The role of intestinal flora in the pathogenesis of biliary atresia

• Project/Area Number: 26461609
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Osaka University
• Principal Investigator: Bessho Kazuhiko 大阪大学, 医学系研究科, 講師 (80423169)
• Co-Investigator(Kenkyū-buntansha): 近藤 宏樹 大阪大学, 医学系研究科, 招へい教員 (10373515)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 胆道閉鎖症 / 腸内細菌叢 / 胆汁うっ滞 / 国際情報交換

Outline of Final Research Achievements

We found that in the liver from infants with biliary atresia, the expression level of beta-defensin, an antimicrobial peptide which activates innate immunity against gram-negative bacteria was upregulated compared to livers from diseased and normal controls. The expression level of its receptor, TLR4 was identified on hepatic dendritic cells.
In the rotavirus-induced murine model of biliary atresia, when we kept the colony under bactrim diet, the incidence of obstruction of extrahepatic bile duct was reduced significantly after injection of rotavirus, and a part of gram negative bacteria was decreased in the stool of mouse from the bactrim-diet colony.

Research Products

• [Int'l Joint Research] Cincinnati Children's Hospital(米国)
• [Int'l Joint Research] CCHMC(米国)
• [Journal Article] Total Bile Acid Concentration in duodemal fluid Is a Useful Preoperative Screening Marker to Rule Out Biliary Atresia (2018)
  • Author(s): Tomoya Fukuoka, Kazuhiko Bessho, Makiko Tachibana, Yoshinori Satomura, Akiko Konishi, Kie Yasuda, Takeshi Kimura, Yasuhiro Hasegawa, Takehisa Ueno, Yoko Miyoshi, and Keiichi Ozono
  • Journal Title: Journal of Pediatric Gastroenterology and Nutrition Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment. (2017)
  • Author(s): Nagasaka H, Komatsu H, Inui A, Nakacho M, Morioka I, Tsukahara H, Kaji S, Hirayama S, Miida T, Kondou H, Ihara H, Yagi M, Kizaki Z, Bessho K, Kodama T, Iijima K, Saheki T, Yorifuji T, Honda A
  • Journal Title: Mol. Genet. Metab. Volume: 120 Issue: 3 Pages: 207-212
  • DOI: 10.1016/j.ymgme.2016.12.011
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates. (2017)
  • Author(s): Carey AN, Zhang W, Setchell KD, Simmons JE, Shi T, Lages CS, Mullen M, Carroll K, Karns R, Bessho K, Sheridan R, Zhao X, Weber SN, Miethke AG
  • Journal Title: Pediatr Res. Volume: 印刷中 Issue: 1 Pages: 122-132
  • DOI: 10.1038/pr.2017.78
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Donor-Specific Antibodies on Graft Fibrosis After Pediatric Living Donor Liver Transplantation for Biliary Atresia. (2016)
  • Author(s): Ueno T, Zenitani M, Yamanaka H, Tanaka N, Uehara S, Tazuke Y, Bessho K, Okuyama H.
  • Journal Title: Transplant Proc. Volume: 48 Issue: 4 Pages: 1095-1099
  • DOI: 10.1016/j.transproceed.2016.02.011
  • Peer Reviewed / Open Access
• [Journal Article] Disseminated Metastatic Tissue Calcification After Orthotopic Liver Transplantation: A Case Report (2016)
  • Author(s): Deguchi K, Ueno T, Matsuura R, Yamanaka H, Nara K, Uehara S, Tazuke Y, Bessho K, Okuyama H.
  • Journal Title: Transplant Proc Volume: 48 Issue: 1 Pages: 251-254
