Gut-renal axis: microbiota and chronic kidney disease

• Project/Area Number: 16K19474
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Eikan Mishima 東北大学, 大学病院, 助教 (00706939)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 腸腎連関 / 慢性腎臓病 / 腸内細菌叢 / メタボローム / メタゲノム / 尿毒素 / 短鎖脂肪酸 / 無菌マウス / 腎不全 / アミノ酸 / 腸内細菌 / 臨床

Outline of Final Research Achievements

Microbiota is involved in pathophysiology of renal disease such as accumulation of uremic solutes. We compared renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles using CE-TOFMS. We revealed that 11 solutes were considered microbiota-derived uremic solutes. Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Thus, microbiota contributes to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression. We examined the effect of canagliflozin, a SGLT inhibitor, on the accumulation of uremic toxins using renal failure mice. Canagliflozin treatment significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate and altered the microbiota composition.

Research Products

• [Journal Article] Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model (2018)
  • Author(s): Mishima Eikan、Fukuda Shinji、Kanemitsu Yoshitomi、Saigusa Daisuke、Mukawa Chikahisa、Asaji Kei、Matsumoto Yotaro、Tsukamoto Hiroki、Tachikawa Tatsuki、Tsukimi Tomoya、Fukuda Noriko N、Ito Sadayoshi、Soga Tomoyoshi、Tomioka Yoshihisa、Abe Takaaki
  • Journal Title: Am J Physiol Renal Physiol Volume: 印刷中 Issue: 4 Pages: 824-833
  • DOI: 10.1152/ajprenal.00314.2017
  • Peer Reviewed / Open Access
• [Journal Article] Stress-induced tRNA cleavage and tiRNA generation in rat neuronal PC12 cells (2018)
  • Author(s): Alaa E、Mishima E、Niizuma K、Akiyama Y、Fujimura M、Tominaga T、Abe T
  • Journal Title: J Neurochem Volume: - Issue: 5 Pages: 560-569
  • DOI: 10.1111/jnc.14321
  • Peer Reviewed
• [Journal Article] Impact of the oral adsorbent AST-120 on organ-specific accumulation of uremic toxins: LC-MS/MS and MS imaging techniques (2018)
  • Author(s): Emiko Sato, Daisuke Saigusa, Eikan Mishima, Taeko Uchida, Daisuke Miura, Tomomi Morikawa-Ichinose, Kiyomi Kisu, Akiyo Sekimoto, Ritsumi Saito, Yuji Oe, Yotaro Matsumoto, Yoshihisa Tomioka, Takefumi Mori, Nobuyuki Takahashi, Hirosi Sato, Takaaki Abe, Toshimitsu Niwa, and Sadayosi Ito
  • Journal Title: Toxins Volume: 10 Issue: 1 Pages: 19-33
  • DOI: 10.3390/toxins10010019
  • URL: https://pure.teikyo.jp/en/publications/38415128-9d93-475a-999c-0ebe6631ad11
  • Peer Reviewed / Open Access
• [Journal Article] Focal Segmental Glomerulosclerosis Associated with Chronic Progressive External Ophthalmoplegia and Mitochondrial DNA A3243G Mutation. (2018)
  • Author(s): Narumi K, Mishima E, Akiyama Y, Matsuhashi T, Nakamichi T, Kisu K, Nishiyama S, Ikenouchi H, Kikuchi A, Izumi R, Miyazaki M, Abe T, Sato H, Ito S
  • Journal Title: Nephron Volume: 138 Issue: 3 Pages: 243-248
  • DOI: 10.1159/000485109
  • Peer Reviewed
• [Journal Article] Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach (2017)
  • Author(s): †Mishima, E., †Fukuda, S. (†equally contributed), Mukawa, C., Yuri, A., Kanemitsu, Y., Matsumoto, Y., Akiyama, Y., Fukuda, NN., Tsukamoto, H., Asaji, K., Shima, H., Kikuchi, K., Suzuki, T., Tomioka, Y., Soga, T., Ito, S., Abe, T.
  • Journal Title: Kidney International Volume: 92 Issue: 3 Pages: 634-645
  • DOI: 10.1016/j.kint.2017.02.011
  • Peer Reviewed / Open Access
