研究 消化器内科

1.研究の流れ

我々は、消化器疾患のなかでも、炎症性腸疾患などの消化管疾患を中心に、膵疾患、肝疾患の研究に取り組んでいます。常に臨床と密接に関連した研究の展開を心がけ、細胞や動物レベルでの研究の結果を実際の臨床の場にフィードバックするよう努力しています。

わが国では、食事の欧米化にともなって、潰瘍性大腸炎やクローン病などの炎症性腸疾患が急増しています。しかし、未だその病因は明らかになっていません。我々は、炎症性腸疾患の病因解明へのアプローチとして、腸内環境による腸上皮細胞機能の制御機構に着目して研究を進めてきました。すなわち、腸上皮細胞の消化吸収機能や免疫機能は、食事や腸内細菌叢さらには上皮細胞を支える筋線維芽細胞などにより巧妙に制御されています。この制御機構の破綻が炎症性腸疾患の発症に結びつくと考え、さまざまな分子生物学的手法を取り入れて研究を進めています。

例えば、長鎖脂肪酸は腸上皮細胞のNF-kBの活性化を誘導しIL-8などの炎症メディエーターの放出を惹起することを見いだし、この基礎データに基づき、栄養療法における脂肪の添加がクローン病の緩解率の低下を招くことを臨床的に証明しました。腸上皮細胞に発現するアミノ酸やペプチド輸送担体の発現も、食事中に存在する基質の影響を強く受けています。

さらに、食物繊維に由来する短鎖脂肪酸の抗炎症作用を見いだし、発芽大麦由来の繊維成分を潰瘍性大腸炎の治療に応用し、その有効性を報告してきました。最近、炎症性腸疾患患者の病変粘膜においてインターロイキン(IL)-17というサイトカインの発現が増強していることを見いだし、動物モデルをもちいて抗IL-17中和抗体の効果について検討しています。 慢性膵炎は膵臓の線維化により膵外分泌、内分泌障害をもたらしますが、我々は、ヒトの膵臓より筋線維芽細胞を分離し、この細胞の炎症、線維化における意味を細胞外基質分泌能、免疫機能の面から検討しています。

2.主要研究テーマ

  1. 骨髄細胞を用いた腸管、膵組織の再生に関する研究
  2. 慢性腸炎発症におけるIL-17の意義に関する研究
  3. ヒト大腸および膵筋線維芽細胞機能の解析
  4. 腸粘膜におけるサイトカインネットワークの解析
  5. GERDおよびBarrett上皮の病因解明をめざした免疫組織化学的検討
  6. 炎症性腸疾患の病態における腸内細菌叢の関与の分子生物学的解析

3.学会活動

日本内科学会、日本消化器病学会、日本消化器内視鏡学会、日本膵臓学会

日本消化器免疫学会、日本消化吸収学会、日本肝臓学会、日本消化管学会

日本カプセル内視鏡学会、日本静脈経腸栄養学会など

4.研究業績(今年度分)

