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New Horizons in the Pathogenesis of Gastrointestinal Neuromuscular Disease

Knowles, Charles H

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Journal of Pediatric Gastroenterology and Nutrition: December 2007 - Volume 45 - Issue - p S97-S102
doi: 10.1097/MPG.0b013e31812e6569
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The question of what defines a gastrointestinal neuromuscular disease is not as simple as it may first appear, it being possible to define such disorders on the basis of clinical, radiological, specialist physiological (eg, manometric), or histopathological criteria. The dichotomy of opinion regarding attempts to classify patients with functional gastrointestinal disorders attests to this problem, with symptom-based criteria favoured by some (1) and measurement based by others (2). On these bases many disorders have been defined as symptom based (eg, irritable bowel syndrome [IBS], functional dyspepsia, idiopathic constipation) and measurement based (eg, enteric dysmotility, intestinal pseudoobstruction, slow-transit constipation).

Both systems have their merits and criticisms, which will not be discussed further here; however, these taxonometric considerations may lead one to conclude that gastrointestinal neuromuscular disease should be defined only on the basis of evident pathology. This approach leads to further problems. First, nearly all abnormalities lie in the enteric neuronal plexuses or in the muscularis propria, and are thus not amenable to examination on endoscopic mucosal biopsies. In this respect, the advance of minimally invasive surgical techniques has permitted the safe performance of laparoscopic intestinal biopsy (3), providing adequate full-thickness tissue for subsequent detailed analysis, but it is still a significant undertaking. Second, the yield of abnormalities is heavily dependent on the lengths taken to analyse tissues, with subtle abnormalities only found using immunocytochemistry on a panel of neuromuscular epitopes or using ultrastructural analysis, techniques unavailable to many centres for financial or technical reasons. Finally, even when pathological abnormality is evident, it is often difficult to determine the relationship of this to the observed clinical/physiological phenotype. Whilst some abnormalities, such as those with widespread degeneration/fibrosis or large inflammatory infiltrates, almost certainly will be causative in terms of dysfunction, many described findings may reflect plastic changes of cells to injury, such as altered neurochemistry (see below), or even responses to treatment, such as melanosis. Such observations may provide useful biomarkers, but probably have little or no role in causation.

Two recently popularised findings that may reflect this problem are smooth muscle α-actin deficiency and alterations in number and morphology of interstitial cells of Cajal (ICCs). The former is seen in the jejunum of chronic idiopathic intestinal pseudoobstruction (CIPO) (3–5), but it is also subject to differential expression with age and gut locality, and in heterogeneous disorders (3). The latter has been reported in an expanding list of at least 9 disparate conditions (congenital, acquired, inflammatory, and noninflammatory) occurring from oesophagus to anus (6). Although ICCs have a well-established role in the control of normal motility (7), the observation that ICCs decrease in an experimental model of intestinal obstruction (8) lends further weight to changes seen in motility disorders being a secondary phenomenon. Finally, it is possible that sensorimotor dysfunction could occur without any evident pathology. Several diseases in other areas of the peripheral nervous system have no evident pathology but significant functional consequences, such as channelopathies (9).

There is thus clearly a need to reach some consensus in the near future regarding the definition of neuromuscular gastrointestinal disorder (NMGID), possibly assigning different functional gastrointestinal disorders on the basis of a hierarchy of agreed-upon pathophysiological criteria. This system (a possible template is given in Table 1) also could take into account whether an aetiopathogenic mechanism is established. Of course, whether such a classification would lead to more or fewer arguments will remain to be seen.

Classification of pathogenic mechanisms in enteric neuromuscular diseases


In Table 1, group 1A would include a few disorders in which the aetiology/pathogenic mechanism largely has been determined. Examples would be Hirschsprung disease, MEN 2B, mitochondriopathies, some infantile pseudoobstruction cases, and secondary neuromuscular disorders occurring with Chagas disease, scleroderma, paraneoplasia, and some autonomic neuropathies. Whilst these disorders are of great interest to the neurogastroenterologist for genetic and molecular insights, they represent a minute proportion of a large group of patients with functional gastrointestinal disorders, who make up to 40% of Western outpatient surgical and medical gastroenterological practice, with an annual fiscal demand estimated to be €28 billion in European Union countries (10).

The pathogenesis of NMGID is considered here using the scheme shown in Fig. 1. This demonstrates the possibility of contributions from abnormal development, abnormal ageing/repair and plasticity, and finally from exogenous injury. Although it is accepted that many disorders may be multifactorial, the evidence for each will be considered below in turn.

FIG. 1
FIG. 1:
Framework used to consider factors in the pathogenesis of neuromuscular gastrointestinal disease.


