Role of Micribiota and Metaborome in NAFLD

• Project/Area Number: 17H04165
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Yokohama City University
• Principal Investigator: Atsushi Nakajima 横浜市立大学, 医学研究科, 教授 (30326037)
• Co-Investigator(Kenkyū-buntansha): 今城 健人 横浜市立大学, 附属病院, 助教 (30600192)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 腸管透過性 / 腸内細菌 / NAFLD / NASH / 非アルコール性脂肪肝炎 / ＮＡＳＨ

Outline of Final Research Achievements

We found the decreased Faecalibacterium Prausnitzii (FP) abundance, hyper-intestinal permeability and high plasma endotoxin level in NAFLD patients with advanced fibrosis. In a mouse NAFLD model, the FP administration improved the intestinal barrier function and eventually prevented from developing not only liver dysfunctions but also dyslipidaemia, insulin resistance and atherosclerosis. Here we show that the high level of plasma choline that was attributable to an impaired hepatic choline uptake could travel back into the colon under the leaky gut condition. This efflux of choline increased trimethylamine which was biotransformed by intestinal microbiota and plasma level of trimethylamine-N-oxide, subsequently promoting atherosclerosis. Thus, this study implicated a novel therapeutic approach; improvement of intestinal barrier function by the FP administration as a central management for NAFLD.

Academic Significance and Societal Importance of the Research Achievements

全身疾患であるNASH/NAFLDにおける腸内細菌を軸とした病態異常の根底に腸管透過性の亢進があり、腸管のバリア機能の改善が全身疾患の治療につながるという点で当該研究領域にパラダイムシフトをもたらす結果である。現在治療薬のない本疾患の新規治療法につながる可能性がある。

Research Products

• [Journal Article] Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative (2018)
  • Author(s): 498.Chan WK, Treeprasertsuk S, Imajo K, Nakajima A, Seki Y, Kasama K, Kakizaki S, Fan JG, Song MJ, Yoon SK, Dan YY, Lesmana L, Ho KY, Goh KL, Wong VW
  • Journal Title: Aliment Pharmacol Ther Volume: 47 Issue: 6 Pages: 816-825
  • DOI: 10.1111/apt.14506
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 食事内容の変化がもたらすLeaky gut SyndromeやNASHに対するFaecalibacteriumu prausnitziiの治療効果 (2019)
  • Author(s): 小林貴、結束貴臣、中島淳
  • Organizer: 日本消化器病学会
• [Presentation] NASH における Faecalibacterium prausnitzii 減少の機序と菌体成分による治療の可能性 (2019)
  • Author(s): 小林貴、結束貴臣、中島淳
  • Organizer: 日本消化器病学会
• [Presentation] CHARACTERISTICS OF FECAL MICROBIOTA IN JAPANESE PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE: A CONNECTION AMONG GUT-PERMEABILITY, ENDOTOXIN AND NAFLD. (2017)
  • Author(s): 47.Takaomi Kessoku, Kento Imajo, Yasushi Honda, Takayuki Kato, Yuji Ogawa, Wataru Tomeno, Takuma Higurashi, Masato Yoneda, Masaki Shimakawa, Yoshiki Tanaka, Tomohiro Kawahara, Satoru Saito, Usuda Haruki, Koichiro Wada, Atsushi Nakajima
  • Organizer: AASLD
  • Int'l Joint Research