Analysis of intestinal and oral bacterial flora in patients with ulcerative colitis aimed for optimization of treatment

• Project/Area Number: 19K08381
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kansai Medical University (2020-2021); Keio University (2019)
• Principal Investigator: NAGANUMA Makoto 関西医科大学, 医学部, 教授 (00265810)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腸内細菌叢 / 疾患活動性 / カルプロテクチン / 潰瘍性大腸炎 / 難治性 / 5-ASA製剤不耐

Outline of Research at the Start

潰瘍性大腸炎の病因に関する研究は、免疫学的機序に関する研究が中心であり、その成果は多くの治療薬の開発につながっているが、近年環境因子の一つである腸内細菌叢に関する研究が注目を浴びている。本研究では腸内細菌叢の異常が潰瘍性大腸炎患者の予後に与えている影響を明らかにし、さらに治療戦略を確立することを目標とする。以下の３点について研究を行う。
1)　既存治療抵抗・長期寛解維持被験者に特異的な腸内細菌叢・口腔内細菌叢および代謝産物の同定
2)　UCの基本治療薬である5-ASA製剤不耐の細菌学的機序の解明
3)　細菌叢パターンによる予後予測因子の同定と治療への応用

Outline of Final Research Achievements

It has been reported that intestinal dysbiosis is partially involved in the etiology and pathophysiology of ulcerative colitis (UC), which is a refractory inflammatory disease. There are few studies to evaluate whether intestinal dysbiosis is associated with the long-term prognosis of UC. In this study, we performed a bacterial flora analysis by the 16S rRNA-sequencing method on the relationship between activity, refractory, clinical relapse and intestinal flora disturbance and bacterial species differences. A decrease in the genus Bifidobacterium was confirmed in patients with both clinically severe UC and high fecal calprotectin levels. In the refractory cases, the Shannon index was lower than in the non-refractory cases, but no significantly difference could be confirmed in the bacterial species between refractory and no-refractory group. Significant differences in the two bacterial flora contributing to clinical relapse were also confirmed in this study.

Academic Significance and Societal Importance of the Research Achievements

潰瘍性大腸炎（Ulcerative colitis；UC）の病態に腸内細菌叢の構成異常（dysbiosis）が指摘されているが，腸内細菌叢の構成と寛解期UC患者の予後の関連についての検討は少ない。本研究において寛解期UCの再燃予測における腸内細菌叢解析の有用性が確認された。UCに対するプロバイオティクスの有用性はcontroversialであるが、UC患者の便中菌叢解析により、有効例の絞り込みをおこなえる可能性が示唆された。

Research Products

• [Journal Article] Prospective feasibility study of indigo naturalis ointment for chemotherapy-induced oral mucositis (2022)
  • Author(s): Hirata K, Yamada Y, Hamamoto Y, Tsunoda K, Muramatsu H, Horie S, Sukawa Y, Naganuma M, Nakagawa T, Kanai T
  • Journal Title: BMJ Support Palliat Care . Volume: Oct 14 Issue: e3 Pages: e1001-e1007
  • DOI: 10.1136/bmjspcare-2021-003199
  • Peer Reviewed
• [Journal Article] Potential benefits of immunomodulator use with vedolizumab for maintenance of remission in ulcerative colitis (2022)
  • Author(s): Naganuma Makoto, Watanabe Kenji, Motoya Satoshi, Ogata Haruhiko, Matsui Toshiyuki, Suzuki Yasuo, ursos Lyann, Sakamoto Shigeru, Shikamura Mitsuhiro, Hori Tetsuharu, Frenandez Jovelle, Watanabe Mamoru, Hibi Toshifumi, Kanai Takanori
  • Journal Title: J Gastroenterol Hepatol. Volume: 1 Issue: 1 Pages: 81-88
  • DOI: 10.1111/jgh.15667
  • Peer Reviewed
• [Journal Article] A review on the current status and definitions of activity indices in inflammatory bowel disease: how to use indices for precise evaluation (2022)
  • Author(s): Kishi M, Hirai F, Takatsu N, Hisabe T, Takada Y, Beppu T, Takeuchi K, Naganuma M, Ohtsuka K, Watanabe K, Matsumoto T, Esaki M, Koganei K, Sugita A, Hata K, Futami K, Ajioka Y, Tanabe H, Iwashita A, Shimizu H, Arai K, Suzuki Y, Hisamatsu T.
  • Journal Title: J Gastroenterol. Volume: 4 Issue: 4 Pages: 246-266
  • DOI: 10.1007/s00535-022-01862-y
  • Peer Reviewed
• [Journal Article] 炎症性腸疾患に対する生物学的製剤・JAK阻害剤―IBD診療ガイドライン2020を読み解く― (2021)
  • Author(s): 長沼誠, 深田憲将, 福井寿朗
  • Journal Title: 日本消化器病学会雑誌 Volume: 8 Pages: 618-627
  • NAID: 130008064498
  • Peer Reviewed
• [Journal Article] Solving the questions regarding 5-aminosalitylate formulation in the treatment of ulcerative colitis (2020)
  • Author(s): Naganuma M
  • Journal Title: J Gastroenterol Volume: 55 Issue: 11 Pages: 1013-1022
  • DOI: 10.1007/s00535-020-01713-8
  • Peer Reviewed / Open Access
• [Journal Article] Mucosal concentrations of N-acetyl-5-aminosalicylic acid is related to endoscopic activity in ulcerative colitis patients with mesalamine. (2020)
  • Author(s): Fukuda T, Naganuma M, Takabayashi K, Hagihara Y, Tanemoto S, Nomura E, Yoshimatsu Y, Sugimoto S, Nanki K, Mizuno S, Mikami Y, Fukuhara K, Sujino T, Mutaguchi M, Inoue N, Ogata H, Iwao Y, Abe T, Kanai T.
  • Journal Title: J Gastroenterol Hepatol. Volume: 35 Issue: 11 Pages: 1878-1885
  • DOI: 10.1111/jgh.15059
  • Peer Reviewed / Open Access
• [Journal Article] 5-Aminosalicylic acid intolerance is associated with a risk of adverse clinical outcomes and dysbiosis in patients with ulcerative colitis. (2020)
  • Author(s): Mizuno S, Naganuma M, Kanai T et al.
  • Journal Title: Intestinal Research Volume: 18 Issue: 1 Pages: 69-78
  • DOI: 10.5217/ir.2019.00084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of Conducting 2 Types of Fecal Tests in Patients with Ulcerative Colitis. (2019)
  • Author(s): Naganuma M, Kobayashi T, Nasuno M, Motoya S, Kato S, Matsuoka K, Hokari R, Watanabe C, Sakamoto H, Yamamoto H, Sasaki M, Watanabe K, Iijima H, Endo Y, Ichikawa H, Ozeki K, Tanida S, Ueno N, Fujiya M, Sako M, Takeuchi K, Sugimoto S, Abe T, Hibi T, Suzuki Y, Kanai T.
  • Journal Title: Clin Gastroenterol Hepatol Volume: 19 Issue: 5 Pages: 30843-2
  • DOI: 10.1016/j.cgh.2019.07.054
  • Peer Reviewed / Open Access
• [Presentation] A step forward:proactive TDM (2021)
  • Author(s): Naganuma M
  • Organizer: The 9th Annual Meeting of the Asian Organization for Crohn's and Colitis
  • Invited
• [Presentation] 潰瘍性大腸炎に対するステロイド初期投与量および減量速度と治癒効果との関係 (2021)
  • Author(s): 長沼誠
  • Organizer: 第76回日本大腸肛門病学会学術集会