2. Academic Validation
  3. Bombesin improves visceral hypersensitivity and colonic hyperpermeability via BB1 receptor-dependent multi-pathway mechanisms in a rat model of irritable bowel syndrome

Bombesin improves visceral hypersensitivity and colonic hyperpermeability via BB1 receptor-dependent multi-pathway mechanisms in a rat model of irritable bowel syndrome

  • Eur J Pharmacol. 2026 Feb 15:1015:178566. doi: 10.1016/j.ejphar.2026.178566.
Tsukasa Nozu 1,  Saori Miyagishi 2,  Masatomo Ishioh 3,  Kaoru Takakusaki 4,  Toshikatsu Okumura 5
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; Department of General Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. Electronic address: [email protected].
  • 2 Department of General Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. Electronic address: [email protected].
  • 3 Department of General Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. Electronic address: [email protected].
  • 4 Division of Neuroscience, Department of Physiology, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. Electronic address: [email protected].
  • 5 Department of General Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. Electronic address: [email protected].
PMID: 41548687 DOI: 10.1016/j.ejphar.2026.178566
Abstract

Visceral hypersensitivity and impaired gut barrier function, along with immune dysregulation, are hallmarks of irritable bowel syndrome (IBS). Key contributors to these gastrointestinal (GI) disturbances include corticotropin-releasing factor (CRF), Toll-like Receptor 4 (TLR4) and proinflammatory cytokine signaling. Bombesin-related peptides and their receptors (BB1 and BB2) are widely expressed in the central nervous system and peripheral tissues, particularly within the GI tract, where they regulate gut function and exert anti-inflammatory effects. We hypothesized that bombesin could improve visceral hypersensitivity and restore gut barrier integrity to alleviate IBS symptoms. Using lipopolysaccharide (LPS)- and CRF-induced IBS rat models, visceral pain was assessed by electromyographic recording of abdominal muscle contractions during colonic balloon distention, and colonic permeability was measured by Evans blue dye absorption. Colonic occludin expression and interleukin (IL)-1β levels were quantified by immunoblotting and ELISA. Intraperitoneal bombesin dose-dependently attenuated LPS- and CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were abolished by BB1 receptor antagonism and reproduced by BB1 receptor activation, whereas BB2 receptor activation was ineffective. Mechanistic analyses revealed involvement of multiple gut-brain axis pathways, including AMP-activated protein kinase, GABAA, nitric oxide, opioid, peripheral CRF receptor subtype 2, Neurotensin Receptor 1 signaling, and central orexin, dopamine D2 and muscarinic receptors. Bombesin also prevented LPS-induced reductions in occludin expression and increases in colonic IL-1β. Collectively, these findings demonstrate that bombesin ameliorates IBS-related GI alterations via BB1 receptor-dependent modulation of diverse gut-brain signaling networks, leading suppression of proinflammatory cytokine activity, highlighting its therapeutic potential for IBS.

Keywords

BB(1) receptor; Bombesin; Gut barrier; Irritable bowel syndrome; Visceral pain.

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