Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis

Black, Christopher J; Burr, Nicholas; Quigley, Eamonn Martin; Martin, Paul; Houghton, Lesley A.; Ford, Alexander C

doi:10.1053/j.gastro.2018.08.021

Cited by 128 publications

(138 citation statements)

References 37 publications

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“…As a novel class of laxatives, intestinal secretagogues, such as lubiprostone, linaclotide, elobixibat, and tenapanor, recently exhibit efficacy against chronic constipation [85,86]. Lubiprostone is a chloride channel activator that increases water secretion into the intestinal lumen and enhances colonic transit.…”

Section: Laxativesmentioning

confidence: 99%

Constipation in chronic kidney disease: it is time to reconsider

Ikee

Yano

Tsuru³

2019

Ren Replace Ther

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Constipation is highly prevalent in patients with chronic kidney disease (CKD) and is primarily characterized by decreased intestinal motility. This chronic disorder affects the quality of life of patients. However, nephrologist and dialysis clinicians have long had a disproportionately limited understanding of constipation. Accumulating evidence has revealed a relationship between constipation and cardiovascular disease and CKD. The pathogenesis of constipation in CKD patients is multifactorial: decreased physical activity, comorbidities affecting bowel movement, such as diabetes mellitus, cerebrovascular disease, and hyperparathyroidism, a restricted dietary intake of plantbased fiber-rich foods, and multiple medications, including phosphate binders and potassium-binding resins, have all been implicated. CKD is associated with alterations in the composition and function of the gut microbiota, socalled gut dysbiosis. Recent studies showed that CKD-related gut dysbiosis decreased intestinal motility via intestinal inflammation or the increased generation of gut-derived uremic toxins, such as indoxyl sulfate and pcresyl sulfate. Furthermore, the gastrointestinal secretion of mucin was found to be decreased in CKD animal models, which may delay colonic transit by diminished lubrication in the alimentary tract. Thus, CKD-related gut dysbiosis may play a role in constipation, but limited information is currently available. Since constipation is often intractable, particularly in CKD patients, every available means needs to be employed in its treatment. The effects of probiotics, prebiotics, and synbiotics on the composition of the gut microbiota and gut-derived uremic toxins have been increasingly reported. However, their effects on stool consistency or frequency in CKD patients remain unclear. Some laxatives may be beneficial for improving not only bowel habits but also gut dysbiosis. Further studies are required to elucidate the CKD-specific pathogenesis of constipation and develop novel effective treatment options.

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Section: Laxativesmentioning

confidence: 99%

Constipation in chronic kidney disease: it is time to reconsider

Ikee

Yano

Tsuru³

2019

Ren Replace Ther

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“…In addition, cGMP inhibited murine colon nociception with the effect much greater in mice with chronically induced visceral hypersensitivity (41–43). Most of these studies were undertaken to support the concept that linaclotide, which clinically is an effective laxative, reduces abdominal discomfort associated with IBS-C; with an important preliminary observation that this effect occurs even without the laxative effect occurring (19, 20).…”

Section: Discussionmentioning

confidence: 99%

“…ST is structurally and functionally related to the endogenously expressed enteric hormones guanylin and uroguanylin, as well as the synthetic peptide linaclotide, which is used to treat chronic constipation and IBS-C (9, 18). Interestingly, linaclotide has been previously reported to induce secretion of cGMP, that has been suggested as playing a role in symptomatic treatment of IBS-C (19). For this reason, apical (AP), basolateral (BL), and intracellular (IC) pools of cGMP were compared following ST exposure in the Intestine-Chip under static, flow, and flow plus rhythmic deformation (stretch) conditions.…”

Section: Introductionmentioning

confidence: 99%

Mechanical Stimuli Affect E. Coli Heat Stable Enterotoxin (ST)-Cyclic GMP Signaling in a Human Enteroid Intestine-Chip Diarrhea Model

