Novel therapy for obesity and diabetes through intestinal bile acid metabolism

• Project/Area Number: 18K08526
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Keio University
• Principal Investigator: IRIE Junichiro 慶應義塾大学, 医学部(信濃町), 講師 (70306687)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 肥満症治療 / 腸内環境 / 胆汁酸 / 腸内細菌叢 / 耐糖能障害 / 腸内細菌 / dysbiosis / メタボリックシンドローム / 肥満症 / 糖尿病 / 腸管

Outline of Final Research Achievements

We have shown that the changes in bile acid metabolism in the intestinal tract cause a deviation in the intestinal microbiota and their function to metabolize the intestinal contents, resulting in the pathophysiology of obesity and diabetes. It was revealed that intestinal bile acids have important roles to determine the composition of the intestinal microbiota and the metabolism of bile acids in the intestine in subjects with obesity and diabetes. The increase in a high-fat diet-induced bile acid secretion would cause the deviation in the intestinal microbiota and the altered intestinal microbiota would make further changes in bile acid metabolism in the initiation of high-fat diet-induced obesity and diabetes in animals and humans.

Academic Significance and Societal Importance of the Research Achievements

本検討は、高脂肪食による肥満症・糖尿病の発症において、エネルギー摂取の増加ではなく、食事の質の違いにより惹起される胆汁酸代謝の変化に注目したものであり、カロリー計算と三大栄養素の割合で論じることが多い現在の食事療法について、新たな解釈を可能とするものである。有効な治療法に乏しい肥満・糖尿病において、腸管機能の維持を意識した治療法の開発に繋がるものと考えている。本研究から得られた知見に基づき、食事の質に注目した新たな栄養処方、および腸管腔内に作用する新たな肥満・糖尿病治療薬物の開発が期待される。

