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.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
Biomed Pharmacother. 2021 Jul;139:111649. doi: 10.1016/j.biopha.2021.111649. Epub 2021 May 3.
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, N-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.
内脏敏感性增加和肠道屏障功能受损是肠易激综合征（IBS）病理生理学的关键因素，这些因素是通过促肾上腺皮质释放因子（CRF）-Toll 样受体 4-促炎细胞因子信号转导介导的。根皮苷是一种钠依赖性葡萄糖转运体（SGLTs）抑制剂，具有抗细胞因子特性。因此，我们假设根皮苷可能改善 IBS 患者的这些胃肠道变化，并在 LPS 或 CRF 诱导的内脏敏感性增加和结肠高通透性的大鼠 IBS 模型中测试了这一假设。通过肌电图评估结肠球囊扩张引起的腹部肌肉收缩来估计内脏疼痛阈值，通过定量测量结肠组织中吸收的 Evans 蓝来测量结肠通透性。皮下注射根皮苷可剂量依赖性抑制 LPS 诱导的内脏敏感性增加和结肠高通透性。根皮苷还阻断了 CRF 诱导的这些胃肠道变化。根皮苷已知可抑制 SGLT1 和 SGLT2，但胃内给予根皮苷可能仅抑制 SGLT1，因为肠道主要表达 SGLT1。我们发现胃内给予根皮苷没有任何作用，但伊格列净，一种口服活性和选择性 SGLT2 抑制剂，改善了 LPS 模型中的胃肠道变化。AMPK 抑制剂 Compound C、一氧化氮（NO）合成抑制剂 N-硝基-L-精氨酸甲酯和阿片受体拮抗剂纳洛酮逆转了根皮苷的作用。总之，根皮苷改善了 IBS 模型中的内脏敏感性增加和结肠高通透性。这些作用可能是由于抑制 SGLT2 引起的，并且是通过 AMPK、NO 和阿片途径介导的。根皮苷可能对 IBS 的治疗有效。
