The management of intractable constipation has been underestimated for a long time, but with its increasing incidence, it has attracted more and more attention from researchers. Colon slow transit constipation (CSTC), also known as slow transit constipation or colonic inertia, refers to constipation caused by slow passage of bowel contents due to dysfunction of colonic transit. The etiology of the disease is unclear, the symptoms are persistent, and there are many factors affecting it. Although subtotal colectomy has achieved better results in most patients, how to diagnose CSTC more accurately and comprehensively in order to select the appropriate surgical approach to achieve better results; how to explore the pathogenesis of CSTC so as to prevent and treat it fundamentally is still a hot spot of research in this field. I. Intestinal dynamics changes in CSTC Slowed transmission in CSTC can occur in the whole colon or in a certain section of the colon. Bassotti [1] performed gastric and small bowel manometry in 21 patients with CSTC and found that 70% of the patients had sudden nonpropagating contractions during fasting and had a significantly shorter anogenital response after eating than the control group. of CSTC patients have jejunal neuromuscular dysfunction, so it is likely that the slowed colonic transmission function in some CSTC patients is only part of the generalized total bowel dysfunction. This may be one of the reasons why constipation does not resolve after total colectomy in some CSTC patients. The abnormalities of colonic dynamics in CSTC are mainly manifested by the significantly lower number and duration of colonic group motility than in the normal group. In the past, due to the limitation of technical means, studies mainly focused on the detection of sigmoid and rectal dynamics. It was suggested that the temporal and spatial uncoordination of smooth muscle contraction could manifest as abnormal excitatory contraction of the distal large intestine, resulting in resistance to the proximal intestinal fecal flow and causing slowed colonic transmission. In recent years, technological advances have made it possible to detect proximal colonic dynamics. It was found that high amplitude propagating contractions of the CSTC colon are absent or begin in the distal colon and travel significantly shorter distances, and in addition, sensation of pressure load is absent while sensation of nociception is present. In patients with severe constipation, the number of colonic giant migratory contractions is significantly reduced, the temporal phase is shortened, and there is a lack of colonic electromyographic responses after eating. This lack of postprandial reflexes suggests a neurohumoral regulation of colonic motility, and therefore the role of the enteric nervous system (ENS) in the pathogenesis of CSTC has received increasing attention. ENS and CSTC (a) Histological study of ENS in CSTC Because there are no abnormal findings in routine pathological examination, CSTC is often called “chronic idiopathic constipation” or “idiopathic slow-transit constipation”. In fact, some specific stains can reveal pathological changes in the nerves within the colonic wall of CSTC. Silverophilic staining reveals a decrease in the number of silverophilic neurons in the intermuscular plexus of the CSTC colon, and the residual cells are small, crinkled, and unevenly stained. The number of neurofilament (NF) in CSTC colonic wall was significantly reduced or even absent, and the immunoreactivity of S-100 protein was abnormally increased. NF is a type of intermediate filament, which is the main component of the neural cytoskeleton and may play an important role in macromolecular axonal transport. suggesting a proliferation of nerve support tissue in the intermuscular plexus of CSTC. This suggests that CSTC is likely to be associated with lesions of the enteric nerve and is not a simple functional disorder. (B) ENS transmitter studies in CSTC Over the past decade or so, more studies have been reported on changes in enteric nerve transmitters in CSTC, based on the understanding that CSTC must be associated with abnormalities in certain enteric neurotransmitters, and that exploring these abnormal changes in transmitters may reveal the pathogenesis of CSTC. The first to attract attention were vasoactive intestinal peptide (VIP) and substance P (SP), which is also a major inhibitory neurotransmitter in ENS and an important excitatory transmitter in SP. It was found that CSTC colonic SP content was significantly lower and SP immunoreactivity was reduced, which may be one of the reasons for the reduced colonic motility. However, unexpectedly, most studies have found reduced levels of the inhibitory neurotransmitter VIP. It has been hypothesized that the reduced VIP content is not contradictory to the result of slowed colonic transmission. When the colonic giant migratory contraction spreads downward, it must be accompanied by relaxation of the distal intestinal canal for the intestinal contents to move downward, which is called upward excitation and downward inhibition, and the reduced VIP content may impair the downward inhibition and thus lead to impaired transmission of the giant migratory contraction. Later, a variety of abnormalities of intestinal neurotransmitters such as growth inhibitor, 5-hydroxytryptamine, ATP, neuropeptide YY, and gastric actin have been reported successively, but many of the results are somewhat controversial. One of the major inhibitory neurotransmitters in the ENS is nitric oxide (NO), which must be produced in vivo by nitric oxide synthase (NOS). Most studies have found significantly elevated NOS immunoreactivity in both the intermuscular and submucosal plexus [8], which at least partially confirms the role of NOS in the pathogenesis of CSTC, and the mechanism may be that the release of NO from a large number of