Tranilast alleviates visceral hypersensitivity and colonic hyperpermeability by suppressing NLRP3 inflammasome activation in irritable bowel syndrome rat models

Tsukasa Nozu; Hideyuki Arie; Saori Miyagishi; Masatomo Ishioh; Kaoru Takakusaki; Toshikatsu Okumura

doi:10.1016/j.intimp.2024.112099

Tranilast alleviates visceral hypersensitivity and colonic hyperpermeability by suppressing NLRP3 inflammasome activation in irritable bowel syndrome rat models

Int Immunopharmacol. 2024 Apr 20:133:112099. doi: 10.1016/j.intimp.2024.112099. Online ahead of print.

Authors

Tsukasa Nozu¹, Hideyuki Arie², Saori Miyagishi³, Masatomo Ishioh³, Kaoru Takakusaki⁴, Toshikatsu Okumura⁵

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: tnozu@sea.plala.or.jp.
² Department of Regional Medicine and Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
³ Department of General Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
⁴ Division of Neuroscience, Department of Physiology, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
⁵ Department of General Medicine, 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.

PMID: 38643709
DOI: 10.1016/j.intimp.2024.112099

Abstract

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1β, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1β were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1β, and tranilast inhibited these changes. β-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1β induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.

Keywords: Gut barrier; Irritable bowel syndrome; NLRP3 inflammasome; Tranilast; Visceral pain; β-hydroxy butyrate.