Much is now known of the normal processes that underlie migration, colonisation, and differentiation of enteric nervous system progenitors during development, and that continue into the postnatal period. These are well-reviewed elsewhere (11). In general, 2 approaches have been taken to elucidate possible genetic alterations that disturb these processes, leading to disease. The first, the use of natural or targeted mutations in mice, has identified genes for which mutation leads to phenotypes akin to some human neuromuscular disorders such as Hirschsprung disease/megacolon (12), CIPO (13), and achalasia (14). Regrettably, because most thus far identified genes have early roles in development, resulting mouse knockouts have gross phenotypes, the majority having either aganglionosis or hyperganglionosis affecting long segments of bowel, often with associated extraintestinal organ dysgenesis. One exception is the more recently developed variant of the Ret knockout, miRet51, which does at least have a phenotype closely resembling colonic Hirschsprung disease (15). More common disorders have few mouse counterparts, although this area is progressing rapidly with observations of delayed transit and constipation knockouts for c-kit (7) and the 5HT4 receptor (16), and an IBS-like alternating-diarrhoea/constipation phenotype in serotonin transporter gene knockouts (17).

The second approach has been the identification of specific mutations in human patients with these disorders. Best studied is Hirschsprung disease, with mutations now identified (1994 to date) in at least 9 loci, most commonly in the RET protooncogene (20%–25%) (18) and the endothelin receptor B (5%–10%) (19), or its ligand endothelin 3 (5%–10%) (20). In CIPO 3 case reports identify loci or mutations in humans (21,22) with some further genetic mutations identified in small numbers of patients with mitochondriopathy-related pseudoobstruction (23,24). Thus far, mutations have been found only in these relatively rare disorders, and thence only in a minority of familial or syndromic cases. Where studied, genotypes have not as yet been identified in common disorders such as slow-transit constipation, even in familial cases (25,26), although a recent study of functional dyspepsia is encouraging (27).

Ageing, Repair, and Plasticity

It is widely acknowledged that a global decline in gastrointestinal function frequently accompanies advancing age (eg, loss of taste, appetite, and teeth; constipation; incontinence). In parallel with this are observed changes, particularly of neuronal loss that occur in humans (28) and experimental animals in a diet-dependent fashion (29). Plasticity (changes in neuronal structure and function in response to alterations in input) and repair (including regeneration) are possible within the enteric nervous system as in other areas of the nervous system, and these are demonstrated by recovery of neuronal function after surgery (30), as well as numerous surgical and chemical denervation experiments (31). Some plastic changes also may optimise function in postnatal development (32) and an ageing system (33,34). The mechanisms underlying such plasticity and repair include the action of an expanding list of neurotrophins, as well as important contributions from glial and smooth muscle cells (35), with the former used as potential therapy for some patients with slow-transit constipation (36). Whilst there is no current evidence to suggest that dysregulated plasticity/repair leads per se to NMGIDs, this remains an attractive hypothesis. Of more relevance may be the contribution that these processes make to the interpretation of observed changes in these disorders, particularly widely cited alterations in neuropeptide levels (37), and perhaps the changes in ICCs/smooth muscle α-actin described above.

Exogeneous Injury

It is intuitive to believe that the majority of NMGIDs may arise from noxious stimulation from the lumen. The gut is well designed as a barrier to direct neural injury, with no neural tissue actually exposed on the epithelial surface and the majority deeply embedded in the wall. Nevertheless, transepithelial-transduction mechanisms allow sampling of the luminal environment, and noxious stimuli are able to induce programmed intrinsic motor responses with the purpose of evicting the offending agent. The innate and adaptive immune responses that mediate alterations in motor function are well described and are perhaps best studied in the Trichinella spiralis–infected mouse model (38). The resulting paradigm (Fig. 2) has been championed by many as the underlying mechanism in patients with postinfective IBS, in which changes in sensorimotor function (particularly hypersensitivity/contractility) persist (as in the mouse model) after the initial stimulus (the infection) has been eradicated. This role of inflammation is supported, at least in IBS, by several studies that have demonstrated increased numbers of intramucosal mast cells (39) and T lymphocytes (40), as well as increased levels of proinflammatory mediators (39). Small numbers of such cells deeper in the muscle wall or in the myenteric plexus (as observed in Chagas disease) tend to be associated with more severe motor dysfunction (41).

FIG. 2
FIG. 2:
Trichinella paradigm.

Its weakness is in relevance and generality (ie, jejunal site, helminth induction, and mouse species). Furthermore, epidemiological data only support an infective role in approximately 20% of patients with IBS, and other NMGIDs do not commonly follow reported infection. Nevertheless, the continued detailed study of immune-mediated alterations in neuromuscular function will undoubtedly be of value, especially when extended to other models such as Citrobacter rodentium(42,43). Similarly, central nervous system modulation of this response (eg, with stress) by the so-called psycho-neuro-mucosal-immune axis is deservedly receiving much attention (44), particularly because the sex-dependent peripheral action of corticotropin-releasing factor in rodent models (45) may help to explain the marked sex differences that are seen in some disorders (46).

