Investigation of the pathogenesis of pulmonary hypertension focused on the impact of intestinal dysbiosis

• Project/Area Number: 17K09604
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: TANABE Nobuhiro 千葉大学, 大学院医学研究院, 特任教授 (40292700)
• Co-Investigator(Kenkyū-buntansha): 重城 喬行 千葉大学, 大学院医学研究院, 特任助教 (90736422) ; 坂尾 誠一郎 千葉大学, 大学院医学研究院, 准教授 (80431740) ; 國澤 純 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 ワクチン・アジュバント研究センター, センター長 (80376615)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺高血圧症 / 腸内細菌叢 / 病態機序 / 肺高血圧 / 病態メカニズム / 慢性血栓塞栓性肺高血圧症 / 炎症 / 肺循環

Outline of Final Research Achievements

In this study, it was reported that gut microbiota plays a causative role in the development of pulmonary arterial hypertension (PAH). We investigated the following two points: (1) whether the alteration of gut microbiota in pulmonary hypertension exists and (2) whether the alteration is a cause or a result of the development of pulmonary hypertension. First, we collected fecal samples from PAH rats (Su/Hx) and control rats. Thereafter, 16s rRNA sequencing was conducted. The 16s RNA analysis demonstrated the difference in the compositions of gut microbiota between the two groups. Moreover, Su/Hx rats were treated with four antibiotics (Su/Hx + ABx) in order to alter the gut microbiota. The Su/Hx + ABx rats had a different composition of gut microbiota and less severe pulmonary hypertension compared to Su/Hx rats. These results suggested that gut microbiota can be a causative factor in the development of PAH and may offer a new approach in the prevention of PAH in the future.

Academic Significance and Societal Importance of the Research Achievements

本研究の意義は腸内細菌叢の異常が肺高血圧症の病態進展に与える要因の一つとなりうること、何らかの方法により腸内細菌叢を改変することで肺高血圧症の進行を予防することができることを明らかにした点にある。これまでBMPR2やALK1などの肺高血圧症と関連した遺伝子異常を持つなどの明確なリスクを持っている患者において発症を予防する方法は発見されていなかった。本研究の成果は何らかの方法で腸内細菌叢を改変することで肺高血圧症の進行を予防することができる可能性を示すものである。さらに将来的には腸内環境を整える食生活の改善、腸内ワクチンによる肺高血圧症予防法の開発へつながっていくことも期待される。

Research Products

• [Journal Article] Gut microbiota modification suppresses the development of pulmonary arterial hypertension in a Su/Hx rat model (2020)
  • Author(s): Takayuki Jujo Sanada, Koji Hosomi, Hiroki Shoji, Jonguk Park, Akira Naito, Yumiko Ikubo, Asako Yanagisawa, Takayuki Kobayashi, Hideki Miwa, Rika Suda, Seiichiro Sakao, Kenji Mizuguchi, Jun Kunisawa, Nobuhiro Tanabe, Koichiro Tatsumi
  • Journal Title: Pulmonary Circulation Volume: - Issue: 3 Pages: 1-10
  • DOI: 10.1177/2045894020929147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The effect of altering gut microbiota on the development of pulmonary hypertension (2019)
  • Author(s): Jujo T, Tanabe N, Hosomi K, Shoji H, Park J, Ikubo Y, Yanagisawa A, Kobayashi T, Yamamoto K, Miwa H, Naito A, Kasai H, Suda R, Sekine A, Nishimura R, Sugiura T, Shigeta A, Sakao S, K Mizuguchi, J Kunisawa J, Tatsumi K
  • Organizer: European Resripatory Society International Congress 2019
  • Int'l Joint Research