Sunuwar

Yin²,

Kasendra³

et al. 2019

Preprint

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Modeling host-pathogen interactions with human intestinal epithelia using enteroid 20 monolayers on permeable supports (such as Transwells) represents an alternative to animal studies or 21 use of colon cancer-derived cell lines. However, the static monolayer model does not expose epithelial 22 Introduction: 43Human adult intestinal stem cell-derived enteroids/organoids retain intestinal segment-specific 44 transcriptional as well as phenotypic characteristics, that enable study of untransformed, non-cancer 45 epithelia (1)(2)(3)(4) . Enteroids are generally propagated as 3-dimensional (3D) basement membrane matrix-46 embedded spheroids that are polarized such that the inward facing apical cell surface is not directly 47 accessible. This places limitations on host-pathogen interaction studies. Enteroids grown as monolayers 48 on collagen IV-coated permeable supports overcome the challenges of 3D culture, by permitting direct 49 application of commensal organisms, pathogens, toxins, nutrients, electrolytes and drugs to the apical 50 cell surface and enabling subsequent sampling of exported metabolites from both apical and basolateral 51 surfaces (2, 5-8). 52Static enteroid monolayers do not, however, recreate mechanical forces acting on intestinal epithelia in 53 vivo (4), lacking luminal flow and blood flow (shear stress forces) and the rhythmic contractions that are 54 part of peristalsis. Although multiple efforts have yielded microengineered cell culture systems with flow 55 to recapitulate physical forces of flow and stretch in Organ-on-Chip models (9-12), evidence of discrete 56 advantages associated with inclusion of mechanical forces for modeling host-pathogen interactions 57 within human intestinal epithelia in these systems is not yet clear. In this study, we evaluated the effects 58 of mechanical forces on both baseline characteristics and the responses to heat stable enterotoxin (ST), 59 a virulence factor of enterotoxigenic E. coli (ETEC) infection that is associated with a large burden of 60 diarrheal illness in low-middle income countries (13). The model was a micro-engineered 61 polydimethylsiloxane (PDMS)-based 14, 15). The chip contains two parallel hollow 62 channels separated by a flexible permeable membrane that enables human intestinal epithelial cells to 63 be cultured in the presence of physiologically-scaled fluid shear stress forces and repetitive lateral 64 mechanical deformation (14, 15). 65 5 CA). Enteroids were cultured in a 5% CO2 atmosphere at 37°C and passaged every 7-12 days. Expansion 90 medium was supplemented with 10 μmol/L Y-27632 (Tocris) and 10 μmol/L CHIR99021 (Tocris) during 91 the first 2 days after passaging. Studies were performed with a jeunal enteroid line (passage numbers 92 30-45). 93Intestine-Chip: Organ-Chips were fabricated from PDMS and assembled as described (14, 23, 24) 94 (Emulate Inc.,Boston, MA). The top (1 mm high × 1 mm wide) and bottom (0.2 mm high x 1 mm wide) 95 channels were separated by a thin (50 μm) flexible, PDMS membrane containing 7 μm diam...

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“…There are statistically significant baseline differentials between pre-and post-TNBS VMRs at all CRD pressures ranging from 20 (non-noxious) to 60 (noxious) mm Hg intensities and this preclinical model has already predicted clinical reversal of the pain state by active drugs. 34,35 Notably, the antihyperalgesic pharmacology associated with the early phases of the TNBS models (when persistent inflammation is still present) appear to differ from the antihyperalgesic pharmacology observed after colonic histology has returned to a normative state (that phase of the model most closely modeling IBS). The model has also been useful for reverse translational studies to investigate the mechanisms of colonic hypersensitivity.…”

Section: Critic Al E Valuati On Of E Xperimental Pain Model S For Tmentioning

confidence: 99%

Critical evaluation of animal models of visceral pain for therapeutics development: A focus on irritable bowel syndrome

Johnson

Farmer

Ness

et al. 2019

Neurogastroenterology Motil

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The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut‐brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.

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Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis

Cited by 128 publications

References 37 publications

Constipation in chronic kidney disease: it is time to reconsider

Constipation in chronic kidney disease: it is time to reconsider

Mechanical Stimuli Affect E. Coli Heat Stable Enterotoxin (ST)-Cyclic GMP Signaling in a Human Enteroid Intestine-Chip Diarrhea Model

Critical evaluation of animal models of visceral pain for therapeutics development: A focus on irritable bowel syndrome

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