  • DOI: 10.1016/j.transproceed.2015.12.033
  • Peer Reviewed / Open Access
• [Journal Article] Complications and Quality of Life in Long-Term Survivors of Biliary Atresia with Their Native Livers (2015)
  • Author(s): Bessho K
  • Journal Title: J Pediatr Volume: 167 Issue: 6 Pages: 1202-1206
  • DOI: 10.1016/j.jpeds.2015.08.041
  • Peer Reviewed / Open Access
• [Journal Article] Natural killer cells promote long-term hepatobiliary inflammation in a low-dose rotavirus model of experimental biliary atresia. (2015)
  • Author(s): Squires JE, Shivakumar P, Mourya R, Bessho K, Walters S, Bezerra JA
  • Journal Title: PLoS One Volume: 10 Issue: 5 Pages: 1-15
  • DOI: 10.1371/journal.pone.0127191
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reply: To PMID 24493287 (2015)
  • Author(s): Mourya R, Bessho K, Shivakumar P, Bezerra JA
  • Journal Title: Hepatology Volume: 61 Issue: 2 Pages: 732-3
  • DOI: 10.1002/hep.27231
  • Peer Reviewed / Open Access
• [Journal Article] Gene expression signature for biliary atresia and a role for Interleukin-8 in pathogenesis of experimental disease (2014)
  • Author(s): Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Jegga AG, Rao M and Bezerra JA
  • Journal Title: Hepatology Volume: 60 Issue: 1 Pages: 211-23
  • DOI: 10.1002/hep.27045
  • Peer Reviewed / Open Access
• [Presentation] 胆道閉鎖症の診断における十二指腸液採取と肝胆道シンチグラフィの有用性に対する検討 (2017)
  • Author(s): 福岡智哉，橘真紀子，里村宜紀，安田紀恵，長谷川泰浩，別所一彦，三善陽子，大薗恵一
  • Organizer: 第30回近畿小児科学会
  • Place of Presentation: 大阪
  • Year and Date: 2017-03-12
• [Presentation] 現在の移植医療の問題点 (2017)
  • Author(s): 別所一彦
  • Organizer: 第9回日本小児栄養消化器肝臓学会卒後教育セミナー
  • Place of Presentation: 川崎
  • Year and Date: 2017-01-14
  • Invited
• [Presentation] 胆道閉鎖症の遺伝的素因について (2017)
  • Author(s): 別所一彦
  • Organizer: BA brain storming
  • Place of Presentation: 東京
  • Year and Date: 2017-01-09
  • Invited
• [Presentation] The role of immune response and gene variations in the etiology of biliary atresia. (2017)
  • Author(s): Bessho K
  • Organizer: The 54 Annual Congress of the Japanese Society of Pediatric Surgery and the 7th International Sendai Symposium on Biliary Atresia
  • Int'l Joint Research / Invited
• [Presentation] 胆道閉鎖症の診断における十二指腸液採取と肝胆道シンチグラフィの有用性に対する検討 (2016)
  • Author(s): 福岡智哉，橘真紀子，里村宜紀，小西暁子，安田紀恵，木村武司，倉川佳世、長谷川泰浩，別所一彦，三善陽子，大薗恵一
  • Organizer: 第43回日本小児栄養消化器肝臓学会
  • Place of Presentation: つくば
  • Year and Date: 2016-09-16
• [Presentation] 肝組織像からPFIC3が疑われ、遺伝子検査にて診断確定した2歳男児の1例. (2016)
  • Author(s): 里村宜紀，小西暁子，安田紀恵，長谷川泰浩，別所一彦，三善陽子，大薗恵一
  • Organizer: 第33回日本小児肝臓研究会
  • Place of Presentation: 岐阜
  • Year and Date: 2016-07-02
• [Presentation] Dissociation Between Clinical Evaluation and PELD Score in The Setting of Pediatric Living-Related Liver Transplantation in JAPAN: A 18 Year Single Center Experience. (2016)
  • Author(s): Bessho K, Hasegawa Y, Fukuda H, Hagiwara K, Ueno T, Miyoshi Y, Kondou H, Mushiake S, Okuyama H, Ozono K.
  • Organizer: The International Liver Congress 2016
