The Role of Purported Mucoprotectants in Dealing with Irritable Bowel Syndrome, Functional Diarrhea, and Other Chronic Diarrheal Disorders in Adults

Chronic diarrhea is a frequent presenting symptom, both in primary care medicine and in specialized gastroenterology units. It is estimated that more than 5% of the global population suffers from chronic diarrhea. and that about 40% of these subjects are older than 60 years. The clinician is frequently faced with the need to decide which is the best therapeutic approach for these patients. While the origin of chronic diarrhea is diverse, impairment of intestinal barrier function, dysbiosis. and mucosal micro-inflammation are being increasingly recognized as underlying phenomena characterizing a variety of chronic diarrheal diseases. In addition to current pharmacological therapies, there is growing interest in alternative products such as mucoprotectants, which form a mucoadhesive film over the epithelium to reduce and protect against the development of altered intestinal permeability, dysbiosis, and mucosal micro-inflammation. This manuscript focuses on chronic diarrhea in adults, and we will review recent evidence on the ability of these natural compounds to improve symptoms associated with chronic diarrhea and to exert protective effects for the intestinal barrier

5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein-coupled receptor D.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca2+ imaging of dorsal root ganglion (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)-positive DRG neurons through a phospholipase C (PLC)- and pertussis toxin-dependent mechanism, suggesting that the effect was mediated by a G protein-coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C.BBSRC BB/R006210/1 to James R F Hockley and Ewan St John Smith Rosetrees 834 Postdoctoral Grant (A1296) awarded to James R F Hockley and Ewan St John Smit

The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis

Loss of Guanylyl Cyclase C (GCC) Signaling Leads to Dysfunctional Intestinal Barrier

Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function.Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC-/-) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN-/-) mice. IFNγ and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC-/- and UGN-/- mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC-/- mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC-/- and UGN-/- mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability.GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury

Antidiarrhoeal properties of a novel sigma ligand (JO 2871) on toxigenic diarrhoea in mice: mechanisms of action

Background and aims: Sigma ligands display antisecretory activity against various secretagogues, suggesting antidiarrhoeal properties. In this study, we evaluated: (i) the antidiarrhoeal effect of JO 2871, a high affinity sigma ligand, in three models of toxigenic diarrhoea in mice; and (ii) the site and mechanism of action of this compound. Methods: Faeces were collected after toxin or vehicle administration in male DBA2 or NMRI mice. Diarrhoea was determined by cumulative stool weight (mg) over a 120 minute period. Diarrhoea was induced by intravenous administration of Salmonella enteriditis lipopolysaccharide (LPS), or oral administration of Escherichia coli heat stable (E coli-sta) or Clostridium difficile toxins. Two sigma ligands, igmesine and JO 2871, were administered either orally or intravenously, 60 and 30 minutes before the toxins, respectively. JO 2871 was also given orally 30 minutes after E coli-sta. In addition, JO 2871 was administered intracerebroventricularly five minutes before LPS and E coli-sta. BMY 14802 (1000 μg/kg orally), a sigma receptor antagonist, or cyclosomatostatin (CSS 1 μg/kg intravenously), a somatostatin antagonist, were given five minutes prior to JO 2871 in LPS, E coli-sta, and C difficile toxin treated mice. Gastric emptying and intestinal transit were evaluated after oral JO 2871 and BMY 14802 and intravenous CSS. Results: Stool weight measured 120 minutes after administration of the toxins was significantly increased. Oral JO 2871 and igmesine dose dependently inhibited toxigenic diarrhoea in all models. ED(50) values obtained using JO 2871 (1–20 μg/kg) were more than 40 times lower than those obtained with igmesine. Oral JO 2871 given after E coli-sta also inhibited diarrhoea in a dose dependent manner (ED(50) 50 μg/kg). Both sigma ligands were active by the intravenous route on LPS and E coli-sta induced stool weight increases. JO 2871 administered intracerebroventricularly failed to block this effect at any dose tested. Both BMY 14802 and CSS reversed the antidiarrhoeal effect of oral JO 2871. JO 2871, BMY 14802, and CSS did not affect transit parameters. Conclusions: JO 2871 exerts a potent oral antidiarrhoeal effect, acting peripherally through sigma sites and somatostatin release