Table 2.
Summary of published literature on the role of soluble mediators in IBS
| Supernatant of Stool or Mucosal Biopsies | Patient Group | Receptor/Mechanism of Action | Biological Effect | Citation (Ref. no.) |
|---|---|---|---|---|
| CPA from FSN | Sum of two cohorts; 26 IBS-D, 44 IBS-C, 56 HC | CPA levels are increased in IBS-C vs. HC and IBS-D | Level of CPA correlated with pain. Increased visceral hypersensitivity in PAR2-deficient and normal mice infused with FSN from high-CPA IBS-C vs. normal-CPA IBS-C and HC. | Annahazi et al. (2) |
| Decreased occludin in mice and T84 cells after repeated infusion of FSN in IBS-C vs. HC and in colonic mucosal biopsies in 8 IBS-C vs. 6 HC. | Increased intestinal permeability in PAR2 knockout mice and T84 cells infused with FSN in high-CPA IBS-C vs. normal-CPA IBS-C and HC. | |||
| Serine protease from mucosal biopsies | 10 IBS-D, 5 IBS-C, 12 HC | Activation of PAR2 receptors | Increased hyperexcitability in DRG neurons from wild-type mice vs. PAR2-deficient mice in IBS-D vs. IBS-C and HC. | Valdez Morales et al. (52) |
| CPA from mucosal biopsies | Cysteine protease receptor | Increased hyperexcitability in DRG neurons from mice in 1 IBS-D. | ||
| Serine protease (tryptase), histamine and serotonin from mucosal biopsies | 7 IBS-D, 4 IBS-C, 5 HC | Serine protease, serotonin and histamine receptors | Activation of submucosal neurons in surgical specimen of human colon, mediated by H1–H3, 5HT3 and serine protease receptors. | Buhner et al. (8) |
| Mucosal biopsies | 17 IBS-D, 19 IBS-C, 15 IBS-A, 14 HC | Incubation with IBS SUP (all subtypes) decreased ZO-1 mRNA expression in Caco-2 cells | Increased intestinal permeability in Caco-2 cells incubated with SUP of 39 IBS patient (15 IBS-C, 14 IBS-D, 14 IBS-A) vs. 14 HC. | Piche et al. (43) |
| Decreased ZO-1 expression in colonic biopsies of 21 IBS vs. 12 HC | Increased permeability in colonic biopsies of 12 IBS (3 IBS-C, 4 IBS-D, 5 IBS-A) vs. 5 HC | |||
| Serine proteases from FSN | 24 IBS-D, 18 IBS-C, 10 IBS-A, 17 UC | Activation of PAR2 receptors | Increased visceral hypersensitivity in wild-type mice vs. PAR2-deficient mice | Gesce et al. (27) |
| 23 INF, 25 HC | Increased phosphorylation of myosin light chain; internalization of ZO-1 | Increased permeability in wild-type mice vs. PAR2-deficient mice | ||
| 22 IBS-D, 17 HC | PAR2-mediated increased brain-derived neurotrophic factor expression in Caco-2 cells and mice; p38 MAPK phosphorylation in Caco-2 cells. | Increased visceral hypersensitivity in mice | Wang et al. (56) | |
| Serine proteases from mucosal biopsies | 20 IBS-D, 10 IBS-C, 10 IBS-M, 11 HC | PAR2 mediated increased 5,6-EET in DRG neurons from mice and increased stimulation of transient receptor potential vanilloid-4 in mice treated with SUP in IBS-D vs. HC. | Increased visceral hypersensitivity in mice exposed to SUP in IBS-D patients. | Cenac et al. (15) |
| Histamine | 8 IBS, 7 HC | Mouse single-serosal afferents and DRG sensitized by SUP in IBS compared with control. | Effect mediated by HRH1 interacting with TRPV1. | Wouters et al. (58) |
| 55 IBS patients (44 analyzed) | HRH1 antagonist decreased the potentiating effect of SUP on DRG neurons in IBS-D patients. | Ebastine, HRH1 antagonist, decreased rectal sensation, abdominal pain, and improved quality of life compared with placebo in a group of IBS patients. | ||
| Reactive oxygen species from mucosal biopsies | 14 PI IBS-D, 12 HC | Activation of PAR2 receptors on mast cells in rats. | Mast cell activation in rats with production of histamine. | Han et al. (29) |
| Mesotrypsin in colonic mucosal biopsies | 10 IBS, 9 HC | Response to inflammatory stimuli and induction of hyperexcitability of mouse DRG neurons in a PAR2-dependent fashion | Intestinal epithelial cells produce and release mesotrypsin in IBS and upon inflammatory stimulation, specifically at their basolateral side. | Fourcade et al. (24); Lopez-Lopez et al. (37) |
CPA, cysteine proteases; FSN, fecal supernatant; protease activated receptors, PAR2; H, histamine; HC, healthy controls; 5-HT, serotonin; ZO-1, zonula occludens-1; EET, epoxyeicosatrienoic acid; MAPK mitogen-activated protein kinase; IBS-A, alternating-pattern irritable bowel syndrome; UC, ulcerative colitis; INF, infectious acute diarrhea; SUP, supernatant; DRG, dorsal root ganglion; HRH1, histamine receptor H1; TRPV1, transient reporter potential channel V1.