Identification of gut microbiota- derived metabolites and the mechanisms that impair glucose metabolism

• Project/Area Number: 17K09821
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: University of Toyama
• Principal Investigator: Fujisaka Shiho 富山大学, 学術研究部医学系, 助教 (30512082)
• Co-Investigator(Kenkyū-buntansha): 戸辺 一之 富山大学, 学術研究部医学系, 教授 (30251242) ; 薄井 勲 獨協医科大学, 医学部, 教授 (50377272)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: インスリン抵抗性 / 腸内細菌 / 腸内細菌叢 / 肥満 / 糖代謝異常 / 糖尿病 / 代謝産物

Outline of Final Research Achievements

We analyzed plasma and cecal metabolomics data of genetically different mice treated with a high fat- diet and/or antibiotics and identified several metabolites that correlated with insulin resistance of the host（Fujisaka et al. Cell Reports. 22: 3072-3086, 2018）. We also reported that Bofutsushosan (BFT), a Japanese herbal medicine which has been clinically used for constipation in Asian countries, ameliorates glucose metabolism in mice with diet-induced obesity. As the mechanism, we found that BFT modified the gut microbiota, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to attenuation of diet-induced inflammation and glucose intolerance (Fujisaka et al. Sci. Rep. 10: 5544, 2020）.

Academic Significance and Societal Importance of the Research Achievements

肥満やメタボリック症候群の人口は近年世界的に増加しており、その合併症を引き起こすインスリン抵抗性の病態を克服することは喫緊の課題である。本研究を通じ、腸内細菌叢が血中の代謝産物の量に大きな影響を及ぼし、それがインスリン抵抗性の病態に大きく関与することを見出した。また、漢方薬である防風通聖散が、腸内細菌叢を変化させることでインスリン抵抗性の病態を改善しうる多面的作用があることを見出した。インスリン抵抗性を制御する上での腸内細菌叢の新たな役割を明らかにできたと考えられる。

