Neurostimulation procedures that have been investigated include sacral nerve stimulation, peripheral nerve stimulation, and magnetic stimulation. However, there is not yet consensus about efficacy of neurostimulation for clinical use.

Bowel dysfunction in spinal cord injury. The general principles of management of neurogastroenterological disorders are applicable in spinal cord injury. Patients with lower motor neuron bowel tend to suffer more difficulties in management of their neurogenic bowel than those with upper motor neuron bowel. Therefore, more intensive and aggressive bowel care programs should be provided for patients with spinal cord injury and lower motor neuron bowel.

Constipation is the most common problem. The use of cisapride for constipation in these patients is empirical and does not fulfill the criteria for evidence-based medicine. In clinical trials, cisapride does not seem to have clinically useful effects in people with spinal cord injuries. The antegrade continence enema procedure is a safe and effective means of treating intractable constipation and fecal incontinence in the adult spinal cord injury patient. This approach should be considered for those persons in whom medical management of bowel care has been unsuccessful.

There is often a fine dividing line between the constipation and fecal incontinence in patients with spinal cord injury; with any management intended to ameliorate, one risks precipitating the other. Functional magnetic stimulation is a noninvasive method for managing neurogenic bowel in individuals with spinal cord injury. Sacral nerve stimulation via subcutaneously implanted electrodes has been shown to symptomatically improve a minority of patients with resistant idiopathic slow transit constipation. Further studies are needed to identify patients who may benefit and to determine optimal stimulation parameters.

Implantable neuroprostheses are used for the simultaneous management of both bladder and fecal incontinence. In paraplegic patients where incontinence may alternate with constipation, attempts have been made by computerized stimulation of the sacral anterior roots to restore normal function to the anal sphincters. Long-term follow-up studies have shown that neural stimulation is a safe and effective method of bladder and bowel management after suprasacral spinal cord injury.

Gastrointestinal disorders with involvement of the enteric nervous system. Management of some of these disorders may require neurologic approaches.

Irritable bowel syndrome and inflammatory bowel disease. The difference between the two disorders is lack of inflammation in the former. Neuroimmune interactions have been implicated in irritable bowel syndrome. A pilot study of temporary sacral nerve stimulation for treatment of irritable bowel syndrome showed significant reduction of symptoms in patients with diarrhea as a predominant feature (34).

Chronic vagus nerve stimulation has antiinflammatory properties in a rat model of colitis and in a pilot study performed in patients with moderate Crohn disease, a form of inflammatory bowel disease (04). The basis for this is that the vagus nerve has dual antiinflammatory properties through its afferent, (ie, hypothalamic-pituitary-adrenal) axis and efferent (ie, the anti-tumor necrosis factor alfa) effect of the cholinergic antiinflammatory pathway fibers. This is a safer, nondrug therapy based on a physiological pathway, as compared with other treatments, such as drugs with anti-tumor necrosis factor alfa effects.

Fibromyalgia. There is considerable overlap between fibromyalgia and inflammatory bowel disease. Many patients experience both conditions together, and both involve pain and visceral hypersensitivity. A pilot trial (NCT00977197) showed that pregabalin, an antiepileptic used for the treatment of diabetic neuropathy and fibromyalgia, has shown some efficacy in irritable bowel syndrome for relief of abdominal pain and diarrhea (54).

SARS-CoV-2 infection and the enteric nervous system. COVID-19 is associated with gastrointestinal manifestation in a subset of patients. SARS-CoV-2 infects gastrointestinal epithelial cells expressing angiotensin-converting enzyme 2 receptors, which triggers a cascade of events and leads to mucosal inflammation with impact on the function of the enteric nervous system and activation of sensory fibers conveying information to the CNS; this may produce symptoms such as vomiting and diarrhea attributed to COVID-19 (37). Neurologic involvement can aggravate the course of the disease as coronaviruses can penetrate the cerebrospinal fluid and damage the structure and function of the nervous system. There are no specific drugs for the treatment of gastrointestinal symptoms in patients with COVID‐19, but systemic therapies may be used. The contribution of gut microbiota to severity and progression of the disease and the long‐term sequelae of the infection on digestive functions need further investigation.

Treatment of disorders of the ENS. Advances in neurogastroenterology have improved the prospects of improved management of enteric neuropathies. These include intestinal transplantation, novel drugs, neuromodulation, transfer of fecal microbiota, as well as stem cell and gene therapy (46). Among the experimental methods, transplantation of neural stem cells is a promising therapeutic approach for disorders of the enteric nervous system characterized by a loss of critical neuronal subpopulations. ENS progenitor or stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS (06). However, several obstacles need to be overcome to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.

