in recent years , the improvement of technology and the increase in knowledge have shifted several strongly held paradigms . this is particularly true in gastroenterology , and specifically in the field of the so - called  functional  or disease , where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have , in fact , be reconducted to an organic basis ( or , at the very least , have shown one or more demonstrable abnormalities ) . this is particularly true , for instance , for irritable bowel syndrome ( ibs ) , the prototype entity of functional gastrointestinal ( gi ) disorders , where low - grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated ( 1 , 2 ) . thus , researchers have also investigated other functional / idiopathic gi disorders , and found that some organic ground is present , such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia ( 35 ) and mucosal immune activation and mild eosinophilia in functional dyspepsia ( 6 , 7 ) . here we show evidence , based on our own and other authors work , that chronic constipation should no more be considered as a functional / idiopatic gi disorder , but instead as a true enteric neuropathic abnormality . chronic constipation is a frequent disorder , characterized by reduction of bowel movements and/or defecatory difficulties ( 8) but probably represents a multifaceted entity that may be broadly classified in two main subgroups ( i.e. , slow transit constipation , stc , and obstructed defecation , od ) ( 9 ) . the pathophysiological grounds of constipation have been traditionally attributed to the dysfunction of anorectal ( 1016 ) and/or colonic motility ( 17 , 18 ) , even though the basic mechanisms responsible for this dysfunction still remains quite obscure . however , there is some evidence that constipated patients may have qualitative and quantitative changes in the enteric nervous system ( ens ) of the colon such as abnormal enteric neurochemistry ( 1921 ) , reduction of intraganglionic neurofilaments ( 22 ) , myenteric plexus hypoganglionosis ( 23 ) , and decreased colonic interstitial cells of cajal ( icc ) ( 24 , 25 ) , even though discrepancies have been reported in other studies ( 26 , 27 ) . in these last years , thanks to the availability of full - thickness surgical specimens from patients with different subtypes of chronic constipation , we were able to investigate in a more comprehensive way some abnormalities of the ens present in these subjects . one of the subtypes of constipation more often labeled as intractable and refractory to any form of medical treatment is stc ( 28 , 29 ) , a form that sometimes requires a surgical approach ( 30 ) . in a study on surgically resected stc patients , we demonstrated that , together with an important and significant decrease of enteric neurons ( due to increased apoptotic phenomena ) and icc compared to controls , these patients also displayed a significant decrease of enteric glial cells ( egc ) in both the myenteric and the submucous plexus , a decrease not due to increased apoptotic phenomena ( 31 ) . since similar neuropathological abnormalities were found in the terminal ileum of these patients , we suggested that the neuropathologic process might not be limited to the colon in these subjects ( 32 ) . in another investigation , conducted on the ens of patients with od ( in whom the pathophysiologic mechanisms are thought to be different ) undergoing surgery for refractory symptoms , we found that , compared to control , a significant reduction of the enteric neurons only in the submucosal plexus , whereas there was a loss of egc in both the myenteric and the submucosal plexus . no differences between patients and controls were found concerning icc and the number of apoptotic neurons ( 33 ) . subsequently , we studied colonic specimens of patients with idiopathic megacolon and chagas 's disease , undergoing surgery for intractable constipation ( often the only therapeutic option in these cases ( 34 ) ; in both conditions we found a decreased number of of enteric neurons and of egc ( the latter being more accentuated in chagasic patients ) ( 35 ) . interestingly , other authors have then reported that , in patients with chagasic megacolon , the destruction of the enteric neurons is preceded by the loss of egc , leading to the hypothesis that this cell population might prevent colonic dilatation , protecting the ens against the inflammatory process and neuronal destruction ( 36 ) . chronic constipation is a frequent feature of diverticular disease of the colon ( 37 ) , but its pathophysiologic basis still remain largely unknown ( 38 ) . in particular , very few data are available concerning ens abnormalities in this condition ( 39 ) . however , we and other authors documented that these patients , compared to controls , display a normal number of myenteric and submucosal plexus neurons , whereas icc and egc are significantly decreased ( 40 , 41 ) . from the above considerations , based on our own and other