Phlorizin attenuates visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome.

Abstract

Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4-pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.

• Authors: Tsukasa Nozu, Saori Miyagishi, Masatomo Ishioh, Kaoru Takakusaki, Toshikatsu Okumura
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 139 Pg. 111649 (Jul 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 33957565 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Lipopolysaccharides
• Naloxone
• Corticotropin-Releasing Hormone
• Phlorhizin
• NG-Nitroarginine Methyl Ester

Topics

• Abdominal Muscles (drug effects)
• Animals
• Colon (drug effects, metabolism)
• Corticotropin-Releasing Hormone (pharmacology)
• Dose-Response Relationship, Drug
• Electromyography
• Hyperalgesia (drug therapy)
• Injections, Subcutaneous
• Irritable Bowel Syndrome (drug therapy)
• Lipopolysaccharides (pharmacology)
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Naloxone (pharmacology)
• Permeability
• Phlorhizin (antagonists & inhibitors, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley