Research for induction or normalization factor for colonic TRPV4 methylation aiming at curing constipation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08366
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Toyama
• Principal Investigator: Mihara Hiroshi 富山大学, 学術研究部医学系, 助教 (00612623)
• Co-Investigator(Kenkyū-buntansha): 内田 邦敏 静岡県立大学, 食品栄養科学部, 准教授 (20581135) ; 南條 宗八 富山大学, 学術研究部医学系, 助教 (70649285)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 慢性便秘 / TRPV4 / 腸内細菌 / 大腸菌 / 腸球菌 / K.oxytoca / 上皮

Outline of Final Research Achievements

TRPV4 ion channel, a receptor for stretching and microinflammation, was highly expressed in the epithelium in constipated patients from the small intestine to the rectum and was associated with decreased stool frequency and duration of disease. When colon epithelial cell lines and bacteria were co-cultured, bacteria was divided into those that transiently decreased, those that remained constant, and those that increased TRPV4 expression. ; K.oxytoca, E.faecalis, and E.coli increased TRPV4 expression; the bacteria themselves did not increase the expression, but culture components did. Butyrate, a short-chain fatty acid, and TNF-α inhibitors suppressed increased expression, and constipation symptoms were associated with the ratio of E.faecalis in the colonic mucosa of constipated patients, suggesting that maintaining butyrate-producing bacteria and suppressing the TNF-α pathway may prevent or treat chronic constipation.

Free Research Field

消化器

Academic Significance and Societal Importance of the Research Achievements

慢性便秘症は有病率5％の高頻度疾患であり、今後も増加することが危惧されている。その慢性便秘症において、腸内細菌のTRPV4発現増加への影響及び、酪酸とTNFα阻害による発現増加抑制効果が明らかとなったことにより、慢性便秘症の病態解明及び、酪酸産生菌投与や、TNFα阻害剤の新規治療法の開発につながり、患者のQOL向上、医療費低減につながる可能性がある。また、TRPV4は結腸以外の消化管だけでなく、膀胱、皮膚、気管などの細菌が暴露する上皮でTRPV4が生理的機能、病態に関与していることが知られており、他領域疾患の研究への波及効果が期待される。