Research Products

• [Journal Article] C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice (2021)
  • Author(s): Amiya Takeru、Nakamoto Nobuhiro、Irie Junichiro、Taniki Nobuhito、Chu Po-Sung、Koda Yuzo、Miyamoto Kentaro、Yamaguchi Akihiro、Shiba Shunsuke、Morikawa Rei、Itoh Hiroshi、Kanai Takanori
  • Journal Title: Diabetologia Volume: 64 Issue: 3 Pages: 603-617
  • DOI: 10.1007/s00125-020-05349-4
  • Peer Reviewed
• [Journal Article] Contribution of uremic dysbiosis to insulin resistance and sarcopenia. (2020)
  • Author(s): Uchiyama K, Wakino S, Irie J, Miyamoto J, Matsui A, Tajima T, Itoh T, Oshima Y, Yoshifuji A, Kimura I, Itoh H.
  • Journal Title: Nephrol Dial Transplant. Volume: 35 Issue: 9 Pages: 1501-1517
  • DOI: 10.1093/ndt/gfaa076
  • Peer Reviewed
• [Journal Article] 腸内細菌叢と生活習慣病 -肥満・糖尿病の病態と腸内細菌叢- 胆汁酸を介した宿主のエネルギー・糖代謝調整 (2020)
  • Author(s): 入江潤一郎, 伊藤裕
  • Journal Title: 糖尿病 Volume: 63 Pages: 377-381
  • Peer Reviewed / Open Access
• [Journal Article] 食文化と腸内細菌 -米食文化とPrevotella属- (2020)
  • Author(s): 中島裕也, 入江潤一郎, 伊藤裕
  • Journal Title: Modern Media Volume: 66 Pages: 211-215
• [Journal Article] 腸内細菌叢と内分泌代謝疾患・加齢 (2020)
  • Author(s): 加藤麻里, 入江潤一郎
  • Journal Title: 老年内科 Volume: 2 Pages: 176-183
  • NAID: 40022574808
• [Journal Article] 肥満症に対するプロバイオティクスの可能性 (2020)
  • Author(s): 杉山和俊, 入江潤一郎, 伊藤裕
  • Journal Title: カレントテラピー Volume: 38 Pages: 821-825
• [Journal Article] 肥満・炎症と腸内細菌叢 (2020)
  • Author(s): 入江潤一郎, 伊藤裕
  • Journal Title: 医学のあゆみ Volume: 274 Pages: 1036-1040
• [Journal Article] Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice (2020)
  • Author(s): Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K.
  • Journal Title: Science Volume: 367 Issue: 6481 Pages: 8429-8429
  • DOI: 10.1126/science.aaw8429
  • Peer Reviewed / Open Access
• [Journal Article] Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men (2020)
  • Author(s): Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H
  • Journal Title: Endocrine Journal Volume: 67 Issue: 2 Pages: 153-160
  • DOI: 10.1507/endocrj.EJ19-0313
  • NAID: 130007802884
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy and safety of once-weekly exenatide after switching from twice-daily exenatide in patients with type 2 diabetes (2020)
  • Author(s): Watanabe Y, Saisho Y, Inaishi J, Kou K, Yamauchi A, Kanazawa Y, Okubo Y, Tokui M, Imai T, Murakami R, Tsuchiya T, Sasaki H, Masaoka T, Irie J, Meguro S, Itoh H
  • Journal Title: J Diabetes Investig Volume: 11 Issue: 2 Pages: 382-388
  • DOI: 10.1111/jdi.13146
  • Peer Reviewed / Open Access
• [Journal Article] 糖尿病と腸内細菌:がんと腸内細菌 (2020)
  • Author(s): 竹林駿太, 入江潤一郎, 伊藤裕
  • Journal Title: 糖尿病ケア Volume: 17 Pages: 40-41
• [Journal Article] 糖尿病と腸内細菌: 腸腎連関と腸内細菌 (2020)
  • Author(s): 入江潤一郎, 伊藤裕
  • Journal Title: 糖尿病ケア Volume: 17 Pages: 37-39
• [Journal Article] Background characteristics and postoperative outcomes of insufficient weight loss after laparoscopic sleeve gastrectomy in Japanese patients. (2019)
  • Author(s): Saiki A, Yamaguchi T, Tanaka S, Sasaki A, Naitoh T, Seto Y, Matsubara H, Yokote K, Okazumi S, Ugi S, Yamamoto H, Ohta M, Ishigaki Y, et al
  • Journal Title: Ann Gastroenterol Surg. Volume: 3 Issue: 6 Pages: 638-647
  • DOI: 10.1002/ags3.12285
  • Peer Reviewed / Open Access
• [Journal Article] Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions (2019)
  • Author(s): Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I
  • Journal Title: Proc Natl Acad Sci USA Volume: 116 Issue: 47 Pages: 23813-23821
  • DOI: 10.1073/pnas.1912573116
  • Peer Reviewed / Open Access
• [Journal Article] Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids (2019)
  • Author(s): Miyamoto J, Igarashi M, Watanabe K, Karaki SI, Mukouyama H, Kishino S, Li X, Ichimura A, Irie J, Sugimoto Y, Mizutani T, Sugawara T, Miki T, Ogawa J, Drucker DJ, Arita M, Itoh H, Kimura I