To discover rational and more effective therapies for neurogastrointestinal disorders, important future challenges include a proper understanding of the molecular and cellular changes that underlie enteric neuropathies. For research in functional gastrointestinal disorders, a multidisciplinary approach that integrates neuroimaging studies with methods from other branches of neuroscience, particularly, cognitive and autonomic neuroscience, has been suggested to develop personalized approaches to problems with interindividual variations such as visceral pain (13).

References

01: Avetisyan M, Schill EM, Heuckeroth RO. Building a second brain in the bowel. J Clin Invest 2015;125(3):899-907. PMID 25664848
02: Beumont W. Experiments and observations on the gastric juice and the physiology of digestion. New York: Dover Publications, 1833:280.
03: Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci 2018;12:49.** PMID 29467611
04: Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med 2017;282(1):46-63. PMID 28421634
05: Browning KN, Travagli RA. Plasticity of vagal brainstem circuits in the control of gastrointestinal function. Auton Neurosci 2011;161(1-2):6-13. PMID 21147043
06: Burns AJ, Goldstein AM, Newgreen DF, et al. White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. Dev Biol 2016;417(2):229-51. PMID 27059883
07: Camilleri M. Pharmacological agents currently in clinical trials for disorders in neurogastroenterology. J Clin Invest 2013;123(10):4111-20. PMID 24084743
08: Cannon WB. The movements of the intestines studied by means of the roentgen rays. Am J Physiol 1902;7(1):72-5. PMID 19971454
09: Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil 2007;19(12):951-60. PMID 17971027
10: Diaconu G, Burlea M, Grigore I, Anton DT, Trandafir LM. Celiac disease with neurologic manifestations in children. Rev Med Chir Soc Med Nat Iasi 2013;117(1):88-94. PMID 24505898
11: Dodiya HB, Kuntz T, Shaik SM, et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med 2019;216(7):1542-60. PMID 31097468
12: Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:1377-90. PMID 16678553
13: Farmer AD, Aziz Q, Tack J, Van Oudenhove L. The future of neuroscientific research in functional gastrointestinal disorders: integration towards multidimensional (visceral) pain endophenotypes. J Psychosom Res 2010;68(5):475-81. PMID 20403507
14: Francesconi W, Sánchez-Alavez M, et al. The proinflammatory cytokine interleukin 18 regulates feeding by acting on the bed nucleus of the stria terminalis. J Neurosci 2016;36(18):5170-80. PMID 27147667
15: Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 2012;9(5):286-94. PMID 22392290
16: Furness JB, Callaghan BP, Rivera LR, Cho HJ. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol 2014;817:39-71. PMID 24997029
17: Fynne L, Worsøe J, Gregersen T, Schlageter V, Laurberg S, Krogh K. Gastric and small intestinal dysfunction in spinal cord injury patients. Acta Neurol Scand 2012;125(2):123-8. PMID 21428967
18: Gonzalez A, Hyde E, Sangwan N, Gilbert JA, Viirre E, Knight R. Migraines are correlated with higher levels of nitrate-, nitrite-, and nitric oxide-reducing oral microbes in the American Gut Project Cohort. mSystems 2016;1(5);pii:e00105-16. PMID 27822557
19: Herath M, Hosie S, Bornstein JC, Franks AE, Hill-Yardin EL. The role of the gastrointestinal mucus system in intestinal homeostasis: implications for neurological disorders. Front Cell Infect Microbiol 2020;10:248.** PMID 32547962
20: Hijaz NM, Bracken JM, Chandratre SR. Celiac crisis presenting with status epilepticus and encephalopathy. Eur J Pediatr 2014;173(12):1561-4. PMID 23900521
21: Ho LKH, Tong VJW, Syn N, et al. Gut microbiota changes in children with autism spectrum disorder: a systematic review. Gut Pathog 2020;12:6. PMID 32025243
22: Jacobs HI, Riphagen JM, Razat CM, Wiese S, Sack AT. Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. Neurobiol Aging 2015;36(5):1860-7. PMID 25805212
23: Kang DW, Adams JB, Gregory AC, et al. Microbiota tansfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 2017;5(1):10. PMID 28122648
24: Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 2017;112(Pt B):399-412. PMID 27392632
25: Kim S, Kwon SH, Kam TI, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 2019.** PMID 31255487
26: Korsak K, Dolatshad NF, Silva AT, Saffrey MJ. Ageing of enteric neurons: oxidative stress, neurotrophic factors and antioxidant enzymes. Chem Cent J 2012;6(1):80. PMID 22857398
27: Kulkarni S, Micci MA, Leser J, et al. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis. Proc Natl Acad Sci U S A 2017;114(18):E3709-18. PMID 28420791
28: Lai NY, Mills K, Chiu IM. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J Intern Med 2017;282(1):5-23. PMID 28155242
29: Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol 2015;12(10):561-71. PMID 26260366
30: Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi. Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015;7(7):5532-9. PMID 26184290
31: Lipowska AM, Micic D, Cavallo A, McDonald E. Autoimmune gastrointestinal dysmotility due to small cell lung cancer. BMJ Case Rep 2017;2017. PMID 28801331