• [Journal Article] Inherited, not acquired, Gitelman syndrome in a patient with Sj?gren’s syndrome: importance of genetic testing to distinguish the two forms (2017)
  • Author(s): Mishima E, Mori T, Sohara E, Uchida S, Abe T, Ito S.
  • Journal Title: CEN Case Reports Volume: 6 Issue: 2 Pages: 180-184
  • DOI: 10.1007/s13730-017-0271-4
  • Peer Reviewed
• [Journal Article] Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases (2017)
  • Author(s): Tetsuro Matsuhashi, Takeya Sato,（間30名）,Yuji Owada, 他9名
  • Journal Title: EBioMedicine Volume: 20 Pages: 27
  • DOI: 10.1016/j.ebiom.2017.05.016
  • NAID: 120007134536
  • URL: https://pure.teikyo.jp/en/publications/b6fee86c-4659-43f6-98ca-a57629957a0b
  • Peer Reviewed / Open Access
• [Journal Article] Selective embolization therapy for intrarenal artery stenosis causing renovascular hypertension: Efficacy and follow-up renal imaging (2017)
  • Author(s): Eikan Mishima, Takehiro Suzuki, Kazumasa Seiji, Yasutoshi Akiyama, Hideki Ota, Junichiro Hashimoto, Kei Takase, Takaaki Abe, Sadayoshi Ito
  • Journal Title: J Clin Hypertens Volume: 19 Issue: 10 Pages: 1028-1031
  • DOI: 10.1111/jch.13040
  • Peer Reviewed / Open Access
• [Journal Article] Potential Drug Interactions Mediated by Renal Organic Anion Transporter OATP4C1 (2017)
  • Author(s): Sato Toshihiro、Mishima Eikan、Mano Nariyasu、Abe Takaaki、Yamaguchi Hiroaki
  • Journal Title: J Pharmacol Exp Ther Volume: 362 Issue: 2 Pages: 271-277
  • DOI: 10.1124/jpet.117.241703
  • Peer Reviewed
• [Journal Article] A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β₁ pathways (2017)
  • Author(s): Shima, H., Sasaki, K., Suzuki, T., Mukawa, C., Obara, T., Oba, Y., Matsuo, A., Kobayashi, T., Mishima, E., Watanabe, S., Akiyama, Y., Kikuchi, K., Matsuhashi, T., Oikawa, Y., Nanto, F., Ho, H.J., Suzuki, C., Saigusa, D., Masamune, A., Tomioka, Y., Masaki, T., Ito, S., Hayashi, K.I., Abe, T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 1884-1884
  • DOI: 10.1038/s41598-017-01702-7
  • URL: https://pure.teikyo.jp/en/publications/fc29d296-8e68-4680-9b19-9fefc3896de0
  • Peer Reviewed / Open Access
• [Journal Article] 'Lead pipe'-like stiff aorta with grossly widened pulse pressure in burned-out Takayasu arteritis (2017)
  • Author(s): Eikan Mishima, Takehiro Suzuki, Junichiro Hashimoto, Takaaki Abe, Sadayoshi Ito
  • Journal Title: Eur Heart J Cardiovasc Imaging Volume: 18 Issue: 7 Pages: 819-819
  • DOI: 10.1093/ehjci/jex047
  • Peer Reviewed
• [Journal Article] Evaluation of the impact of gut microbiota on uremic solute accumulation by CE-TOFMS-based metabolomics approach (2017)
  • Author(s): Eikan Mishima, Shinji Fukuda, Chikahisa Mukawa, Akinori Yuri, Yoshitomi Kanemitsu, Yotaro Matsumoto, Yasutoshi Akiyama, Noriko N. Fukuda, Hiroki Tsukamoto, Kei Asaji, Hisato Shima, Koichi Kikuchi, Chitose Suzuki, Takehiro Suzuki, Yoshihisa Tomioka, Tomoyoshi Soga, Sadayoshi Ito and Takaaki Abe
  • Journal Title: Kidney International Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease (2016)
  • Author(s): Sato E, Mori T, Mishima E, Suzuki A, Sugawara S, Kurasawa N, Saigusa D, Miura D, Morikawa-Ichinose T, Saito R, Oba-Yabana I, Oe Y, Kisu K, Naganuma E, Koizumi K, Mokudai T, Niwano Y, Kudo T, Suzuki C, Takahashi N, Sato H, Abe T, Niwa T, Ito S
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 36618-36618
  • DOI: 10.1038/srep36618