  1. Bamba S, Sakemi R, Fujii T, Takeda T, Fujioka S, Takenaka K, Kitamoto H, Umezawa S, Sakuraba H, Inokuchi T, Fukata N, Mizuno S, Yamashita M, Shinzaki S, Tanaka H, Takedatsu H, Ozaki R, Moriya K, Ishii M, Kinjo T, Ozeki K, Ooi M, Hayashi R, Kakimoto K, Shimodate Y, Kitamura K, Yamada A, Sonoda A, Nishida Y, Yoshioka K, Ashizuka S, Takahashi F, Shimokawa T, Kobayashi T, Andoh A, Hibi T. A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn's disease. J Gastroenterol. 2020 Jan 27. doi: 10.1007/s00535-020-01670-2. [Epub ahead of print]
  2. Sugitani Y, Nishida A, Inatomi O, Ohno M, Imai T, Kawahara M, Kitamura K, Andoh A. Sodium absorption stimulator prostasin (PRSS8) has an anti-inflammatory  effect via downregulation of TLR4 signaling in inflammatory bowel disease. J Gastroenterol. 2020 Jan 8. doi: 10.1007/s00535-019-01660-z. [Epub ahead of print]
  3. Koizumi Y, Okuno T, Minamiguchi H, Hodohara K, Mikamo H, Andoh A. Survival of a case of Bacillus cereus meningitis with brain abscess presenting as immune reconstitution syndrome after febrile neutropenia - a case report and literature  review. BMC Infect Dis. 2020 Jan 6;20(1):15.
  4. Morita Y, Imai T, Bamba S, Takahashi K, Inatomi O, Miyazaki T, Watanabe K, Nakamura S, Yoshida A, Endo Y, Ohmiya N, Tsujikawa T, Andoh A. Clinical relevance of innovative immunoassays for serum ustekinumab and anti-ustekinumab antibody levels in Crohn's disease. J Gastroenterol Hepatol. 2019 Dec 20. doi: 10.1111/jgh.14962. [Epub ahead of print]
  5. Andoh A. The 15th Annual Meeting of the Japanese Gastroenterological Association. Digestion. 2020;101(1):5.
  6. Chatani M, Kishita M, Inatomi O, Takahashi K, Sugimoto M, Sonoda A, Kawahara M, Bamba S, Kito K, Kushima R, Andoh A. Severe Colitis with Portal Venous Gas Caused by Brachyspira pilosicoli Infection. Intern Med. 2019;58(23):3409-3413.
  7. Kakuta Y, Izumiyama Y, Okamoto D, Nakano T, Ichikawa R, Naito T, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Kudo H, Minegishi N, Kawai Y, Tokunaga K, Nagasaki M, Kinouchi Y, Suzuki Y, Masamune A; MENDEL study group. Correction to: High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype. J Gastroenterol. 2020 Jan;55(1):132.
  8. Fukuda M, Miyake T, Matsubara A, Ikai N, Tanaka E, Namura T, Wada Y, Noujima M, Moritani S, Murakami K, Andoh A, Tani M, Kushima R. Sclerosing Mesenteritis Mimicking IgG4-related Disease. Intern Med. 2020 Feb 15;59(4):513-518.
  9. Tatsumi G, Kawahara M, Yamamoto R, Hishizawa M, Kito K, Suzuki T, Takaori-Kondo A, Andoh A. LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia. Leukemia. 2019 Nov 1. doi: 10.1038/s41375-019-0614-6. [Epub ahead of print]
  10. Kokubu H, Nishikawa J, Kato T, Imaeda H, Kito K, Andoh A, Namura T, Moritani S, Tanaka T, Fujimoto N. Sézary syndrome involving the intestinal tract. Clin Exp Dermatol. 2019 Oct 23. doi: 10.1111/ced.14131. [Epub ahead of print]
  11. Tatsumi G, Kawahara M, Imai T, Nishishita-Asai A, Nishida A, Inatomi O, Yokoyama A, Kakuta Y, Kito K, Andoh A. Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15(R138C) knock-in mice. Leukemia. 2019 Oct 24. doi: 10.1038/s41375-019-0583-9. [Epub ahead of print]
  12. Kakuta Y, Izumiyama Y, Okamoto D, Nakano T, Ichikawa R, Naito T, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Kudo H, Minegishi N, Kawai Y, Tokunaga K, Nagasaki M, Kinouchi Y, Suzuki Y, Masasmune A; MENDEL study group. High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype. J Gastroenterol. 2020 Jan;55(1):67-77.
