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Chronic constipation is a common gastrointestinal disease severely affecting the patient׳s quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical...
Citations
... В исследовании была изучена степень влияния дисплазии соединительной ткани на состояние структуры и функции ободочной кишки у 130 больных с диагностированным синдромом раздраженного кишечника. Было установлено, что дисплазия является фактором, усиливающим клинические проявления, связанные с повышенной чувствительностью прямой кишки, снижением качества жизни, присоединением депрессивной и ипохондрической реакции на патологию, а также более тяжелыми вегетативными нарушениями и тревогой, которые имеют конституциональный характер [28]. ...
This paper presents a review of the literature, which covers the main issues of the etiology and pathogenesis of chronic colonic stasis, starting from the era of Avicenna to modern views. Various classifications are provided, covering all the nuances of this polyetiological problem, and risk factors that contribute to the development of such a severe pathology.
... Lubiprostone, an activator of voltage-gated ClC-2 channels, was recently launched as the first Cl − channel modulator to treat chronic constipation. 86) We are optimistic for the future development of Cl − channel modulators as drugs for various diseases. ...
Cl⁻ influx and efflux through Cl⁻ channels play a role in regulating the homeostasis of biological functions. Therefore, the hyperfunction or dysfunction of Cl⁻ channels elicits pathological mechanisms. The Cl⁻ channel superfamily includes voltage-gated Cl⁻ (ClC) channels, Ca²⁺-activated Cl⁻ channels (ClCa; TMEM16A/TMEM16B), cystic fibrosis transmembrane conductance regulator channels, and ligand-gated Cl⁻ channels. These channels are ubiquitously expressed to regulate ion homeostasis, muscle tonus, membrane excitability, cell volume, survival, neurotransmission, and transepithelial transport. The activation or inhibition of Cl⁻ channels changes the membrane potential, thereby affecting cytosolic Ca²⁺ signals. An elevation in cytosolic [Ca²⁺] triggers physiological and pathological responses in most cells. However, the roles of Cl⁻ channels have not yet been examined as extensively as cation (Na⁺, Ca²⁺, and K⁺) channels. We recently reported the functional expression of: (i) TMEM16A/ClCa channels in portal vein and pulmonary arterial smooth muscle cells (PASMC), pinealocytes, and brain capillary endothelial cells; (ii) TMEM16B/ClCa channels in pinealocytes; (iii) ClC-3 channels in PASMC and chondrocytes; and (iv) ClC-7 channels in chondrocytes. We also showed that the down-regulation of TMEM16A and ClC-7 channel expression was associated with cirrhotic portal hypertension and osteoarthritis, respectively, whereas the enhanced expression of TMEM16A and ClC-3 channels was involved in the pathogenesis of cerebral ischemia and pulmonary arterial hypertension, respectively. Further investigations on the physiological/pathological functions of Cl⁻ channels will provide insights into biological functions and contribute to the screening of novel target(s) of drug discovery for associated diseases.
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... Для регуляции стула ряд специалисты рекомендуют внести коррекцию в рацион питания пациента путём назначения частого и дробногопитания с использованием продуктов с содержанием клетчатки, приём большого количества жидкости в объеме 2 и более литров в течение суток, а также поддерживать активный образ жизни [31,32]. Другие же авторы не выявили наличие прямой связи между объёмом принятой жидкости и восстановлением частоты и характера стула, если у пациента отсутствовали симптомы обезвоживания [33]. ...
The article provides a review of the literature data on the study of diagnostics and the choice of a conservative or surgical method for the treatment of chronic colonic stasis (CCS). The literature data on the information content of various methods for diagnosing malformations and fixation of the colon, studying the rate of movement of intestinal contents along the colonic part of the gastrointestinal tract are presented. It has been established that in the diagnosis of chronic colonic stasis there are a number of difficulties, for the solution of which it is necessary to use a complex of various methods of instrumental diagnostics. The views on conservative treatment and approaches to the choice of surgical treatment option for CCS are highlighted. Literature data indicate that the most accurate indications for the use of conservative or surgical methods of treatment have not yet been established, and criteria for selecting patients have not been established.