32: Liu B, Fang F, Pedersen NL, et al. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 2017;88(21):1996-2002.** PMID 28446653
33: Loman BR, Jordan KR, Haynes B, Bailey MT, Pyter LM. Chemotherapy-induced neuroinflammation is associated with disrupted colonic and bacterial homeostasis in female mice. Sci Rep 2019;9(1):16490. PMID 31712703
34: Lundby L, Krogh K, Buntzen S, Laurberg S. Temporary sacral nerve stimulation for treatment of irritable bowel syndrome: a pilot study. Dis Colon Rectum 2008;51(7):1074-8. PMID 18418655
35: Lynch AC, Wong C, Anthony A, Dobbs BR, Frizelle FA. Bowel dysfunction following spinal cord injury: a description of bowel function in a spinal cord-injured population and comparison with age and gender matched controls. Spinal Cord 2000;38(12):717-23. PMID 11175370
36: Mao JH, Kim YM, Zhou YX, et al. Genetic and metabolic links between the murine microbiome and memory. Microbiome 2020;8(1):53. PMID 32299497
37: Marasco G, Lenti MV, Cremon C, et al. Implications of SARS-CoV-2 infection for neurogastroenterology. Neurogastroenterol Motil 2021;33(3):e14104. PMID 33591607
38: Marin IA, Goertz JE, Ren T, et al. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci Rep 2017;7:43859. PMID 28266612
39: Martino R, Foley N, Bhogal S, et al. Dysphagia after stroke: incidence, diagnosis, and pulmonary complications. Stroke 2005;36(12):2756-63. PMID 16269630
40: Mathias JR, Clench MH. Neuromuscular diseases of the gastrointestinal tract. Postgrad Med 1995;97(3):95-106. PMID 7877932
41: Melzer TM, Manosso LM, Yau SY, Gil-Mohapel J, Brocardo PS. In pursuit of healthy aging: effects of nutrition on brain function. Int J Mol Sci 2021;22(9):5026.** PMID 34068525
42: Neuhuber W, Wörl J. Monoamines in the enteric nervous system. Histochem Cell Biol 2018;150(6):703-9. PMID 30250972
43: O’Mahony SM, Coelho AM, Fitzgerald P, et al. The effects of gabapentin in two animal models of co-morbid anxiety and visceral hypersensitivity. Eur J Pharmacol 2011;667(1-3):169-74. PMID 21645509
44: Pallis CA, Lewis PD. The neurology of gastrointestinal disease. Philadelphia: WB Saunders, 1974.
45: Parkinson J. An essay on shaking palsy. London: Whittingham and Rowland, 1817.
46: Pesce M, Borrelli O, Saliakellis E, Thapar N. Gastrointestinal neuropathies: new insights and emerging therapies. Gastroenterol Clin North Am 2018;47(4):877-94. PMID 30337038
47: Polster SP, Sharma A, Tanes C, et al. Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma. Nat Commun 2020;11(1):2659. PMID 32461638
48: Prakash S, Gastrointestinal beriberi: a forme fruste of Wernicke's encephalopathy? BMJ Case Rep 2018;2018. PMID 29982183
49: Psichas A, Reimann F, Gribble FM. Gut chemosensing mechanisms. J Clin Invest 2015;125(3):908-17. PMID 25664852
50: Ramakrishna C, Kujawski M, Chu H, Li L, Mazmanian SK, Cantin EM. Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis. Nat Commun 2019;10(1):2153. PMID 31089128
51: Rana MV, Knezevic NN. Tripolar spinal cord stimulation for the treatment of abdominal pain associated with irritable bowel syndrome. Neuromodulation 2013;16(1):73-7. PMID 22493949
52: Rogers RC, Hermann GE. Vagal afferent stimulation-evoked gastric secretion suppressed by paraventricular nucleus lesion. J Auton Nerv Syst 1985;13(3):191-9. PMID 4031362
53: Rothhammer V, Mascanfroni ID, Bunse L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016;22(6):586-97. PMID 27158906
54: Saito YA, Almazar AE, Tilkes K, et al. A placebo-controlled trial of pregabalin for irritable bowel syndrome. Am J Gastroenterol 2016;111:S236.
55: Selim MM, Wendelschafer-Crabb G, Redmon JB, et al. Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy. Neurology 2010;75(11):973-81. PMID 20837965
56: Singh A, Dawson TM, Kulkarni S. Neurodegenerative disorders and gut-brain interactions. J Clin Invest 2021;131(13):e143775. PMID 34196307
57: Smith JR, Lahann RR, Chestnut RM, et al. Thyrotropin-releasing hormone: stimulation of colonic activity following intracerebroventricular administration. Science 1977;196:660-1. PMID 404705
58: Spear ET, Holt EA, Joyce EJ, et al. Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil 2018:e13349**. PMID 29644797
59: Spencer NJ, Hibberd TJ, Travis L, et al. Identification of a rhythmic firing pattern in the enteric nervous system that generates rhythmic electrical activity in smooth muscle. J Neurosci 2018;38(24):5507-22.** PMID 29807910
60: Suarez AN, Hsu TM, Liu CM, et al. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun 2018;9(1):2181.** PMID 29872139
61: Thomas GP, Dudding TC, Rahbour G, Nicholls RJ, Vaizey CJ. Sacral nerve stimulation for constipation. Br J Surg 2013;100(2):174-81. PMID 23124687
62: Tilg H. A gut feeling about thrombosis. N Engl J Med 2016;374(25):2494-6. PMID 27332910
63: Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 2013;144(7):1394-401. PMID 23474283
64: van Hemert S, Breedveld AC, Rovers JM, et al. Migraine associated with gastrointestinal disorders: review of the literature and clinical implications. Front Neurol 2014;5:241. PMID 25484876