NOS neurons in the plexus leads to the inhibition of colonic propulsive contractions. Research on gastrointestinal neurotransmitters is still emerging, and only some neuropeptides have been found to be involved in the pathogenesis of CSTC, but the underlying coordinating mechanisms are far from being elucidated. Some neuropeptides have neurotrophic effects, such as VIP and SOM, which promote neuronal mitosis and increase neuronal survival, and 5-hydroxytryptamine, which affects the synthesis of phenotypic markers in neurons and subsequently the function of neuronal cells. In this way, it seems that the abnormal changes of enteric neurotransmitters in CSTC patients not only affect the balance of excitation and inhibition, but also may affect the development of neuronal cells and their normal function, which results in a weakened colonic dynamics. The role of interstitial cells of Cajal (ICC) in the regulation of gastrointestinal motility is receiving more and more attention. The role of ICC in the pathogenesis of CSTC has also attracted a lot of attention. Lyford reported a significant reduction in ICC throughout the colon in STC patients, and our observation of the distribution of ICC in the sigmoid colon of CSTC confirms this conclusion. c-kit signaling pathway is essential for the phenotypic stability of ICC, and blocking the c-kit pathway may lead to changes in ICC phenotype and thus loss of function. Our recent study found a significant decrease in c-kit gene and protein expression in CSTC colon, suggesting an important role of ICC in its pathogenesis. abnormalities of various neurotransmitters in CSTC colon, such as VIP, SP and NOS, have also been reported, as well as abnormalities in S-100 protein and neurofilament immunoreactivity. The question at hand is how these abnormal findings can be integrated to propose a convincing pathophysiological process. The key to solving this problem may lie in exploring in greater depth the mechanisms underlying the reduction in colonic ICC in CSTC patients and the interrelationship with abnormalities in intestinal neurotransmission. IV. Laxatives and CSTC Almost all patients with CSTC have a history of long-term laxative use, and commonly used laxatives include stimulant laxatives such as rhubarb, phenolphthalein, and senna. There is controversy as to whether some of the pathological changes found in CSTC are primary or secondary to laxative use. Rats fed with sennosides and anthraquinone for 6 months were found to have a tendency to decrease the frequency and amplitude of contractions of the descending colon. However, Fioramonti measured colonic electromyography in rats fed with sennosides for 6 months and found no abnormal electromyography. We fed rats with rhubarb or phenolphthalein for 1 to 3 months, and mimicked the characteristics of laxatives in CSTC patients by increasing the dosage of laxatives to keep half of the animals with diarrhea, and found that intestinal transmission was significantly slowed down in rats, and the frequency of colonic slow waves was slowed down. Long-term application of stimulant laxatives may cause some damage to the ENS, and Dufour reported no abnormal changes in colonic ultrastructure in mice receiving sennosides for 4 months, whereas administration of 1,8 dihydroxyanthraquinone showed significant degeneration of the axonal vacuoles of the intercolonic plexus and an increase in lysosomal-like material. The effect of anthraquinone on neuropeptides in the colon wall of rats was measured by radioimmunoassay, and it was found that the content of VIP and SOM in the mucosal, submucosal and muscular layers decreased, while the SP did not change significantly. Our study found abnormal changes in the histomorphology of the colonic ENS and some major neurotransmitters (VIP, SP, NOS, etc.) in rats fed with rhubarb or phenolphthalein for 3 months, and there were similarities with the changes in the colonic ENS of CSTC, suggesting that the neuropathological changes in the colonic wall of CSTC are related to the administration of laxatives [15]. Stimulant laxatives have an important role in the evolution of CSTC, and long-term administration may induce or exacerbate the colonic lesions and functional changes in CSTC. V. Diagnosis of CSTC The clinical diagnosis of intractable constipation is not difficult; what is difficult is to accurately classify constipation, identify the main factors causing the symptoms and take into account the concomitant secondary factors in order to correctly select a treatment plan. Two important advances have contributed significantly to the research on the diagnosis of constipation. First, a change in the concept that constipation is not a single-factor disease, but rather a group of symptoms that may be produced by a combination of multiple factors and diseases. Second, advances in research technology, including advances in colonoscopy, bowel dynamics testing, electromyographic stress testing, radiological imaging analysis techniques and even psychological research. In 1980, the Rome criteria for the diagnosis of functional constipation were finally published and immediately gained wide acceptance, making it possible for the first time to standardize the clinical diagnosis of constipation. After more than 10 years of clinical application and discussion, the Rome II criteria for the diagnosis of constipation were officially published in 1999, leading to a consensus on the classification and diagnosis of constipation. The conditions related to chronic constipation in the Rome II criteria include functional constipation, pelvic floor defecation disorder and constipated irritable bowel syndrome (IBS). In the case of CSTC, it is necessary not only to exclude organic causes and pharmacological factors, but also to understand whether there is concomitant pelvic floor dysfunction and to strictly differentiate it from constipated IBS.