The gut as a neurological organ

We refer to the gut as a neurological organ to emphasize the particular importance of the nervous system in the regulation of digestive functions, given that the gastrointestinal tract is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents. Virtually each aspect of digestive activity is under the regulatory influence of neurons, among which the enteric nervous system (ENS) plays the most important part. The ENS acts like a brain in the gut that functions independently of the central nervous system, contains programmes for a variety of gastrointestinal behaviours and governs the activity of all gastrointestinal effector systems according to need. Intrinsic sensory neurons supply the ENS with the kind of information that this system requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about any data that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. Many diseases of the gut, particularly the functional bowel disorders, seem to be related to dysfunction of the ENS and other components of the gastrointestinal innervation. The ENS and extrinsic afferents are hence prime targets for the therapeutic management of gut diseases and for the relief of the pain and discomfort associated with these disorders.     

Autonomic nervous system dysfunction after spinal cord injury

The autonomic nervous system (ANS) plays a key role in the regulation of many physiologic processes, mediated by supraspinal control from centers in the central nervous system. The role of autonomic dysfunction in persons with spinal cord injuries is crucial to understand because many aspects of the altered physiology seen in these individuals are directly caused by ANS dysregulation.     

The abdominal brain and enteric nervous system

Conventional medical treatment for neurologic disorders such as epilepsy, migraine, and autism focuses on the brain. Although standard medical treatment is often helpful, the underlying causes of these disorders are not well understood. Furthermore, some individuals respond poorly or not at all to regular medicine. Evidence is accumulating in the medical literature that the enteric nervous system (ENS)-that part of the nervous system associated with the alimentary canal-also plays a role in these disorders. Historically, the concept of an autonomous abdominal nervous system was advocated by Byron Robinson, Johannis Langley, and Edgar Cayce. The work of these three prominent historical figures is considered along with modem view-points on the abdominal nervous system. Complementary therapies that address the nervous system of the abdomen have potential as useful adjuncts to conventional treatment for certain neurologic disorders.     

Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system

The enteric nervous system (ENS) consists of neurons and glial cells that differentiate from neural crest progenitors. During embryogenesis, development of the ENS is controlled by the interplay of neural crest cell–intrinsic factors and instructive cues from the surrounding gut mesenchyme. However, postnatal ENS development occurs in a different context, which is characterized by the presence of microbiota and an extensive immune system, suggesting an important role of these factors on enteric neural circuit formation and function. Initial reports confirm this idea while further studies in this area promise new insights into ENS physiology and pathophysiology.     

LPAR1 regulates enteric nervous system function through glial signaling and contributes to chronic intestinal pseudo-obstruction

Gastrointestinal motility disorders involve alterations to the structure and/or function of the enteric nervous system (ENS) but the causal mechanisms remain unresolved in most cases. Homeostasis and disease in the ENS are processes that are regulated by enteric glia. Signaling mediated through type I lysophosphatidic acid receptors (LPAR₁) has recently emerged as an important mechanism that contributes to disease, in part, through effects on peripheral glial survival and function. Enteric glia express LPAR₁ but its role in ENS function and motility disorders is unknown. We used a combination of genetic, immunohistochemical, calcium imaging, and in vivo pharmacological approaches to investigate the role of LPAR₁ in enteric glia. LPAR₁ was enriched in enteric glia in mice and humans and LPA stimulated intracellular calcium responses in enteric glia, subsequently recruiting activity in a subpopulation of myenteric neurons. Blocking LPAR₁ in vivo with AM966 attenuated gastrointestinal motility in mice and produced marked enteric neuro- and gliopathy. Samples from humans with chronic intestinal pseudo-obstruction (CIPO), a severe motility disorder, showed reduced glial LPAR₁ expression in the colon and ileum. These data suggest that enteric glial LPAR₁ signaling regulates gastrointestinal motility through enteric glia and could contribute to severe motility disorders in humans such as CIPO.     