Less well studied with respect to adaptive immune responses is the role of humoral autoimmunity. A variety of methods can detect autoantibodies in putative autoimmune neurological disorders, although the exact method of measurement, and particularly subsequent interpretation, remain important before attaching significance to results, especially with respect to disease-specific causation (47). Humoral autoimmunity directed to native enteric neuronal (usually nuclear or cytoplasmic) antigens has been demonstrated by immunocytochemistry using sera from patients with severe gut dysmotility associated with paraneoplasia (48), some connective tissue disorders (49), Chagas disease (50), idiopathic achalasia (51), and in a small number of children with myenteric plexitis but no apparent primary disease (5,52). It is not clear, however, whether these antibodies have direct effects on gut function or are merely markers of an inflammatory response (47).

In contrast, the pathogenic role of antibodies to ion channels in several neurological diseases has been clearly demonstrated by a variety of approaches (9,47), and has more recently been investigated as a pathogenic mechanism in NMGID. In chagasic patients with achalasia (53) and megacolon (54), a single group have detected serum immunoglobulin G anti-M2 AChR antibodies using enzyme-linked immunoabsorbent assays to detect binding to purified antigen on plates. These antibodies displayed muscarinic-agonistlike activity in oesophageal muscle strips (53). A similar pathogenic role has been demonstrated for autoantibodies in patients with scleroderma-induced intestinal pseudoobstruction. In these, M3-mAChR-mediated contractions were inhibited by immunoglobulin fractions, or possibly by inhibiting L-type voltage-gated calcium channels (55). In idiopathic neuromuscular disease, only 2 studies have used contempory methodology (immunoprecipitation assays) to identify antineuronal antibodies in 9% of patients with CIPO (positive assays to 125I-epibatidine-ganglionic nicotinic ACh receptor complex (56) and 2 of 11 patients with idiopathic adult-onset (de novo) slow-transit constipation with antibodies to voltage-gated potassium channels (57), respectively). Further preliminary data also suggest the presence of antineuronal a3-AChR antibodies in a small proportion of patients with low-grade inflammatory enteric neuropathy, as described by Dr Hans Tornblom (personal communication, 2006). Finally, a recent study that used preincubation of gastric fundal tissue with sera from patients with achalasia suggests subsequently altered neurochemistry and motor function (58). Whether this is antibody-mediated or due to some other agent (eg, cytokines) remains to be determined, as perhaps does the validity of this novel method in general for detecting humoral autoimmunity. Thus, whilst the evidence for autoimmunity in NMGID is not strong, these studies present an interesting platform for further study.

Future Directions

It is clear that much remains unanswered in understanding the pathogenesis of the majority of NMGID. One key question is this: When a human population similarly develops, ages, and is exposed to noxious luminal contents, why do only a minority of individuals develop sensorimotor dysfunction? From a differential exposure perspective, Chagas disease (protozoal) and postinfective IBS (bacterial) have been discussed. Several studies also have addressed whether viral infection (particularly herpetoviridae) acting via a direct cytopathic effect, or mediated via the host immune response, may lead to a variety of NMGIDs with conflicting results (59–62).

From a host perspective, dysregulated immune responses to flora/pathogens in a spectrum of gastrointestinal inflammatory disorders (eg, coeliac disease, IBS, lymphocytic colitis) are the subject of much ongoing research. The gut epithelial barrier represents a highly dynamic structure that limits but does not exclude antigens from entering the tissues, and also has the ability to directly sense commensal and pathogenic microorganisms by mammalian pattern recognition receptors that recognise conserved structures of bacteria and viruses and generally activate proinflammatory pathways (63,64). Recent molecular insights in the receptors involved include Toll-like receptors and nucleotide-binding oligomerisation domain molecules (known as Nod1 and Nod2, or Card4 and Card15) have led to the finding of susceptibility genes including polymorphisms of Nod2 in Crohn disease (65). It is my view that this line of investigation and the characterisation of probiotic and colitogenic microorganisms will be most rewarding in the future understanding of NMGIDs, particularly the adult-onset varieties. Other studies focussing on genetic variation in the synthesis of other immunoregulatory cytokines are under way, but have not yielded positive results (66).


In relation to neuromuscular gastrointestinal disorders, the following are noted:

  • The current taxonomy is confusing and could be improved.
  • The significance and specificity of histopathological phenotypes should be carefully determined (especially with respect to characterising plastic changes).
  • The aetiopathogenesis is only well understood in a minority of conditions.
  • Developmental abnormalities probably account for a proportion of a small number of rare conditions, although genotyping of more common disorders may prove rewarding.
  • Exogenous injury and immune dysregulation will continue to be the most important areas of study.


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Chronic intestinal pseudoobstruction; Hirschsprung disease; MEN 2B; Mitochondriopathies; Secondary neuromuscular disorders

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