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41467-019-11978-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acquired partial lipodystrophy with metabolic disease in children following hematopoietic stem cell transplantation: a report of two cases and a review of the literature. (2019)
  • Author(s): Hosokawa M, Shibata H, Hosokawa T, Irie J, Ito H, Hasegawa T
  • Journal Title: J Pediatr Endocrinol Metab Volume: 32 Issue: 5 Pages: 537-541
  • DOI: 10.1515/jpem-2018-0356
  • Peer Reviewed
• [Journal Article] Efficacy and safety of switching to insulin glargine 300 U/mL from 100 U/mL in Japanese patients with type 2 diabetes: A 12-month retrospective analysis. (2019)
  • Author(s): Sugiyama K, Meguro S, Saisho Y, Irie J, Tanaka M, Itoh H
  • Journal Title: Heliyon Volume: 5 Issue: 2 Pages: e01257-e01257
  • DOI: 10.1016/j.heliyon.2019.e01257
  • Peer Reviewed / Open Access
• [Journal Article] Societal Marketing in the Treatment of Type 2 Diabetes Mellitus: A Longitudinal Questionnaire Survey for Michelin-Starred Restaurants in Japan. (2019)
  • Author(s): Yamada S, Yamada Y, Irie J, Hara K, Kadowaki T, Atsumi Y
  • Journal Title: Int J Environ Res Public Health Volume: 16 Issue: 4 Pages: 636-636
  • DOI: 10.3390/ijerph16040636
  • Peer Reviewed / Open Access
• [Journal Article] 肥満症と腸内細菌 (2019)
  • Author(s): 中島裕也, 入江潤一郎, 伊藤裕
  • Journal Title: 最新医学 Volume: 74 Pages: 75-81
• [Journal Article] 【病気のしくみ・合併症・治療による変化がわかる 糖尿病の病態生理イラスト図鑑】食事・運動・薬 腸内細菌叢 (2019)
  • Author(s): 入江潤一郎
  • Journal Title: 糖尿病ケア Volume: 春季増刊 Pages: 180-183
• [Journal Article] メトホルミンの腸内細菌叢に対する作用 (2019)
  • Author(s): 入江潤一郎
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 49 Pages: 193-197
• [Journal Article] 【がん、糖尿病の合併症】腸内細菌と糖尿病・がん (2019)
  • Author(s): 入江潤一郎、伊藤裕
  • Journal Title: 糖尿病合併症 Volume: 33 Pages: 270-273
• [Journal Article] Oral adsorbent AST-120 ameliorates gut environment and protects against the progression of renal impairment in CKD rats. (2018)
  • Author(s): Yoshifuji A, Wakino S, Irie J, Matsui A, Hasegawa K, Tokuyama H, Hayashi K, Itoh H.
  • Journal Title: Clin Exp Nephrol. Volume: 19 Issue: 5 Pages: 1069-1078
  • DOI: 10.1007/s10157-018-1577-z
  • Peer Reviewed
• [Journal Article] Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice. (2018)
  • Author(s): Miyamoto J, Watanabe K, Taira S, Kasubuchi M, Li X, Irie J, Itoh H, Kimura I.
  • Journal Title: PLoS One. Volume: 13 Issue: 4 Pages: e0196579-e0196579
  • DOI: 10.1371/journal.pone.0196579
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of a Moderately Low Carbohydrate Diet in a 36-Month Observational Study of Japanese Patients with Type 2 Diabetes (2018)
  • Author(s): Sanada Mariko、Kabe Chinatsu、Hata Hisa、Uchida Junichi、Inoue Gaku、Tsukamoto Yoko、Yamada Yoshifumi、Irie Junichiro、Tabata Shogo、Tabata Mitsuhisa、Yamada Satoru
  • Journal Title: Nutrients Volume: 10 Issue: 5 Pages: 528-528
  • DOI: 10.3390/nu10050528
  • Peer Reviewed
• [Journal Article] Association of Maternal Factors with Perinatal Complications in Pregnancies Complicated with Diabetes: A Single-Center Retrospective Analysis. (2018)
  • Author(s): Endo S, Saisho Y, Miyakoshi K, Ochiai D, Matsumoto T, Kawano Y, Mitsuishi M, Irie J, Tanaka M, Meguro S, Tanaka M, Itoh H.
  • Journal Title: J Clin Med Volume: 7 Issue: 1 Pages: 5-5
  • DOI: 10.3390/jcm7010005
  • Peer Reviewed / Open Access
• [Journal Article] 糖尿病と腸内細菌叢のここがわからない. (2018)
  • Author(s): 入江潤一郎
  • Journal Title: Diabetes Strategy Volume: 8 Pages: 61-67
• [Journal Article] 肥満症における腸内細菌叢 (2018)
  • Author(s): 入江 潤一郎, 伊藤 裕
  • Journal Title: Bio Clinica Volume: 33 Pages: 424-428
• [Journal Article] 生活習慣病における腸内細菌叢 (2018)
  • Author(s): 入江 潤一郎, 伊藤 裕
  • Journal Title: 腎臓内科・泌尿器科 Volume: 7 Pages: 593-598
  • NAID: 40021606586
• [Journal Article] 腸内細菌叢異常が疾病を惹起するメカニズム. (2018)