Heart rate recovery: a practical clinical indicator of abnormal cardiac autonomic function

The autonomic nervous system (ANS) and cardiovascular function are intricately and closely related. One of the most frequently used diagnostic and prognostic tools for evaluating cardiovascular function is the exercise stress test. Exercise is associated with increased sympathetic and decreased parasympathetic activity and the period of recovery after maximum exercise is characterized by a combination of sympathetic withdrawal and parasympathetic reactivation, which are the two main arms of the ANS. Heart rate recovery after graded exercise is one of the commonly used techniques that reflects autonomic activity and predicts cardiovascular events and mortality, not only in cardiovascular system disorders, but also in various systemic disorders. In this article, the definition, applications and protocols of heart rate recovery and its value in various diseases, in addition to exercise physiology, the ANS and their relationship, will be discussed.     

Heart rate recovery: a practical clinical indicator of abnormal cardiac autonomic function

The autonomic nervous system (ANS) and cardiovascular function are intricately and closely related. One of the most frequently used diagnostic and prognostic tools for evaluating cardiovascular function is the exercise stress test. Exercise is associated with increased sympathetic and decreased parasympathetic activity and the period of recovery after maximum exercise is characterized by a combination of sympathetic withdrawal and parasympathetic reactivation, which are the two main arms of the ANS. Heart rate recovery after graded exercise is one of the commonly used techniques that reflects autonomic activity and predicts cardiovascular events and mortality, not only in cardiovascular system disorders, but also in various systemic disorders. In this article, the definition, applications and protocols of heart rate recovery and its value in various diseases, in addition to exercise physiology, the ANS and their relationship, will be discussed.     

Extending the enteric nervous system.

The work reviews the evidence suggesting that lingual components of the autonomic system may be considered the most rostral portion of the enteric nervous system (ENS) defining the concept of lingual ENS (LENS). The LENS is not dissimilar from the more distally located portions of the ENS, however, it is characterized by a massive sensory input generated by collaterals of gustatory and trigeminal fibers. The different neuronal subpopulations that compose the LENS operate reflexes involved in regulation of secretion and vasomotility. Systemic reflexes on the digestive and respiratory apparatus are operated by means of neural connections through the pharynx or larynx. The LENS can modulate the activity of distally located organs by means of the annexed glands.The LENS seems therefore to be a "chemical eye" located at the beginning of the digestive apparatus which analyses the foods before their ingestion and diffuses this information distally. The definition of the LENS supports the concept of an elevated degree of autonomy in the ENS and puts in a new light the role of the gustatory system in modulation of the digestive functions. For its characteristics, the LENS appears to be an ideal model to study the elementary connectivity of the ENS.     

神经生长因子及其受体在人胚胎结肠神经系统中的表达与分布

目的:研究人胚胎结肠神经系统的发育过程中神经生长因子(NGF)与其两个受体TrkA、P75NTR在结肠神经系统中的分布及与结肠神经系统发育的关系.方法:采用一抗为PGP9.5、NGF、TrkA、P75NTR的免疫组织化学技术,显示结肠神经系统中的神经元.结果:随着胚胎结肠神经系统的发育,P75NTR表达水平不断下降,而NGF、TrkA表达水平不断上升,P75NTR与NGF、TrkA的比例在不断变化.结论:NGF、TrkA、P75NTR参与了结肠神经系统的发育.     

Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis

Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest–derived cells. Using X-inactivation mosaicism for the purine salvage gene Hprt, we found that reduced ENS precursor proliferation most likely causes mycophenolate-induced migration defects and aganglionosis. To the best of our knowledge, mycophenolate is the first medicine identified that causes major ENS malformations and Hirschsprung-like pathology in a mammalian model. These studies demonstrate a critical role for de novo guanine nucleotide biosynthesis in ENS development and suggest that some cases of HSCR may be preventable.     

