title: Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1.
abstract: OBJECTIVE
  Many patients with irritable bowel syndrome IBS not only have abdominal pain but also may suffer from visceral hypersensitivity and heighted visceral nociception. Moreover, IBS has few effective therapeutic agents and mechanisms of disease are unclear. Our goals were to (i) identify microRNA (miRNA) expression, signalling and targets in human colon (controls; patients with IBS); (ii) verify in vitro, IBS-associated changes in miRNAs, especially miR-199, which is complementary to the transient receptor potential vanilloid type 1 (TRPV1) gene; and (iii) determine whether modulating the expression of miRNAs in vivo, especially miR-199, reverses associated changes and pathological hallmarks of visceral hypersensitivity via TRPV1 signalling.
  
  
  METHODS
  We evaluated 45 patients with diarrhoea-predominant IBS (IBS-D) and 40 controls with (1) visceral pain severity score and (2) colonoscopy with biopsies. miRNA expression was evaluated in human colon following miRNA array analysis. Luciferase assays were done to confirm relationships between miR-199 and TRPV1 expression. A rat model of visceral hypersensitivity was used to study miR-199 and its target gene (TRPV1) expression in dorsal root ganglion (DRG) and colon in vivo.
  
  
  RESULTS
  Gut miR-199a/b expression in IBS-D was significantly decreased, which correlated directly with both increased visceral pain scores and TRPV1 expression. In vivo upregulation of miR-199a by intraperitoneal injection of lenti-miR-199a precursors decreased visceral hypersensitivity via diminished TRPV1 signalling.
  
  
  CONCLUSIONS
  Decreased colonic miR-199a/b correlates with visceral pain in patients with IBS-D. Similarly, reduced miR-199a expression in rat DRG and colon tissue is associated with heightened visceral hypersensitivity. In vivo upregulation of miR-199a decreases visceral pain via inhibition of TRPV1 signalling. Thus, miR-199 precursors may be promising therapeutic candidates for the treatment in patients with visceral pain.
authors: Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA Department of Veterans Affairs, Cincinnati VAMC, Cincinnati, Ohio, USA.
authors: QiQi
authors: Q
authors: Zhou
authors: Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Liuqing
authors: L
authors: Yang
authors: Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Scott
authors: S
authors: Larson
authors: Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Sapreet
authors: S
authors: Basra
authors: Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Shehzad
authors: S
authors: Merwat
authors: Department of Preventative Health & Community Medicine, Institute for Translational Science, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Alai
authors: A
authors: Tan
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Carlo
authors: C
authors: Croce
authors: Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors: G Nicholas
authors: GN
authors: Verne
mesh_terms: D000818:Animals; D003106:Colon; D005786:Gene Expression Regulation; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D010147:Pain Measurement; D014176:Protein Biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D050916:TRPV Cation Channels / Q000502:physiology*; D015854:Up-Regulation; D059265:Visceral Pain / Q000209:etiology / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C531408:mirn199 microRNA, human
keywords: IRRITABLE BOWEL SYNDROME