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

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

  • Biomed Pharmacother. 2021 Jul:139:111649. doi: 10.1016/j.biopha.2021.111649.
Tsukasa Nozu 1,  Saori Miyagishi 2,  Masatomo Ishioh 2,  Kaoru Takakusaki 3,  Toshikatsu Okumura 4
Affiliations

Affiliations

  • 1 Department of Regional Medicine and Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan; Center for Medical Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan. Electronic address: tnozu@sea.plala.or.jp.
  • 2 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
  • 3 Division of Neuroscience, Department of Physiology, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
  • 4 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan; Department of General Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
PMID: 33957565 DOI: 10.1016/j.biopha.2021.111649
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.

Keywords

Gut barrier; Irritable bowel syndrome; Sodium-linked glucose transporter; Visceral sensation.

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