Elucidation of esophageal achalasia based on their subtypes from the multiple perspectives.

• Project/Area Number: 20K08334
• 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: Kyushu University
• Principal Investigator: IHARA EIKICHI 九州大学, 医学研究院, 准教授 (80612390)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 食道アカラシア / 高解像度食道内圧検査 / アカラシアサブタイプ

Outline of Research at the Start

食道アカラシアの病態は未だ解明されていない。最近、高解像度食道内圧検査の登場によって食道アカラシアの診断が飛躍的に発展し、3つのサブタイプに分類された。本研究では、食道運動を制御する消化管神経細胞-カハール介在細胞 (interstitial cells of Cajal;ICC)-平滑筋細胞のネットワークと各細胞機能に着目し、ブタ食道及びヒト臨床生検サンプルを用いた薬理学的解析、平滑筋収縮タンパク解析、DNAマイクロアレイ及び電顕組織学的解析に加えて、食道細菌叢解析及び数理モデル解析といった多角的な視点から食道アカラシア各サブタイプ別の病態解明に挑む。

Outline of Final Research Achievements

In this study, we elucidated the physiological mechanisms of esophageal motility and the pathology of esophageal achalasia. (1) Lower esophageal sphincter (LES) relaxation induced by stimulation of neuronal nicotinic acetylcholine receptors involves hyperpolarization of Cajal interstitial cells via the neurotransmitter ATP. (2) Myosin light chain phosphorylation level is significantly decreased in patients with esophageal achalasia. (3) Proportions of more than 20 types of bacterial including anaerobic bacteria and α-diversity were increased in esophageal flora of patients with achalasia. (4) We could create a mathematical model that imitates esophageal motility based on the results of high-resolution esophageal manometry. The internal pressure findings of esophageal achalasia could be reproduced using the model.

Academic Significance and Societal Importance of the Research Achievements

食道運動は、食道期の嚥下機能を担う。食道運動が破綻した食道運動機能障害は、つらい症状・嚥下困難から「快食」が妨げられ、生活の質を低下させるのみならず、重症化すれば「誤嚥性肺炎」をきたし生命予後に影響を及ぼすため重要な疾患である。しかしながら、これまで方法論の限界によって、食道期の嚥下機能に関する研究は発展途上であった。本研究の社会的意義は、食道運動の生理機序と破綻状態である食道アカラシアの病態の一端を解明に成功したことで、高齢社会において「快食」と「誤嚥予防」に観点から健康長寿に貢献する今後の研究開発の突破口をつくったことである。

Research Products

• [Journal Article] The treatment effects of acotiamide in esophagogastric outflow obstruction: A prospective longitudinal observational study. (2022)
  • Author(s): Ihara E, Ogino H, Muta K, Hamada S, Wada M, Hata Y, Ikeda H, Bai X, Minoda Y, Esaki M, Tanaka Y, Chinen T, Ogawa Y.
  • Journal Title: Esophagus Volume: 19 Issue: 2 Pages: 332-342
  • DOI: 10.1007/s10388-021-00887-1
  • Peer Reviewed
• [Journal Article] Determination of Region-Specific Roles of the M3 Muscarinic Acetylcholine Receptor in Gastrointestinal Motility (2022)
  • Author(s): Igarashi-Hisayoshi Yoko、Ihara Eikichi、Bai Xiaopeng、Higashi Chika、Ikeda Hiroko、Tanaka Yoshimasa、Hirano Mayumi、Ogino Haruei、Chinen Takatoshi、Taguchi Yasushi、Ogawa Yoshihiro
  • Journal Title: Digestive Diseases and Sciences Volume: 68 Issue: 2 Pages: 439-450
  • DOI: 10.1007/s10620-022-07637-y
  • Peer Reviewed
• [Journal Article] Improved esophagography screening for esophageal motility disorders using wave appearance and supra-junctional ballooning (2022)
  • Author(s): Hata Yoshitaka、Ihara Eikichi、Wada Masafumi、Tsuru Hirotaka、Muta Kazumasa、Minoda Yosuke、Bai Xiaopeng、Esaki Mitsuru、Tanaka Yoshimasa、Chinen Takatoshi、Ogino Haruei、Sakamoto Ryuichi、Ogawa Yoshihiro
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 11 Pages: 838-847
  • DOI: 10.1007/s00535-022-01913-4
  • Peer Reviewed
• [Journal Article] Involvement of interstitial cells of Cajal in nicotinic acetylcholine receptor-induced relaxation of the porcine lower esophageal sphincter (2021)
  • Author(s): Otsuka, Y. Bai, X. Tanaka, Y. Ihara, E. Chinen, T. Ogino, H. Ogawa, Y.
  • Journal Title: Eur J Pharmacol Volume: 910 Pages: 174491-174491
  • DOI: 10.1016/j.ejphar.2021.174491
  • Peer Reviewed
• [Journal Article] Physiological and pathological roles of the accommodation response in lower esophageal sphincter relaxation during wet swallows (2021)
  • Author(s): Muta K, Ihara E, Hamada S, Ikeda H, Wada M, Hata Y, Bai X, Nishihara Y, Tanaka Y, Ogino H and Ogawa Y
  • Journal Title: Scientific Report (In press) Volume: なし
  • Peer Reviewed / Open Access
• [Presentation] Usefulness of onigiri esophagography combined with an obstruction level classification system in screening esophageal motility disorders (2021)
  • Author(s): Ihara E, Hamada S, Muta K, Wada M, Hata Y, Ikeda H, Tanaka Y, Ogino H, Chinen T, Ogawa Y.
  • Organizer: Digestive Disease Week 2021
  • Int'l Joint Research
• [Presentation] Usefulness of barium esophagram with newly developed wave appearance in screening tool for esophageal motility disorders. (2020)
  • Author(s): Hata Y, Hamada S, Wada M, Ikeda H, Komori K, Ogino H, Ihara E, Akiho H and Ogawa Y
  • Organizer: Digestive Disease Week 2020
  • Int'l Joint Research