Research Products

• [Journal Article] Bofutsushosan improves gut barrier function with a bloom of Akkermansia muciniphila and improves glucose metabolism in mice with diet-induced obesity (2020)
  • Author(s): Fujisaka Shiho、Usui Isao、Nawaz Allah、Igarashi Yoshiko、Okabe Keisuke、Furusawa Yukihiro、Watanabe Shiro、Yamamoto Seiji、Sasahara Masakiyo、Watanabe Yoshiyuki、Nagai Yoshinori、Yagi Kunimasa、Nakagawa Takashi、Tobe Kazuyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5544-5544
  • DOI: 10.1038/s41598-020-62506-w
  • Peer Reviewed / Open Access
• [Journal Article] Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. (2018)
  • Author(s): Soto M, Herzog C, Pacheco JA, Fujisaka S, Bullock K, Clish CB, Kahn CR.
  • Journal Title: Mol Psychiatry Volume: 23 Issue: 12 Pages: 2287-2301
  • DOI: 10.1038/s41380-018-0086-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites. (2018)
  • Author(s): Fujisaka S, Avila-Pacheco J, Soto M, Kostic A, Dreyfuss JM, Pan H, Ussar S, Altindis E, Li N, Bry L, Clish CB, Kahn CR.
  • Journal Title: Ｃｅｌｌ Ｒｅｐｏｒｔｓ Volume: 22 Issue: 11 Pages: 3072-3086
  • DOI: 10.1016/j.celrep.2018.02.060
  • Peer Reviewed / Open Access
• [Journal Article] Ratio of low molecular weight serum adiponectin to the total adiponectin value is associated with type 2 diabetes through its relation to increasing insulin resistance. (2018)
  • Author(s): Iwata M, Hara K, Kamura Y, Honoki H, Fujisaka S, Ishiki M, Usui I, Yagi K, Fukushima Y, Takano A, Kato H, Murakami S, Higuchi K, Kobashi C, Fukuda K, Koshimizu Y, Tobe K.
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0192609-e0192609
  • DOI: 10.1371/journal.pone.0192609
  • Peer Reviewed / Open Access
• [Journal Article] Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. (2017)
  • Author(s): Softic S, Gupta MK, Wang GX, Fujisaka S, O'Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR.
  • Journal Title: Ｊｏｕｒｎａｌ ｏｆ Ｃｌｉｎｉｃａｌ Ｉｎｖｅｓｔｉｇａｔｉｏｎ Volume: 127 Issue: 11 Pages: 4059-4074
  • DOI: 10.1172/jci94585
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor. (2017)
  • Author(s): Ussar S, Haering MF, Fujisaka S, Lutter D, Lee KY, Li N, Gerber GK, Bry L, Kahn CR.
  • Journal Title: Diabetes Volume: 66 Issue: 4 Pages: 886-896
  • DOI: 10.2337/db15-1349
  • Peer Reviewed / Open Access
• [Journal Article] CD206+ M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors (2017)
  • Author(s): Nawaz Allah, , Usui Isao, , et al
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 286-301
  • DOI: 10.1038/s41467-017-00231-1
  • NAID: 120006535075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 肥満・糖代謝異常における腸内細菌叢の意義 (2019)
  • Author(s): 藤坂 志帆 戸邉 一之
  • Organizer: 第24回アディポサイエンスシンポジウム
  • Invited
• [Presentation] Bofutsushosan improved gut barrier function with a bloom of Akkermansia muciniphila and improves glucose metabolism in diet-induced obese mice (2018)
  • Author(s): Shiho Fujisaka, Isao Usui, Allah Nawaz, Yoshiko Igarashi, Tomonobu Kado, Okabe Keisuke, Kunimasa Yagi, Takashi Nakagawa, Kazuyuki Tobe
  • Organizer: 78th Scientific Sessions of American Diabetes Association
  • Int'l Joint Research
• [Presentation] Interaction between the gut microbiota and metabolites in insulin resistance and metabolic syndrome (2018)
  • Author(s): Fujisaka S, Soto M. Kahn CR
  • Organizer: 43rd Symposium on Hormones and Cell Regulation. European Society of Endocrinology (Symposium)
  • Int'l Joint Research / Invited
• [Presentation] 腸内細菌叢、食事、遺伝背景による代謝産物の変化と糖代謝 (2018)
  • Author(s): 藤坂 志帆，Kahn CR，戸邉 一之
  • Organizer: 第36回内分泌代謝サマーセミナー
• [Presentation] 腸内細菌叢と糖代謝異常 (2018)
  • Author(s): 藤坂 志帆, Kahn CR, 戸邉 一之.
  • Organizer: 第52回糖尿病学の進歩（シンポジウム）
  • Invited
• [Presentation] 腸内細菌叢による代謝産物の劇的変化と糖代謝. (2018)
  • Author(s): 藤坂 志帆，Kahn CR，戸邉 一之.
  • Organizer: 第23回アディポサイエンス・シンポジウム
• [Presentation] 腸内細菌叢を介した糖代謝制御 (2018)
  • Author(s): 藤坂 志帆, 戸邉 一之, Kahn CR.
  • Organizer: 日本薬学会第138年会（シンポジウム）
  • Invited
• [Presentation] 腸内細菌叢を介した糖代謝制御 (2018)
  • Author(s): 藤坂 志帆、CR Kahn、戸邉 一之
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] 防風通聖散は腸内細菌Akkermansia muciniphilaを増加させ、高脂肪食負荷マウスの糖代謝を改善する (2018)
  • Author(s): 藤坂 志帆、薄井 勲、Allah Nawaz、五十嵐 喜子、角 朝信、古澤 之裕、八木邦公、戸邉 一之
  • Organizer: 第91回日本内分泌学会学術総会
• [Presentation] 腸内細菌叢と糖代謝異常 (2018)
  • Author(s): 藤坂 志帆、CR. Kahn、戸邉 一之
  • Organizer: 第52回糖尿病学の進歩
  • Invited
• [Presentation] 防風通聖散は腸内細菌Akkermansia muciniphilaを増加させ、高脂肪食負荷マウスの耐糖能を改善する (2017)
  • Author(s): 藤坂 志帆、薄井 勲、古澤 之裕、Allah Nawaz、五十嵐 喜子、角 朝信、戸邉 一之
  • Organizer: 第22回日本肥満学会アディポサイエンス・シンポジウム
• [Presentation] Bofutsushosan, an Oriental Herbal Medicine, induces Akkermansia muciniphila and improves glucose metabolism in diet-induced obese mice. (2017)
  • Author(s): Shiho Fujisaka, Isao Usui, Yukihiro Furusawa, Allah Nawaz, Yoshiko Igarashi, Tomonobu Kado, Kazuyuki Tobe
  • Organizer: 77th Scientific Sessions of American Diabetes Association
  • Int'l Joint Research
• [Presentation] 腸内細菌叢が糖代謝に与える影響 (2017)
  • Author(s): 藤坂 志帆、C. Ronald Kahn、戸邉 一之
  • Organizer: 第60回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 腸内細菌叢の変化は血中代謝産物を劇的に変化させ耐糖能を制御する (2017)
  • Author(s): 藤坂 志帆、Jonathan Dreyfuss、Clary Clish、Lynn Bry、戸邉 一之、C.Ronald Kahn
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 腸内細菌叢を規定する遺伝背景と代謝異常 (2017)
  • Author(s): 藤坂 志帆
  • Organizer: CVMW2017 心血管代謝週間
  • Invited