Autonomic neural dysfunction in recently diagnosed diabetic subjects

Because onset of autonomic neural dysfunction in the diabetic syndrome has not been well established, sensitive and quantitative measures of autonomic nervous system (ANS) function were made in 19 non-insulin-dependent (NIDD) and 14 insulin-dependent (IDD) recent-onset diabetic subjects. The known duration of diabetes mellitus in the NIDD subjects was less than or equal to 12 mo. The duration in the IDD subjects was less than or equal to 24 mo. RR-variation during beta adrenergic blockade (an index of an ANS reflex involving the cardiac parasympathetic nervous system [PNS] pathway) was smaller than that of control subjects in both NIDD (P less than 0.001) and IDD subjects (P less than 0.01). This PNS abnormality was not likely to be due to volume depletion since acute volume depletion induced by furosemide in six normal subjects (1608 +/- 105 ml, mean +/- SEM) did not change RR-variation. Dark-adapted pupil size after topical PNS blockade (an index of iris sympathetic nervous system [SNS] activity) was also smaller in both groups of diabetic subjects (NIDD, P less than 0.01; IDD, P less than 0.05). Pupillary latency time (an index of an ANS reflex involving iris PNS pathway) was prolonged in the NIDD subjects (P less than 0.005) but was not significantly altered in the IDD subjects. Thus, it would appear that the ANS is impaired soon after the diagnosis of diabetes mellitus. We hypothesize that early impairment of the ANS is common in IDD and NIDD subjects. This finding is consistent with the hypothesis that abnormal carbohydrate metabolism is an important factor in the etiology of diabetic autonomic neuropathy.     

Do changes of ANS in migraine subjects play a pathogenetic role?

Migraine, characterized by several autonomic disturbances both during and between attacks, suggests an involvement of the autonomic nervous system (ANS). To clarify the role of the ANS in migraine pathogenesis, we reviewed the major studies on autonomic function. The results of these investigations are contradictory, suggesting hypo– and hyperfunctioning of both the sympathetic and parasympathetic nervous systems.     

Behind an enteric neuron there may lie a glial cell

The enteric nervous system (ENS) controls the gastrointestinal system. Enteric glia have long been regarded as the essential "glue" of the ENS. Now, however, two independent reports in this issue of the JCI provide compelling evidence that mouse enteric glia can also be neuronal precursors. These reports show that enteric glia give rise to neurons in vitro and that neurogenesis can be experimentally induced to occur in vivo in the adult mouse ENS. Unfortunately, glia do not constitutively replace neurons, and neurogenesis is not easily provoked. Although these new observations make it clear that clinical trials using glia to replace enteric neurons are more than premature, they are enticing for future research.     

Emerging roles for enteric glia in gastrointestinal disorders

Enteric glia are important components of the enteric nervous system (ENS) and also form an extensive network in the mucosa of the gastrointestinal (GI) tract. Initially regarded as passive support cells, it is now clear that they are actively involved as cellular integrators in the control of motility and epithelial barrier function. Enteric glia form a cellular and molecular bridge between enteric nerves, enteroendocrine cells, immune cells, and epithelial cells, depending on their location. This Review highlights the role of enteric glia in GI motility disorders and in barrier and defense functions of the gut, notably in states of inflammation. It also discusses the involvement of enteric glia in neurological diseases that involve the GI tract.     

Planar cell polarity genes control the connectivity of enteric neurons

A highly complex network of intrinsic enteric neurons is required for the digestive and homeostatic functions of the gut. Nevertheless, the genetic and molecular mechanisms that regulate their assembly into functional neuronal circuits are currently unknown. Here we report that the planar cell polarity (PCP) genes Celsr3 and Fzd3 are required during murine embryogenesis to specifically control the guidance and growth of enteric neuronal projections relative to the longitudinal and radial gut axes. Ablation of these genes disrupts the normal organization of nascent neuronal projections, leading to subtle changes of axonal tract configuration in the mature enteric nervous system (ENS), but profound abnormalities in gastrointestinal motility. Our data argue that PCP-dependent modules of connectivity established at early stages of enteric neurogenesis control gastrointestinal function in adult animals and provide the first evidence that developmental deficits in ENS wiring may contribute to the pathogenesis of idiopathic bowel disorders.     

Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease.