  • URL: https://pure.teikyo.jp/en/publications/6bc0ba1e-d135-4e1a-8266-9c3afd5010a3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 腸内細菌と腎臓病 (2016)
  • Author(s): 三島英換 阿部高明
  • Journal Title: 腎・高血圧の最新治療 Volume: 5 Pages: 187-187
• [Journal Article] 腎臓・透析領域の新薬：ルビプロストン (2016)
  • Author(s): 三島英換 阿部高明
  • Journal Title: 腎と透析 Volume: 81 Pages: 243-245
• [Journal Article] 慢性腎臓病および透析患者の便秘 (2016)
  • Author(s): 三島英換 阿部高明
  • Journal Title: Medicina Volume: 53 Pages: 1420-1423
• [Journal Article] 腸内細菌と慢性腎臓病 (2016)
  • Author(s): 三島英換 福田真嗣 阿部高明
  • Journal Title: アンチ・エイジング医学 Volume: 12 Pages: 18-23
• [Presentation] Evaluation of the impact of gut microbiota on uremic solute accumulation by CE-TOFMS-based metabolomics approach (2017)
  • Author(s): Eikan Mishima, Shinji Fukuda, Takehiro Suzuki, Sadayoshi Ito, Takaaki Abe
  • Organizer: The 6th Chronic kidney disease frontier meeting
  • Place of Presentation: The castle plaza hotel（Nagoya, Japan）
  • Year and Date: 2017-02-25
  • Int'l Joint Research
• [Presentation] ウレミックトキシン蓄積における腸内細菌叢の関与の同定―無菌腎不全マウスのメタボローム解析から (2017)
  • Author(s): 三島英換 福田真嗣 鈴木健弘 伊藤貞嘉 阿部高明
  • Organizer: 第1回Uremic Toxin研究会学術集会
  • Place of Presentation: ベルサール八重洲(東京)
  • Year and Date: 2017-02-18
• [Presentation] 当初無症候性であった腎動脈脈狭窄が進行したことで短期間での腎萎縮を来した１例 (2017)
  • Author(s): 櫻田冴響 三島英換 鈴木健弘 阿部高明 伊藤貞嘉
  • Organizer: 第201回内科学会東北地方会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2017-02-18
• [Presentation] 腸腎連関：慢性腎臓病における腸内細菌叢の関与と治療介入の可能性 (2017)
  • Author(s): 三島英換 阿部高明
  • Organizer: 第40会日本高血圧学会総会
• [Presentation] ウレミックトキシン蓄積における腸内細菌叢の関与の同定―無菌腎不全マウスのメタボローム解析から― (2017)
  • Author(s): 三島英換 福田真嗣 鈴木健弘 伊藤貞嘉 阿部高明
  • Organizer: 第1回Uremic Toxin研究会学術集会
• [Presentation] たこつぼ心筋症の病態形成における発症前からの潜在的心筋虚血の進行：発症前後の心電図変化を捉えた一例から (2016)
  • Author(s): 三島英換 橋本潤一郎 竹内陽一 長澤将 阿部高明 伊藤貞嘉
  • Organizer: 第20回心血管内分泌代謝学会学術総会
  • Place of Presentation: 東京コンベンションホール（東京）
  • Year and Date: 2016-12-17
• [Presentation] 尿毒素蓄積とCKD 病態における腸内細菌叢の関与‐無菌腎不全マウスとCE-TOFMS を用いた解析‐ (2016)
  • Author(s): 三島英換、福田真嗣、島久登、菊地晃一、鈴木健弘、伊藤貞嘉、阿部高明
  • Organizer: 第7回腎不全研究会
  • Place of Presentation: 灘尾ホール（東京）
  • Year and Date: 2016-12-10
• [Presentation] Evaluation of the Impact of Gut Microbiota on Uremic Solute Accumulation by CE-TOFMS-Based Metabolomics Approach (2016)
  • Author(s): Eikan Mishima, Takehiro Suzuki, Hisato Shima, Koichi Kikuchi, Sadayoshi Ito, Takaaki Abe
  • Organizer: ASN Kidney week 2016
  • Place of Presentation: McCormick Place（Chicago, IL, US）
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] わずかな領域の腎虚血が高血圧の原因となった分枝型腎血管性高血圧の一例 (2016)
  • Author(s): 三島英換 鈴木健弘 菊地晃一 島久登 清治和将 高瀬圭 阿部高明 伊藤貞嘉
  • Organizer: 第39回日本高血圧学会学術集会
  • Place of Presentation: 国際センター（仙台）
  • Year and Date: 2016-09-30
• [Presentation] 腎動脈狭窄による腎虚血診断のためのDiffusion-Weighted MRIの有用性と臨床応用性の検討 (2016)
  • Author(s): 三島英換 大田英揮 鈴木健弘 菊地晃一 島久登 橋本潤一郎 高瀬圭 阿部高明 伊藤貞嘉
  • Organizer: 第39回日本高血圧学会学術集会
  • Place of Presentation: 国際センター（仙台）
  • Year and Date: 2016-09-30
• [Presentation] 一般住民における血中1-メチルアデノシン濃度と予後との関連性ー大迫研究ー (2016)
  • Author(s): 三島 英換、菊地 晃一、島 久登、鈴木 健弘、今井 潤、伊藤 貞嘉、阿部 高明
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-06-17
• [Remarks] 東北大学病院腎高血圧内分泌科
  • URL: http://www.int2.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学大学院医工学研究科 分子病態医工学分野
  • URL: http://plaza.umin.ac.jp/~takaabe/
• [Remarks] 東北大学病院 腎・高血圧・内分泌科
  • URL: http://www.int2.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学大学院医工学研究科 生体再生医工学講座 分子病態医工学分野
  • URL: http://plaza.umin.ac.jp/~takaabe/