authors work , it may be inferred that there is a common factor that unifies several conditions characterized by constipation , factor represented by a loss of colonic egc . this and other observations have recently spurred us and other investigators to consider this cell population as an important determinant for gastrointestinal motor activity ( especially in the colon ) ( 4245 ) and a factor of paramount importance in the pathophysiology of constipation ( 46 , 47 ) . egc represent most of the cell population of enteric ganglia , with a ratio of 4:1 compared to neurons ( 48 ) and , in addition to have a mechanical support function due to the adherence to the surface of enteric ganglia and nerve by means of filaments of glial fibrillary acidic protein ( 49 ) . also , they display several other functions such as participation in neurotransmission ( 5052 ) and promotion of synaptic communication in enteric neurons ( 53 ) , in the maintenance of the homeostatic function of the enteric neurons ( 54 , 55 ) , in inflammatory processes and immune functions of the gut ( 56 , 57 ) , and in visceral pain ( 58 ) . it must be firstly taken into account that , notwithstanding the above considerations , most data on egc function originate from animal studies , and human data ( apart from those reported above ) are very scarce . for instance , the absence of trophic glial factor is responsible for the loss of myenteric neurons containing substance p ( an excitatory transmitter ) , which in turn causes decrease of intestinal transit ( 59 ) , and the loss of egc impairs motility and transit in the gut ( 60 ) . since egc provides a feedback system for icc to modulate slow wave activity , their decrease in constipated patients , in whom icc are also often decreased or absent , might further impair the reduced pacemaker signals originating from these cells ( 61 ) . thus , on the above grounds , we have hypothesized that the decrease / loss of egc ( together with other factors , such as the concomitant decrease or loss of enteric neurons , icc , enteric neurotransmitters , variation of colonic mast cell population ( 46 , 47 , 62 ) ) plays a pivotal role in the pathogenesis of constipation . a decrease / loss of egc , through impairment of neurotrophic factors , might for instance be responsible ( similarly to that documented in experimental animal models ) for degeneration of the enteric neurons population . in this respect idiopathic  constipation in addition to the loss of egc is often documented the concomitant decrease of enteric neurons due increased apoptotic phenomena ( 31 , 32 , 63 ) ; on the other hand , in constipated patients with degenerative conditions of the central nervous system ( for instance , alzheimer 's disease ) no egc loss has been reported , and the reduction of enteric neurons is not due to apoptotic phenomena ( 64 ) . how can a selective loss / decrease of egc be explained ? interestingly , recent data suggest that an infectious agent might play a role , as shown by the localization and multiplication of mycobacterium avium subspecies and by the expression of prion protein in these cells ( 6567 ) . moreover , a role for intestinal flora in the plasticity of the ens has been recently hypothesized , since the population of egc may be modulated by altered luminal environment ( 68 ) . the decrease of egc could also be due to an aging process ( 69 , 70 ) , even though such data in human beings are only available for enteric neurons ( 71 ) . other damaging factors on the ens , such as that hypothesized by the use of anthraquinone laxatives , have not been confirmed with modern immunohistochemical techniques ( 72 ) . on the other hand , the demonstration of chromosomal abnormalities of enteric neurons and egc in severely constipated patients requiring surgery suggests the presence of a genetic background possibly responsible for the loss of these elements ( 73 ) . perhaps it is time that egc are viewed not simply as the glue of the gut , but as important and pivotal cells that synchronize the various elements of the ens . with this respect , the demonstration that several entities characterized by constipation display a decrease or loss of egc , should led ( of course , in addition to other abnormalities ) to classify constipation not as a  functional  or idiopathic  condition , but as a neuro - gliopathy of the gut ( 46 , 47 , 74 ) . further studies are needed to establish a more precise role for egc in the pathophysiology of gut motility .
chronic constipation is still considered a functional or idiopathic disorder . however , in recent years there is evidence that its pathopysiological grounds may be actually due to a complex system of abnormalities of the enteric nervous system of these patients . in particular , as reported in this review , the enteric glial cells seem to be constantly involved in constipated patients , suggesting that ( at least some forms of ) constipation should be considered as true neuro - gliopathies .