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] 生体肝移植・これからの課題 肝移植後のグラフト線維化と小児生体肝移植後抗ドナー抗体の影響 胆道閉鎖症に対する生体肝移植後の検討 (2016)
  • Author(s): 上野豪久, 田中夏美, 銭谷昌弘, 山中宏晃, 高間勇一, 田附裕子, 別所一彦, 奥山宏臣
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2016-04-14
• [Presentation] 大阪大学医学部附属病院における小児肝移植適応決定のプロセス (2016)
  • Author(s): 別所一彦
  • Organizer: 第3回小児がん拠点病院放射線技師研修会
  • Place of Presentation: 大阪
  • Year and Date: 2016-02-27
  • Invited
• [Presentation] Phenotyping of patients with biliary atresia towards personalized therapy (2015)
  • Author(s): Bessho K
  • Organizer: The second joint meeting of Japan-Taiwan-Korean Pediatric Societies of Pediatric Gastroenterology, Hepatology and Nutrition
  • Place of Presentation: 東京
  • Year and Date: 2015-11-28
  • Int'l Joint Research / Invited
• [Presentation] 胆道閉鎖症の動物モデル –その有用性と限界点- (2015)
  • Author(s): 別所一彦
  • Organizer: 第42回日本小児栄養消化器肝臓学会
  • Place of Presentation: 広島
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] 胆道閉鎖症患者の肝臓では胆汁酸生合成律速酵素CYP7A1の抑制機構の破綻が起きている (2015)
  • Author(s): 長谷川泰浩, 近藤宏樹, 別所一彦, 川井正信, 安田紀恵, 上野豪久, 里村宜紀, 小西暁子, 木村武司, 倉川佳世, 三善陽子, 道上敏美, 大薗恵一
  • Organizer: 第42回日本小児栄養消化器肝臓学会
  • Place of Presentation: 広島
  • Year and Date: 2015-10-16
• [Presentation] Gene Expression Signature for Biliary Atresia and a Role for IL-8 in the Pathogenesis of Experimental Disease (2015)
  • Author(s): 別所一彦
  • Organizer: 第32回小児肝臓研究会
  • Place of Presentation: 鳥取大学
  • Year and Date: 2015-07-25
  • Invited
• [Presentation] 胆道閉鎖症患者の肝臓では胆汁酸生合成律速酸素CYP7A1の抑制機構の破綻が起きている (2015)
  • Author(s): 長谷川泰浩, 近藤宏樹, 別所一彦, 川井正信, 安田紀恵, 上野豪久, 里村宜紀, 小西暁子, 木村武司, 倉川佳世, 三善陽子, 道上敏美, 大薗恵一
  • Organizer: 第32回日本小児肝臓研究会
  • Place of Presentation: 鳥取
  • Year and Date: 2015-07-25
• [Presentation] A case of chronic rejection after liver transplantation for acute liver failure (2015)
  • Author(s): Zenitani S, Bessho K, Kondou H, Hasegawa Y, Yasuda K, Konishi A, Satomura Y, Miyoshi Y, Ueno T, Ozono K
  • Organizer: 11th Asian Society for Pediatric Research
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-15
  • Int'l Joint Research
• [Presentation] Dysregulation of Cholesterol 7 alpha-hydroxylase (CYP7A1) is involved in the abnormal bile acid synthesis in livers from biliary atresia (BA) children (2014)
  • Author(s): Hasegawa Y, Kondou H, Bessho K, Kawai M, Nakao K, Ueno T, Satomura Y, Konishi A, Kimura T, Ikeda K, Tachibana M, Miyoshi Y, Michigami T, Ozono K
  • Organizer: The Liver Meeting 2014
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2014-11-10
• [Presentation] Gene Expression Signature for Biliary Atresia and a Role for IL-8 in the Pathogenesis of Experimental Disease. (2014)
  • Author(s): Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Jegga AG, Rao M and Bezerra JA
  • Organizer: BARD-Berlin
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2014-10-16
• [Presentation] Introduction, Recent progress in biliary atresia in the world. (2014)
  • Author(s): Bessho K
  • Organizer: 2014 PAS/ASPR Joint Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-05-04