  13. Ng SC, Kamm MA, Yeoh YK, Chan PKS, Zuo T, Tang W, Sood A, Andoh A, Ohmiya N, Zhou Y, Ooi CJ, Mahachai V, Wu CY, Zhang F, Sugano K, Chan FKL. Scientific frontiers in faecal microbiota transplantation: joint document of Asia-Pacific Association of Gastroenterology (APAGE) and Asia-Pacific Society for Digestive Endoscopy (APSDE). Gut. 2020 Jan;69(1):83-91.
  14. Andoh A, Inoue R, Kawada Y, Morishima S, Inatomi O, Ohno M, Bamba S, Nishida A, Kawahara M, Naito Y. Elemental diet induces alterations of the gut microbial community in mice. J Clin Biochem Nutr. 2019 Sep;65(2):118-124.
  15. Naganuma M, Sugimoto S, Fukuda T, Mitsuyama K, Kobayashi T, Yoshimura N, Ohi H, Tanaka S, Andoh A, Ohmiya N, Saigusa K, Yamamoto T, Morohoshi Y, Ichikawa H, Matsuoka K, Hisamatsu T, Watanabe K, Mizuno S, Abe T, Suzuki Y, Kanai T; INDIGO Study Group. Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study. J Gastroenterol. 2020 Feb;55(2):169-180.
  16. Iida H, Osaki R, Fujimoto T, Maehira H, Mori H, Kitamura N, Andoh A, Tani M. Interval between hepatocellular carcinoma treatment and interferon-free direct-acting antiviral agents against hepatitis C is necessary to suppress tumor recurrence. Mol Clin Oncol. 2019 Jul;11(1):99-105. doi: 10.3892/mco.2019.1847. Epub 2019 Apr 24.
  17. Masamune A, Nabeshima T, Kikuta K, Hamada S, Nakano E, Kume K, Kanno A, Sato A, Tachibana Y, Inatomi O, Yamamoto S, Ikeura T, Futagami S, Taguchi M, Hanada K, Shimizu K, Kageoka M, Saito T, Eguchi T, Kubota K, Takenaka M, Mima A, Irisawa A, Ito T, Andoh A, Inui K, Takeyama Y, Yamaue H, Okazaki K, Shimosegawa T. Prospective study of early chronic pancreatitis diagnosed based on the Japanese diagnostic criteria. J Gastroenterol. 2019 Jul 3. doi: 10.1007/s00535-019-01602-9. 
  18. Mori H, Miyake T, Shimizu T, Yamaguchi T, Kaida S, Takebayashi K, Iida H, Otsuki A, Inatomi O, Kitoh K, Andoh A, Tani M. A case of spontaneous colonic perforation in collagenous colitis. Surg Case Rep. 2019 May 31;5(1):90. doi: 10.1186/s40792-019-0647-0.
  19. Fukuda M, Ishigaki H, Sugimoto M, Mukaisho KI, Matsubara A, Ishida H, Moritani S, Itoh Y, Sugihara H, Andoh A, Ogasawara K, Murakami K, Kushima R. Histological  analysis of fundic gland polyps secondary to PPI therapy. Histopathology. 2019 May 14. doi: 10.1111/his.13902. 
  20. Nishida A, Imaeda H, Inatomi O, Bamba S, Sugimoto M, Andoh A. The efficacy of  fecal microbiota transplantation for patients with chronic pouchitis: A case series. Clin Case Rep. 2019 Mar 12;7(4):782-788. doi: 10.1002/ccr3.2096. eCollection 2019 Apr.
  21. Kawada Y, Naito Y, Andoh A, Ozeki M, Inoue R. Effect of storage and DNA extraction method on 16S rRNA-profiled fecal microbiota in Japanese adults. J Clin Biochem Nutr. 2019 Mar;64(2):106-111. doi: 10.3164/jcbn.18-84. Epub 2018 Dec 13.
  22. Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Andoh A. Astaxanthin, a xanthophyll carotenoid, prevents development of dextran sulphate sodium-induced murine colitis. J Clin Biochem Nutr. 2019 Jan;64(1):66-72.
  23. Yasuda H, Kataoka K, Takeyama Y, Takeda K, Ito T, Mayumi T, Isaji S, Mine T, Kitagawa M, Kiriyama S, Sakagami J, Masamune A, Inui K, Hirano K, Akashi R, Yokoe M, Sogame Y, Okazaki K, Morioka C, Kihara Y, Kawa S, Tanaka M, Andoh A, Kimura W, Nishimori I, Furuse J, Yokota I, Shimosegawa T. Usefulness of urinary trypsinogen-2 and trypsinogen activation peptide in acute pancreatitis: A multicenter study in Japan. World J Gastroenterol. 2019 Jan 7;25(1):107-117.