... Bile acids (BAs) are synthesized in the liver, and up to 95% of intestinal bile acids are reabsorbed by ileal bile acid transporters located in the terminal ileum and returned to the liver via the portal vein; only small amounts of bile acids spill over to the colon [49]. BAs might participate in the pathophysiology of constipation; patients with diarrhea had higher levels of BAs in feces than those with constipation [50], and an increase in fecal bile acids is significantly associated with accelerated colonic transit [51,52]. ...
Structural changes in the gut microbiota are closely related to the development of functional constipation, and regulating the gut microbiota can improve constipation. Rifaximin is a poorly absorbed antibiotic beneficial for regulating gut microbiota, but few studies have reported its effects on constipation. The purpose of this study was to investigate the effect of rifaximin on loperamide-induced constipation in SD rats. The results showed that rifaximin improved constipation by increasing serum 5-HT, SP, and the mRNA expression of AQP3, AQP8, and reducing the mRNA expression of TLR2 and TLR4. In addition, rifaximin could regulate the gut microbiota of constipated rats, such as increasing the potentially beneficial bacteria Akkermansia muciniphila and Lactobacillus murinus, reducing the Bifidobacterium pseudolongum. According to metabolomics analysis, many serum metabolites, including bile acids and steroids, were changed in constipated rats and were recovered via rifaximin intervention. In conclusion, rifaximin might improve loperamide-induced constipation in rats by increasing serum excitatory neurotransmitters and neuropeptides, modulating water metabolism, and facilitating intestinal inflammation. Muti-Omics analysis results showed that rifaximin has beneficial regulatory effects on the gut microbiota and serum metabolites in constipated rats, which might play critical roles in alleviating constipation. This study suggests that rifaximin might be a potential strategy for treating constipation.
... Water and sodium metabolism, intestinal inflammation are interacting factors during the disease course of constipation, which participate in intestinal motility and the balance of intestinal barrier (27)(28)(29). AQP3 is a water channel protein required to promote glycerol permeability and water transport across cell membranes (30). There is increasing evidence demonstrating that AQP3 in involved in inflammatory diseases including atopic dermatitis, psoriasis, allergy, and cancer progression, using AQP3 −/− mice and AQP3-knockdown cells (31-33). ...
Background
Constipation is common gastrointestinal disorder with high prevalence and recurrence, making people suffering. However, the treatment for constipation remains ineffectual. We aimed to the study the effects and mechanisms of postbiotic of hawthorn-probiotic on loperamide modeled old KM mice.
Methods
Constipated mice were grouped and treated with 10% lactulose (Y), hawthorn group (S), probiotic group (F) and postbiotic of hawthorn-probiotic (FS). Fecal changes were observed. AQP3 and Enac-γ were measured by RT-qPCR and Western blotting, intestinal barrier by H&E and immunofluorescence staining, cell proliferation and apoptosis by CCK8 and flow cytometry. Gut microbiota was further determined by 16 s rRNA sequence of feces.
Results
Postbiotic of hawthorn-probiotic improved intestinal movement and pathomorphology, elevated AQP3, Enac-γ and mucin-2 expression, accompanied by decreased serum TNF-α and cell apoptosis, but increased proliferation. Furthermore, it modified the gut microbiota of constipated mice, featured by upregulation of Lactobacillaceae.
Conclusion
Postbiotic of hawthorn-probiotic relieved constipation by combined effects of regulating intestinal water and sodium metabolism, maintain intestinal barrier and gut microflora.
Graphical Abstract
... However, these chemical substances sometimes present setbacks such as high cost, accessibility, stomach pain and cramps among others. Other laxative drugs currently used for the treatment of constipation include lubiprostone, linaclotide, prucalopride (Jiang et al., 2015) alvimopan, and methylnaltrexone (Coss-Adame and Rao, 2012). These drugs are classified under serotonin (5-HT4) agonists that act by releasing acetylcholine which in turn improves bowel movement. ...
... These drugs are classified under serotonin (5-HT4) agonists that act by releasing acetylcholine which in turn improves bowel movement. Aside the cost and ease of availability of these drugs to the locals, they have been reported to cause diarrhea, nausea and headache (Jiang et al., 2015). Based on this, the study aimed to research on alternative means of treatment for constipation through the use of Securinega virosa plant. ...
