Idiopathic megacolon describes an abnormality of the colon characterized by a permanent manifold extension of the bowel diameter in the absence of an identifiable reason. The leading clinical symptom is considerable abdominal suffering from intractable chronic constipation that responds poorly to pharmacological, nonsurgical interventions . Both sexes are affected by the disease, and symptoms may start in early or late childhood or in adulthood . In its strict definition, the term idiopathic megacolon excludes congenital innervation defects such as Hirschsprung's disease as well as colon changes secondary to an underlying systemic disorder (so-called colonic pseudoobstruction). Colectomy has been shown to improve the symptoms in patients with idiopathic megacolon. If the extension of the bowel wall does not affect the rectum, simple colectomy appears to be suitable. Otherwise, restorative proctocolectomy is the method of choice .
Evidence exists that different types of alterations within the gut wall can be associated with an idiopathic megacolon. Distinct abnormalities of the enteric and/or extraenteric nervous system have been postulated as a pathophysiological basis in humans [2–4] and, more recently, the interstitial cells of Cajal (ICCs) have been assumed to play a pivotal role in this context [5–7]. ICCs are regarded as intestinal pacemaker cells and a decrease in the number and process length of ICCs has been reported in patients with megacolon or slow-transit constipation .
Further data indicate that abnormalities of smooth muscle cells within the bowel wall might also be relevant for the development of a megacolon [4,9]. For example, alterations in colonic smooth muscle cell function are regarded as the leading cause for the frequent idiopathic megacolon in cats [10,11]. Changes in the contractile protein isoform composition of smooth muscle cells have been described also in the mouse system . A recent histopathological study in humans showed that intestinal smooth muscle cells in patients with colorectal motility disorders/idiopathic megacolon display decreased myofilaments and abnormal expression patterns of smooth muscle markers such as smooth muscle myosin heavy chain, smoothelin or histone deacetylase 8, despite their normal histomorphological appearance in conventional haematoxylin–eosin stainings .
In this issue of the Journal, Meier-Ruge and colleagues  further emphasize a possible role of a metabolic defect of intestinal smooth muscle cells in the pathogenesis of idiopathic megacolon. In their study, the authors report and thereby extend previous observations that cases with idiopathic megacolon are characterized by a prominent atrophy of the collagenous tendinous connective tissue membrane of the myenteric plexus and the tendinous fibre net of the muscularis propria (so-called desmosis). This phenomenon was found to be associated with a decrease in collagen type III, but not collagen II and IV. An important functional role of the intramural tendinous fibre network (TFN) has been shown decades ago by Goerttler  who demonstrated that a normally structured TFN of the muscularis propria is essential for a coordinated gut peristalsis. It is thus reasonable to postulate that an atrophy of this well-defined structure supports intestinal dysmotility and progressive bowel extension in patients with idiopathic megacolon. According to the data of Meier-Ruge and colleagues , atrophy of the TFN seems to be an ubiquitous phenomenon in such cases. In view of the decrease in collagen type III, the authors speculate that a defect in smooth muscle collagen synthesis might be involved in the development of idiopathic megacolon (there are similarities to changes occurring in patients with Ehlers–Danlos syndrome Type IV). This is an attractive hypothesis with respect to the pathogenesis of the disease. Although convincing, their results are, however, basically descriptive at the present stage and do not allow further conclusions concerning the involved cell types, molecular changes and possible genetic influences.
There are hints that several components contribute to a coordinated intestinal peristalsis and the establishment of an intact TFN in a regulated manner, including smooth muscle cells, connective tissue elements, cells of the intestinal nervous system as well as ICCs [7,16]. For example, in a mouse model of congenital megacolon, functional and structural abnormalities in connective tissue, smooth muscle cells, and the nervous system have been shown when the Hoxa-4 gene was overexpressed . The hoxa-4 gene encodes a sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities . Such data indicate that a megacolon can be due to a genetically based injured distribution and interaction of different cellular constituents in the bowel wall. Interferences with extrinsic variables, for example, nutritional components or drugs, also have to be considered .
In conclusion, the term idiopathic megacolon describes a probably heterogeneous group of conditions comprising impaired functions of several cell types and structures within the gut wall. Innovative molecular approaches  are needed to get further insight into the aetiology and pathogenesis of this disease.
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