  • Author(s): 入江 潤一郎, 伊藤 裕
  • Journal Title: 神経内科 Volume: 89 Pages: 179-185
• [Journal Article] メタボリックシンドロームと腸内細菌 (2018)
  • Author(s): 菊地理恵子、入江潤一郎
  • Journal Title: 機能性食品と薬理栄養 Volume: 12 Pages: 60-64
• [Presentation] 糖尿病および合併症に対する腸内細菌を応用した新規治療法 (2020)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第54回糖尿病学の進歩
  • Invited
• [Presentation] 糖エネルギー代謝異常症における腸内細菌の意義 (2020)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第24回日本心不全学会学術集会
  • Invited
• [Presentation] Gut microbiota and environment as therapeutic targets in patients with metabolic diseases. (2019)
  • Author(s): Junichiro Irie, Hiroshi Itoh
  • Organizer: International Conference on Food Factors 2019
  • Int'l Joint Research / Invited
• [Presentation] 肥満・2型糖尿病と腸内細菌叢・胆汁酸. (2019)
  • Author(s): 入江潤一郎
  • Organizer: 第41回胆汁酸研究会
  • Invited
• [Presentation] 社会環境の変化により、嗜好が変化した肥満症の一例. (2019)
  • Author(s): 清水真美子, 入江潤一郎, 後藤伸子, 喜田素子, 伊藤裕
  • Organizer: 第40回日本肥満学会学術集会, 第37回日本肥満症治療学会学術合同集会
• [Presentation] 肥満症治療における「食べたい」を考える. (2019)
  • Author(s): 後藤伸子, 入江潤一郎, 伊藤裕
  • Organizer: 第20回日本内分泌学会関東甲信越支部学術集会
  • Invited
• [Presentation] Intestinal microbiota in obesity, type 2 diabetes, dyslipidemia and cardiovascular diseases. (2019)
  • Author(s): Junichiro Irie, Ikuo Kimura, Hiroshi Itoh
  • Organizer: KSoLA-JAS Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] 減量外科術が日本人肥満症患者の腸内細菌叢と糖代謝指標に与える影響 (2019)
  • Author(s): 入江潤一郎, 菊池理恵子, 後藤伸子, 吉川絵梨, 関洋介, 笠間和典, 伊藤裕
  • Organizer: 第19回抗加齢医学会総会
• [Presentation] Intestinal microbiota in metabolic disorders. (2019)
  • Author(s): Junichiro Irie, Ikuo Kimura, Hiroshi Itoh
  • Organizer: the 62nd annual meeting of the Japan Diabetes Society
  • Invited
• [Presentation] 糖エネルギー代謝異常症と腸内細菌叢 (2019)
  • Author(s): 入江潤一郎, 木村郁夫, 菊地理恵子, 加藤麻里, 田中久美子, 藤田真隆, 杉山和俊, 永久太一, 竹林駿太, 中島裕也, 山口慎太郎, 伊藤裕
  • Organizer: 第92回日本内分泌学会学術総会
  • Invited
• [Presentation] Intestinal microbiota in metabolic disorders. (2019)
  • Author(s): Junichiro Irie, Hiroshi Itoh
  • Organizer: United States- Japan cooperative medical sciences program 21st international conference on emerging infectious diseases in the pacific rim
  • Int'l Joint Research / Invited
• [Presentation] γナイフ治療後にインスリン注射中断によるケトアシドーシスを発症した劇症1型糖尿病 (2019)
  • Author(s): 上妻嵩英, 三石正憲, 税所芳史, 中島裕也, 稲石淳, 入江潤一郎, 田中正巳, 目黒周, 伊藤裕
  • Organizer: 第56回日本糖尿病学会関東甲信越地方会
• [Presentation] 腸内細菌・腸内環境と肥満症・糖尿病 (2018)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第28回臨床内分泌Update
  • Invited
• [Presentation] メタボリックサージェリーの効果 -慢性腎臓病に対する効果と腸内細菌の変化- (2018)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第1回北日本肥満・糖尿病チーム医療セミナー
  • Invited
• [Presentation] 腸内細菌と糖尿病・がん (2018)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第33回日本糖尿病合併症学会
  • Invited
• [Presentation] 肥満症・インスリン抵抗性の治療標的としての腸内細菌 (2018)
  • Author(s): 入江潤一郎
  • Organizer: 第39回日本肥満学会学術集会
  • Invited
• [Presentation] 腸内細菌と肥満症 (2018)
  • Author(s): 入江潤一郎
  • Organizer: 星薬科大学認定薬剤師研修・日本肥満学会連携講座
  • Invited
• [Presentation] 腸内細菌と肥満症・2型糖尿病 (2018)
  • Author(s): 入江潤一郎
  • Organizer: 認定臨床栄養医研修会
  • Invited
• [Presentation] 糖尿病・インスリン抵抗性と腸内細菌 (2018)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第5回肝臓と糖尿病・代謝研究会
  • Invited
• [Presentation] The pathological roles and therapeutic implications of intestinal microbiota in obesity (2018)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 糖尿病・脂質異常症治療薬と腸内細菌叢 (2018)
  • Author(s): 入江潤一郎, 伊藤裕
  • Organizer: 第18回日本抗加齢医学会総会
  • Invited
• [Book] メタボリックサージェリー Clinical Update (2020)
  • Author(s): 入江潤一郎、伊藤裕. （監修：龍野 一郎、笠間 和典、編集：佐々木 章、石垣 泰）
  • Total Pages: 240
  • Publisher: メディカ出版
  • ISBN: 9784840472579
• [Remarks] 慶應義塾大学医学部 腎臓内分泌代謝内科 免疫・腸管代謝グループ ホームページ
  • URL: http://keio-emn.jp/research/group6/
• [Remarks] 慶應義塾大学医学部 腎臓内分泌代謝内科 免疫・腸管代謝グループ ホームページ
  • URL: https://keio-emn.jp/research/group6/
• [Remarks] 慶應義塾大学医学部 腎臓内分泌代謝内科 免疫・腸管代謝グループ
  • URL: http://keio-emn.jp/research/group6/