  24. Takahashi K, Bamba S, Morita Y, Nishida A, Kawahara M, Inatomi O, Sugimoto M, Sasaki M, Andoh A. pH-Dependent 5-Aminosalicylates Releasing Preparations Do Not Affect Thiopurine Metabolism. Digestion. 2019 Jan 2:1-9.
  25. Saida K, Kamei K, Ogura M, Matsumura S, Kano Y, Sato M, Andoh A, Ishikura K. Azathioprine-induced Agranulocytosis and Severe Alopecia After Kidney Transplantation Associated With a NUDT15 Polymorphism: A Case Report. Transplant Proc. 2018 Dec;50(10):3925-3927.
  26. Fujimoto T, Inatomi O, Mizuno R, Shintani S, Nishida A, Bamba S, Sugimoto M, Andoh A. Anaplastic pancreatic cancer diagnosed with endoscopic ultrasound guided fine needle aspiration showing hypervascular tumor: A case report. Medicine (Baltimore). 2018 Dec;97(49):e13473.
  27. Fukuda M, Ishigaki H, Ban H, Sugimoto M, Tanaka E, Yonemaru J, Kuroe S, Namura T, Matsubara A, Moritani S, Murakami K, Andoh A, Kushima R. No transformation of a fundic gland polyp with dysplasia into invasive carcinoma after 14 years of follow-up in a proton pump inhibitor-treated patient: A case report. Pathol Int. 2018 Dec;68(12):706-711.
  28. Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Andoh A. Ameliorating effects of bortezomib, a proteasome inhibitor, on development of dextran sulfate sodium-induced murine colitis. J Clin Biochem Nutr. 2018 Nov;63(3):217-223.
  29. Imai T, Inoue R, Kawada Y, Morita Y, Inatomi O, Nishida A, Bamba S, Kawahara M, Andoh A. Characterization of fungal dysbiosis in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2018 Nov 26.
  30. Hasegawa H, Bamba S, Takahashi K, Murata M, Otsuka T, Matsumoto H, Fujimoto T, Osak R, Imaeda H, Nishida A, Ban H, Sonoda A, Inatomi O, Sasaki M, Sugimoto M, Andoh A. Efficacy and safety of cold forceps polypectomy utilizing the jumbo cup: a prospective study. Intest Res. 2018 Nov 28. doi: 10.5217/ir.2018.00103.
  31. Inatomi O, Imai T, Fujimoto T, Takahashi K, Yokota Y, Yamashita N, Hasegawa H, Nishida A, Bamba S, Sugimoto M, Andoh A. Dexmedetomidine is safe and reduces the additional dose of midazolam for sedation during endoscopic retrograde cholangiopancreatography in very elderly patients. BMC Gastroenterol. 2018 Nov 6;18(1):166. doi: 10.1186/s12876-018-0897-5.
  32. Murata M, Sugimoto M, Otsuka T, Nishida A, Inatomi O, Bamba S, Andoh A. Successful Helicobacter pylori eradication therapy improves symptoms of chronic constipation. Helicobacter. 2018 Dec;23(6):e12543. doi: 10.1111/hel.12543.
  33. Gotoda T, Takano C, Kusano C, Suzuki S, Ikehara H, Hayakawa S, Andoh A. Gut microbiome can be restored without adverse events after Helicobacter pylori eradication therapy in teenagers. Helicobacter. 2018 Dec;23(6):e12541.
  34. Nakamura S, Imaeda H, Nishikawa H, Iimuro M, Matsuura M, Oka H, Oku J, Miyazaki T, Honda H, Watanabe K, Nakase H, Andoh A. Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study. Intest Res. 2018 Oct;16(4):554-562.
  35. Takahashi K, Bamba S, Kawahara M, Nishida A, Inatomi O, Sasaki M, Tsujikawa T, Kushima R, Sugimoto M, Kitoh K, Andoh A. Magnified single-balloon enteroscopy in the diagnosis of intestinal follicular lymphoma: a case series. Intest Res. 2018 Oct;16(4):628-634.
  36. Ban H, Sugimoto M, Otsuka T, Murata M, Nakata T, Hasegawa H, Inatomi O, Bamba S, Andoh A. Usefulness of the clip-flap method of endoscopic submucosal dissection: A randomized controlled trial. World J Gastroenterol. 2018 Sep 21;24(35):4077-4085.