Constipation is the inability of individuals to empty the bowel for a period of three times a week which causes discomfort and even sometimes lead to colorectal cancer. This work was aimed at estimating the laxative potential of ethanol leaf extract of Securinega virosa in constipated rats induced with loperamide. Experimental adult rats were induced with 3 mg/kg body weight of loperamide, while the normal control received normal saline solution. Upon confirmation of constipation, the rats were treated with 50, 100 and 200 mg/kg body weight of ethanol leaf extract of Securinega virosa for 7 days. Senokot was used as the reference drug. During the study period, faecal properties, feed intake, water intake, body weight gain and intestinal motility were recorded. The treatment of constipated rats with 50, 100 and 200 mg/kg body weight greatly improved the faecal properties, decreased body weight and elevated water intake statistically at p ≤ 0.05 as well as the gastrointestinal motility when compared with the constipated untreated experimental group. These proved the laxative effect of the plant, with the best dose being 200 mg of the extract. Thus these results evidenced the ethnobotanical usage of Securinega virosa in the treatment of constipation.
... With its role in promoting motility and intestinal secretion control, 5-HTR4 has been targeted in diseases associated with slow GI transit, such as IBS-C (Cole and Rabasseda, 2004). Prucalopride, a very highly selective 5-HTR4 agonist, is developed as an orally administered, first-in-class drug for treatment of severe chronic constipation (Jiang et al., 2015). ...
... Prucalopride, a highly selective 5-HTR4 agonist, is a first-inclass drug for severe chronic constipation treatment (Jiang et al., 2015). Prucalopride treatment can improve stool frequency and consistency, enhanced colonic transit in chronic constipation patients (Müller-Lissner et al., 2010). ...
Slow transit constipation is an intractable constipation with unknown aetiology and uncertain pathogenesis. The gut microbiota maintains a symbiotic relationship with the host and has an impact on host metabolism. Previous studies have reported that some gut microbes have the ability to produce 5-hydroxytryptamine (5-HT), an important neurotransmitter. However, there are scarce data exploiting the effects of gut microbiota-derived 5-HT in constipation-related disease. We genetically engineered the probiotic Escherichia coli Nissle 1917 (EcN-5-HT) for synthesizing 5-HT in situ. The ability of EcN-5-HT to secrete 5-HT in vitro and in vivo was confirmed. Then, we examined the effects of EcN-5-HT on intestinal motility in a loperamide-induced constipation mouse model. After two weeks of EcN-5-HT oral gavage, the constipation-related symptoms were relieved and gastrointestinal motility were enhanced. Meanwhile, administration of EcN-5-HT alleviated the constipation related depressive-like behaviors. We also observed improved microbiota composition during EcN-5-HT treatment. This work suggests that gut microbiota-derived 5-HT might promise a potential therapeutic strategy for constipation and related behavioral disorders.
... Comprehensive use of 14 diagnostic gut microbiota and metabolite biomarkers may accurately distinguish STC and healthy population with AUC = 0.877. transported to the colon (Jiang et al., 2015). BAs can activate intracellular adenylate cyclase, increase the permeability of the intestinal mucosa, promote intestinal electrolyte and water secretion, strengthen colonic transmission, and stimulate defecation (Chedid et al., 2018). ...
... Animal studies have shown that BAs directly induce accelerated colonic motility (Traub et al., 2008;Kim et al., 2017). Therefore, supplementation of the proper amount of specific BA analogs or the use of drugs that inhibit the reabsorption of ileal BAs is beneficial to improve the clinical symptoms of patients with constipation, and has become one of the new treatment options for the treatment of STC (Jiang et al., 2015). Elobixibat is a highly selective ASBT inhibitor whose mechanism of action is to reduce the ileum reabsorption of BAs and increase the concentration of BAs entering the colon. ...