The spotting lethal rat, a naturally occurring rodent model of Hirschsprung disease, carries a deletion in the endothelin-B receptor (EDNRB) gene that abrogates expression of functional EDNRB receptors. Rats homozygous for this mutation (sl) exhibit coat color spotting and congenital intestinal aganglionosis. These deficits result from failure of the neural crest-derived epidermal melanoblasts and enteric nervous system (ENS) precursors to completely colonize the skin and intestine, respectively. We demonstrate that during normal rat development, the EDNRB mRNA expression pattern is consistent with expression by ENS precursors throughout gut colonization. We used the human dopamine-beta-hydroxylase (DbetaH) promoter to direct transgenic expression of EDNRB to colonizing ENS precursors in the sl/sl rat. The DbetaH-EDNRB transgene compensates for deficient endogenous EDNRB in these rats and prevents the intestinal defect. The transgene has no effect on coat color spotting, indicating the critical time for EDNRB expression in enteric nervous system development begins after separation of the melanocyte lineage from the ENS lineage and their common precursor. The transgene dosage affects both the incidence and severity of the congenital intestinal defect, suggesting dosage-dependent events downstream of EDNRB activation in ENS development.     

Disorders of gastrointestinal motility in neurologic diseases

Neurologic diseases can affect the bowel at several levels of innervation--by altering the electrical activity that controls smooth muscle, the enteric nervous system, or the extrinsic neural pathways to the gut. This review concentrates on disorders of motility that occur in conjunction with diseases of the extrinsic neural supply (from the level of the brain to the postganglionic fibers) and those generalized disorders that affect gut smooth muscle. Modern technology, such as gastrointestinal scintigraphy and manometric techniques that measure esophageal, gastroduodenal, and anorectal motility (intraluminal pressures), has provided better methods to study the pathophysiologic aspects of gut motility in diseases of the nervous system. Distinguishing the neuropathies of the extrinsic nervous system from those of the intrinsic (enteric) nervous system is not always possible because the available techniques evaluate only the end-organ--that is, the motor function of the gut. Degenerative or infiltrative (myopathic) disorders of gut smooth muscle, however, can be distinguished from such neuropathies, and careful and systematic evaluation of autonomic function can often identify the level of disordered function in the neural-gut axis.     

Autonomic nerve disorders in generalized amyloidosis]

Various autonomic disturbances are usually seen in systemic amyloidosis with polyneuropathy, especially in familial amyloid polyneuropathy (FAP). In this paper we summarized the clinicopathological features of these autonomic symptoms. Orthostatic hypotension and bowel dysfunctions are two major autonomic manifestations of FAP, and at autopsy severe deposition of amyloid is observed in an extensive area of peripheral autonomic nervous system including sympathetic ganglia. Remarkable depletion of the extrinsic nerves with relative preservation of the intrinsic nerves is a characteristic finding in the gastrointestinal tract of the patients with FAP, and this abnormal innervation may produce the peculiar bowel disorders. Oral administration of L-threo-3,4-dihydroxyphenylserine, a precursor of noradrenaline, is effective for the treatment of these autonomic symptoms of FAP patients.     

Cardiovascular autonomic response during preoperative stress and postoperative pain

Heart rate response to physiologic maneuvers was used to evaluate autonomic nervous system (ANS) function in normal control subjects and during the stress and pain experienced by patients before and after surgery. In preoperative patients (stressed without pain) and postoperative patients (stressed with pain), maneuvers which routinely increase activity in the parasympathetic or sympathetic divisions of the ANS produced only 50% of the response seen in control subjects. The heart rate response was not further reduced in patients with pain compared to patients with stress alone. The difference in heart rate response between surgical patients and control subjects was not accompanied by a difference in baseline heart rate. The data suggest that tonic stress impairs the ability of the ANS to respond fully to perturbing influences.     

Intérêt de l’exploration du système nerveux autonome dans les troubles vésicosphinctériens

The neurological control of the lower urinary tract is mainly due to the autonomic nervous system (ANS), however, this one remains often unexplored in the analysis of lower urinary tract symptoms (LUTS). The analysis of the ANS function is simple to accomplish by means of cardiovascular tests such as the 30: 15 ratio or the blood pressure response to standing. The disturbance of two tests confirms an autonomic dysfunction, with a peripheral origin (e.g. diabetes) or with a central origin.