The main finding of our study was that patients with colonic diverticulosis have significantly reduced numbers of colonic ICC and enteric glial cells compared with controls. To our knowledge, this is the first study to have revealed such abnormalities. We focused our attention on ICC because an increasing amount of recent evidence indicates that this cell population plays a pivotal role in the regulation of intestinal motor function.11,12
This is supported by the fact that, in addition to functioning as pacemaker cells that generate slow waves, ICC mediate neurotransmission from enteric motor neurones.25
In fact, these cells are an integral part of the neuromuscular junction of the colon, and may be the primary site of innervation; neural regulation of the musculature may also occur via the ICC.26
“The reduction of interstitial cell of Cajal function might be responsible for the significant decrease in rhythmic colonic contractile patterns that we recently described in patients with diverticulosis”
The role of ICC as intestinal pacemakers has been clearly established in experimental animal models, which have shown that a lack of ICC networks leads to the absence of slow waves and is accompanied by delayed or absent intestinal motility.27,28
In the upper gastrointestinal tract a lack or paucity of ICC has been found in diseases associated with gastric and small bowel motility (diabetic gastroparesis, chronic intestinal pseudo-obstruction, etc).29,30
Data on human colonic ICC are still scarce, especially in pathological conditions, and chiefly limited to congenital diseases and slow transit constipation.15,16,31
We decided to study diverticular disease because it is a disorder with frequent and measurable alterations of colonic motility.7,8,32
We found that these patients consistently had a significant reduction of all subpopulations of ICC and of enteric glial cells, whereas the enteric neuronal population appeared to be normal. These alterations might explain the colonic motor abnormalities documented in patients with diverticulosis (increased overall motility, abnormal response to eating, retropropagation of mass movements, etc). We are presently unable to explain why decreased numbers of colonic ICC and S-100 positive cells and structures should be associated with motor abnormalities. It is possible that a reduction or loss of ICC function decreases or eliminates colonic electrical slow wave activity, thereby decreasing the contractile response and resulting in delayed transit. For example, the reduction of ICC function might be responsible for the significant decrease in rhythmic colonic contractile patterns that we recently described in patients with diverticulosis33
; in an experimental animal model these patterns appear to be driven by ICC.34
Moreover, because enteric glial cells are thought to function as intermediaries in enteric neurotransmission,35
their decrease might further weaken the already precarious neuroenteric balance described thus far.
Although ICC drive spontaneous rhythmic motility in the gut, the enteric nervous system may also play a role.36
This is particularly true in diverticulosis, where loss of smooth muscle choline acetyltransferase activity, upregulation of M3 receptors, and increased in vitro sensitivity of the smooth muscle to exogenous acetylcholine have been documented,37,38
suggesting that cholinergic denervation hypersensitivity may occur in this condition. The association of such alterations with a decrease in ICC might contribute to the motor abnormalities described in diverticulosis.
The evidence is clearly insufficient to determine whether loss of ICC in diverticulosis is a primary event or is secondary to another lesion or to the rearrangement that occurs when changes take place in the colonic wall. A mechanical factor (for instance the push leading to diverticula formation with compression/atrophy of surrounding structures, including ICC and nerve structures) cannot be ruled out.
Similar considerations on whether these changes are primary or secondary to (still) unknown factors may be applied to other pathological conditions of the colon in which a decrease of ICC has been demonstrated, such as slow transit constipation15,16
and intestinal pseudo-obstruction. In fact, in about one third of cases of intestinal pseudo-obstruction limited to the colon a consistent reduction of ICC, similar to that found here in patients with diverticulosis, has recently been described.39
However, increasing evidence from experimental animal models and reports in human subjects suggest that the ICC may play an important role in the pathophysiology of gastrointestinal motor abnormalities; these data shed new light on the mechanisms underlying diverticulosis and provide new directions for further studies on motor abnormalities in the gastrointestinal tract, with possible specific targeting of future therapeutic approaches.40
Take home messages
- Numbers of interstitial cells of Cajal and glial cells were decreased in colonic diverticular disease, whereas the numbers of enteric neurones appeared to be normal
- These findings might explain some of the large bowel motor abnormalities known to occur in diverticulosis
- Further studies are needed on motor abnormalities in the gastrointestinal tract