Destructions in the intestinal ecosystem are implicated with changes in slow transit constipation (STC), which is a kind of intractable constipation characterized by colonic motility disorder. In order to deepen the understanding of the structure of the STC gut microbiota and the relationship between the gut microbiota and fecal metabolites, we first used 16S rRNA amplicon sequencing to evaluate the gut microbiota in 30 STC patients and 30 healthy subjects. The α-diversity of the STC group was changed to a certain degree, and the β-diversity was significantly different, which indicated that the composition of the gut microbiota of STC patients was inconsistent with healthy subjects. Among them, Bacteroides, Parabacteroides, Desulfovibrionaceae, and Ruminiclostridium were significantly upregulated, while Subdoligranulum was significantly downregulated. The metabolomics showed that different metabolites between the STC and the control group were involved in the process of bile acids and lipid metabolism, including taurocholate, taurochenodeoxycholate, taurine, deoxycholic acid, cyclohexylsulfamate, cholic acid, chenodeoxycholate, arachidonic acid, and 4-pyridoxic acid. We found that the colon histomorphology of STC patients was significantly disrupted, and TGR5 and FXR were significantly downregulated. The differences in metabolites were related to changes in the abundance of specific bacteria and patients’ intestinal dysfunction. Analysis of the fecal genomics and metabolomics enabled separation of the STC from controls based on random forest model prediction [STC vs. control (14 gut microbiota and metabolite biomarkers)—Sensitivity: 1, Specificity: 0.877]. This study provided a perspective for the diagnosis and intervention of STC related with abnormal bile acid metabolism.
... 60 Lubiprostone is a prosecretory agent that causes chloride secretion into intestine by opening the chloride channel protein two. 61 Lubiprostone increases spontaneous bowel movements within 24 to 48 hours following the initial dose. The most frequent dose-dependent adverse effects of lubiprostone are headache nausea, and diarrhea. ...
Constipation is a commonly reported disorder in many patients. Constipation treatment using laxatives on a regular and long term basis can lead to patient dependence, especially among the elderly. However, there is scanty data on the habit-forming potential of laxatives in Indian constipated patients. This review has explored literature evidence and expert opinion on patients’ experience regarding habit-forming attributes of stimulant and osmotic laxatives. Additionally, structured face-to-face discussions were conducted with 2 key opinion leaders to understand their clinical experience on the habit-forming aspects stimulant and osmotic laxatives in patients with constipation. Based on literature evidence, lactulose is not known to lead to any habit-forming behaviors in patients. Furthermore, experts pointed out that dependence on stimulant laxatives is common, but not on osmotic laxatives, and emphasized that milk of magnesia is not habit forming. In conclusion, no habit-forming characteristics or dependence was observed with the use of osmotic laxatives in India. Nevertheless, real-world, studies exploring patient and physician perspectives are warranted to establish the dependence and habit forming attributes of laxatives.
... Nonselective 5-HT 4 receptor agonists, including tegaserod, have reported cardiovascular adverse events [3]. In contrast, highly selective 5-HT 4 agonists, such as prucalopride, velusetrag, and naronapride, have demonstrated favorable safety and efficacy in the treatment of chronic constipation [4,5]. Prucalopride is the first approved selective 5-HT 4 receptor agonist, but it has a lower efficacy compared with tegaserod in many preclinical models [6,7]. ...
DA-6886 is a novel serotonin (5-hydroxytrypamine [5-HT]) receptor 4 agonist for the potential treatment of constipation-predominant irritable bowel syndrome. The purpose of this study was to validate the quantitative assay of DA-6886 in rat plasma and to evaluate the pharmacokinetics and tissue distribution of DA-6886 in rats. The liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the robust quantification of DA-6886 in rat plasma was successfully validated and applied to the pharmacokinetic studies in rats. The pharmacokinetic parameters of DA-6886 in rats were evaluated following single intravenous or oral administration at three dose levels (2, 10, and 20 mg/kg). DA-6886 exhibited a smaller dose-normalized area under the plasma concentration–time curve (AUC) values and faster clearances in the low-dose group than in the high-dose group following both intravenous and oral administration. The steady-state volume of distribution (Vss) of DA-6886 was relatively large (4.91–7.84 L/kg), which was consistent with its high distribution to the liver, kidney, lung, and digestive tract, and was dose-independent. After oral administration, the extent of absolute bioavailability (F) tended to increase (18.9–55.0%) with an increasing dose. The slope of the log-transformed AUC and/or Cmax values versus log dose was greater than unity and greater for oral administration (~1.9) than for intravenous administration (~1.1). Because the nonlinear pharmacokinetics of DA-6886 was more obviously observed after oral administration, it appears that the saturation of pre-systemic intestinal and/or hepatic first-pass extraction of DA-6886 at high doses occurred.