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Constipation: 564.0

Diarrhea: 558.9

Dysphasia: 787.2

Nausea: 787.0

Syndrome, abdominal, acute: 789.0

Syndrome: irritable bowel: 564.1

Vomiting: 787.0
ICD-10: Acute abdomen: R10.0

Constipation: K59.0

Dysphagia: R13

Irritable bowel syndrome: K58

Nausea and vomiting: R11

Other specified noninfective gastroenteritis and colitis: K52.8

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Neurogastroenterology

Associated Disorders

Acute traumatic spinal cord injury
Amyotrophic lateral sclerosis
Celiac disease
Diabetic neuropathy
Enteric nervous system
- Enteroendocrine system
- Gastroesophageal reflux disorder
- Gastrointestinal disorders
- Irritable bowel syndrome
- Multiple sclerosis
- Parkinson disease
- Shy Drager syndrome
- Spinal cord injury
- Turcot syndrome

Differential Diagnosis

gastrointestinal disorder
neuropathic disorder
myopathic disorder

Also Relevant

Acute autonomic neuropathies
Chronic autonomic neuropathies
Nausea and vomiting
Nutrition and the brain

Clinical Categories

General Neurology

Patient Handouts

Dysphagia

Neurogastroenterology …

Neurogastroenterology

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Neurologic Manifestations of Gastroenterological Disorders

Prognosis and complications

Biological basis

Etiology and pathogenesis

Table 2. Causes of Neurogastroenterological Disorders

Table 3. Significant Gastroenterological Manifestations of Neurologic Disorders

Pathogenesis

Pathogenesis of gastrointestinal disturbances in neurologic disorders.

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

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Also in This Category

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Brain death/death by neurologic criteria

Outpatient rehabilitation of chronic neurologic conditions

Neurogastroenterology

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Neurologic Manifestations of Gastroenterological Disorders

Prognosis and complications

Biological basis

Etiology and pathogenesis

Table 2. Causes of Neurogastroenterological Disorders

Table 3. Significant Gastroenterological Manifestations of Neurologic Disorders

Pathogenesis

Pathogenesis of gastrointestinal disturbances in neurologic disorders.

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Brain death/death by neurologic criteria

Outpatient rehabilitation of chronic neurologic conditions

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