Intestinal Transport in Constipation and Diarrhoea

K, Ewe

doi:10.1159/000138424

Cited by 34 publications

(15 citation statements)

References 12 publications

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“…This diffusion is driven by concentration gradients created by the active transepithelial transport processes. As a consequence of alteration of the paracellular pathway, the intestinal mucosa becomes more permeable, and water and electrolytes, under the force of hydrostatic pressure, leak into the lumen, resulting in diarrhea (27). Interestingly, the ZO may be a major pathway of nutrient uptake (17).…”

Section: Discussionmentioning

confidence: 99%

Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions.

Fasano

Baudry

Pumplin

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

498

325

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Attenuated Vibrio cholerae vaccine strains specifically mutated in genes encoding cholera toxin (CT) are still capable of causing mild to moderate diarrhea. Culture supernatants of V. cholerae strains, both CT-positive and CT-negative, were examined in Ussing chambers, and a toxin was found that increases the permeability of the small intestinal mucosa by affecting the structure of the intercellular tight junction, or zonula occludens. The activity of this toxin is reversible, heat-labile, sensitive to protease digestion, and found in culture supernatant fractions containing molecules between 10 and 30 kDa in size. Production ofthis factor (named ZOT for zonula occludens toxin) correlates with diarrheagenicity of V. cholerae strains in volunteers and may represent another virulence factor of infectious diarrhea that must be eliminated to achieve a safe and effective live oral vaccine against cholera.Vibrio cholerae produces the copious diarrhea characteristic of cholera by means of a potent enterotoxin, cholera toxin (CT). The A subunit of CT, encoded by ctxA, stimulates adenylate cyclase in intestinal epithelial cells, which results in net secretion of fluid into the intestinal lumen (1). Initial recombinant V. cholerae vaccine strains, attenuated by removal of the ctxA gene, were greatly reduced in their ability to induce diarrhea in volunteers (2). However, despite the absence of CT, these strains were still capable of inducing an unacceptable amount of diarrhea. One such strain, V. cholerae CVD101, is a ctxA deletion mutant of V. cholerae strain 395 in which 94% of the sequence encoding the A1 peptide of CT has been removed (3). When evaluated in volunteer studies, CVD101 caused mild to moderate diarrhea (mean stool volume of 0.9 liter with a range of 0.3-to 2.1 liters) in 54% of subjects ingesting this organism (2). While greatly attenuated compared with the parent strain 395 [which induces a mean diarrheal stool volume of 5.5 liters with a range of 0.3-44 liters in >90% of volunteers (4)], the amount of diarrhea induced by CVD101 is still unacceptable for use of this strain as a vaccine.Given the magnitude of the diarrhea induced in the absence of CT, we hypothesized that V. cholerae produced a second toxin, which was still present in strains deleted of the ctxA sequence. To investigate this hypothesis, we examined V. cholerae strains with and without intact ctx genes by using rabbit intestinal tissue mounted in Ussing chambers, a classic technique for studying the process of transport across intestinal tissue (5, 6). The results indicate that V. cholerae produces a toxin that increases intestinal tissue conductance by altering the structure of intercellular tight junctions. Production of this toxin correlates with diarrheagenicity of V. cholerae strains in volunteers and may represent another virulence mechanism of infectious diarrhea. MATERIALS AND METHODSBacterial Strains and Growth Conditions. V. cholerae 395 is a classical Ogawa CT-positive strain that has been extensively studied in volunteer...

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Section: Discussionmentioning

confidence: 99%

Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions.

Fasano

Baudry

Pumplin

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

498

325

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“…A similar study performed in porcine ileum also showed an indirect effect of TNF-α on ion secretion [201]. Another possible mechanism is that TNF-mediated down regulation of Na + /K + -ATPase abolished sodium absorption, as the process is dependent on the function of Na + /K + -ATPase in the basolateral membrane that caused diarrhea [202]. Other mechanisms, such as inhibition of COXs [203,204], PGs [205] and cytokines such as interleukins (ILs) [206], are also implicated.…”

Section: Oral Alkalinizing Agentsmentioning

confidence: 74%

Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea

Yang¹,

Chan³

et al. 2005

CMC

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Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.

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“…CFTR is predominantly expressed in colonic crypts where it plays vital roles in regulating the secretion of electrolytes and fluid across the epithelium [18] . Abnormalities of CFTR function may result in diarrhea [19][20][21] or constipation [22,23] . Therefore, CFTR modulators might be used to treat diarrhea and constipation [24] .…”

Section: Discussionmentioning

confidence: 99%

CFTR chloride channel as a molecular target of anthraquinone compounds in herbal laxatives

Yang

et al. 2011

Acta Pharmacol Sin

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Aim: To clarify whether CFTR is a molecular target of intestinal fluid secretion caused by the anthraquinone compounds from laxative herbal plants. Methods: A cell-based fluorescent assay to measure I -influx through CFTR chloride channel. A short-circuit current assay to measure transcellular Cl -current across single layer FRT cells and freshly isolated colon mucosa. A closed loop experiment to measure colon fluid secretion in vivo. Results: Anthraquinone compounds rhein, aloe-emodin and 1,8-dihydroxyanthraquinone (DHAN) stimulated I -influx through CFTR chloride channel in a dose-dependent manner in the presence of physiological concentration of cAMP. In the short-circuit current assay, the three compound enhanced Cl -currents in epithelia formed by CFTR-expressing FRT cells with EC 50 values of 73±1.4, 56±1.7, and 50±0.5 μmol/L, respectively, and Rhein also enhanced Cl -current in freshly isolated rat colonic mucosa with a similar potency. These effects were completely reversed by the CFTR selective blocker CFTR inh -172. In in vivo closed loop experiments, rhein 2 mmol/L stimulated colonic fluid accumulation that was largely blocked by CFTR inh -172. The anthraquinone compounds did not elevate cAMP level in cultured FRT cells and rat colonic mucosa, suggesting a direct effect on CFTR activity. Conclusion: Natural anthraquinone compounds in vegetable laxative drugs are CFTR potentiators that stimulated colonic chloride and fluid secretion. Thus CFTR chloride channel is a molecular target of vegetable laxative drugs.

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Intestinal Transport in Constipation and Diarrhoea

Cited by 34 publications

References 12 publications

Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions.

Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions.

Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea

CFTR chloride channel as a molecular target of anthraquinone compounds in herbal laxatives

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