  37. Hisamatsu T, Kunisaki R, Nakamura S, Tsujikawa T, Hirai F, Nakase H, Watanabe K, Yokoyama K, Nagahori M, Kanai T, Naganuma M, Michimae H, Andoh A, Yamada A, Yokoyama T, Kamata N, Tanaka S, Suzuki Y, Hibi T, Watanabe M; CERISIER Trial group. Effect of elemental diet combined with infliximab dose escalation in patients with Crohn's disease with loss of response to infliximab: CERISIER trial. Intest Res. 2018 Jul;16(3):494-498. doi: 10.5217/ir.2018.16.3.494. 
  38. Koizumi Y, Sakagami T, Minamiguchi H, Makino A, Aoki A, Hodohara K, Mikamo H, Andoh A, Fujiyama Y. Chylous ascites, anti-interferon-gamma autoantibody, and angioimmunoblastic T-cell lymphoma: a rare but intriguing connection over Mycobacterium avium. Med Microbiol Immunol. 2018 Aug 6. doi:10.1007/s00430-018-0555-0. 
  39. Hosoba S, Kito K, Teramoto Y, Adachi K, Nakanishi R, Asai A, Iwasa M, Nishimura R, Moritani S, Kawahara M, Minamiguchi H, Nanba E, Kushima R, Andoh A. A novel mutation causing type 1 Gaucher disease found in a Japanese patient with gastric cancer: A case report. Medicine (Baltimore). 2018 Jul;97(27):e11361.
  40. Bamba S, Takahashi K, Imaeda H, Nishida A, Kawahara M, Inatomi O, Sugimoto M, Sasaki M, Andoh A. Effect of fermented vegetable beverage containing Pediococcus pentosaceus in patients with mild to moderate ulcerative colitis. Biomed Rep. 2018 Jul;9(1):74-80.
  41. Kakuta Y, Kawai Y, Okamoto D, Takagawa T, Ikeya K, Sakuraba H, Nishida A, Nakagawa S, Miura M, Toyonaga T, Onodera K, Shinozaki M, Ishiguro Y, Mizuno S, Takahara M, Yanai S, Hokari R, Nakagawa T, Araki H, Motoya S, Naito T, Moroi R, Shiga H, Endo K, Kobayashi T, Naganuma M, Hiraoka S, Matsumoto T, Nakamura S, Nakase H, Hisamatsu T, Sasaki M, Hanai H, Andoh A, Nagasaki M, Kinouchi Y, Shimosegawa T, Masamune A, Suzuki Y; MENDEL study group. NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. J Gastroenterol. 2018 Jun 19. doi: 10.1007/s00535-018-1486-7.
  42. Otsuka T, Sugimoto M, Ban H, Nakata T, Murata M, Nishida A, Inatomi O, Bamba S, Andoh A. Severity of gastric mucosal atrophy affects the healing speed of post-endoscopic submucosal dissection ulcers. World J Gastrointest Endosc. 2018 May 16;10(5):83-92. doi: 10.4253/wjge.v10.i5.83.
  43. Yamamoto R, Kawahara M, Ito S, Satoh J, Tatsumi G, Hishizawa M, Suzuki T, Andoh A. Selective dissociation between LSD1 and GFI1B by a LSD1 inhibitor NCD38 induces the activation of ERG super-enhancer in erythroleukemia cells. Oncotarget. 2018 Apr 20;9(30):21007-21021. doi: 10.18632/oncotarget.24774. eCollection 2018 Apr 20.
  44. Koga A, Matsui T, Takatsu N, Takada Y, Kishi M, Yano Y, Beppu T, Ono Y, Ninomiya K, Hirai F, Nagahama T, Hisabe T, Takaki Y, Yao K, Imaeda H, Andoh A. Trough level of infliximab is useful for assessing mucosal healing in Crohn's disease: a prospective cohort study. Intest Res. 2018 Apr;16(2):223-232. doi: 10.5217/ir.2018.16.2.223. Epub 2018 Apr 30.
  45. Kobayashi T, Hisamatsu T, Suzuki Y, Ogata H, Andoh A, Araki T, Hokari R, Iijima H, Ikeuchi H, Ishiguro Y, Kato S, Kunisaki R, Matsumoto T, Motoya S, Nagahori M, Nakamura S, Nakase H, Tsujikawa T, Sasaki M, Yokoyama K, Yoshimura N, Watanabe K, Katafuchi M, Watanabe M, Hibi T. Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries. Intest Res. 2018 Apr;16(2):168-177. doi: 10.5217/ir.2018.16.2.168.
  46. Sugimoto M, Yasuda H, Andoh A. Nutrition status and Helicobacter pylor infection in patients receiving hemodialysis. World J Gastroenterol. 2018 Apr 21;24(15):1591-1600.

2016年度以降の研究業績についてはこちらを御覧ください。