Periodontal disease increases a risk of hepatocarcinogenesis – Investigation of in vivo defense mechanism in a novel NASH model

• Project/Area Number: 18K11094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Kenji Yamagata 筑波大学, 医学医療系, 准教授 (00420084)
• Co-Investigator(Kenkyū-buntansha): 柳川 徹 筑波大学, 医学医療系, 教授 (10312852) ; 蕨 栄治 筑波大学, 医学医療系, 講師 (70396612) ; 正田 純一 筑波大学, 医学医療系, 教授 (90241827)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: NASH / 歯周病 / LPS / メタゲノム解析 / 遺伝子改変マウス / 肝癌 / 歯周病菌 / 転写因子Nrf2 / ゲノム解析 / 脂肪性肝炎 / 運動療法 / 腸内細菌叢 / Kupffer細胞 / 肝星細胞

Outline of Final Research Achievements

Salivary component analysis was performed for obese middle-aged men with NAFLD and periodontal disease. Diversity analysis of oral bacterial flora revealed a decreased alpha- and beta-diversity. In addition, higher salivary immunoglobulin A, cytokine, bacterial LPS, and lactoferrin concentrations were observed. However, an exercise regimen improved the oral environment of NAFLD patients by increasing the diversity of the oral microflora.
p62/Sqstm1-knockout (p62-KO) mice alongside hyperphagia-induced obesity develop phenotypes that are similar to clinical features of human NASH. The phagocytic capacity of Kupffer cells (KCs) were lower in the p62-KO group than in the WT group, but the capacity and LPS clearance increased with long-term exercise. It is suggested that long-term exercise reduces a flux of LPS from oral and intestinal bacteria into the liver and thereby prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis.

Academic Significance and Societal Importance of the Research Achievements

運動が口腔内環境に及ぼす効果として，運動介入試験より，唾液中の炎症に関わる物質の濃度減少，口腔内細菌の種多様性の増大を明らかにした．運動が歯周病の改善をもたらすことのメカニズムが解明された．また，肥満マウスを用いた動物実験において，運動実践が腸内細菌叢や口腔内細菌叢に影響を与えて，LPSの暴露により誘導されるNASH肝病変の発症を予防することも明らかとなった．肥満者，糖尿病，高齢者など歯周病の高リスクグループに対する健康管理の一環として，運動実践の重要性がより明確になった．

Research Products

• [Journal Article] Association between the C-reactive protein/albumin ratio and prognosis in patients with oral squamous cell carcinoma (2021)
  • Author(s): Yamagata K, Fukuzawa S, Ishibashi-Kanno N, Uchida F, Bukawa H
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 5546-5546
  • DOI: 10.1038/s41598-021-83362-2
  • Peer Reviewed
• [Journal Article] The effects of perioperative oral management on perioperative serum albumin levels in patients treated surgically under general anesthesia (2021)
  • Author(s): Yamada S, Koike K, Isomura-Tanak E, Chikazu D, Yamagata K, Iikubo M, Hino S, Hibi H, Katsura K, Nakamura S, Nomura T, Mori Y, Tojyo I, Kanamura N, Yamamori I, Aota K, Fujita S, Tanzawa H, Kurita H
  • Journal Title: Medicine Volume: 100 Issue: 10 Pages: e25119-e25119
  • DOI: 10.1097/md.0000000000025119
  • Peer Reviewed
• [Journal Article] Effects of Exercise on the Oral Microbiota and Saliva of Patients with Non-Alcoholic Fatty Liver Disease (2021)
  • Author(s): Uchida F, Oh S, Shida T, Suzuki H, Yamagata K, Mizokami Y, Bukawa H, Tanaka K, Shoda J
  • Journal Title: Int J Environ Res Public Health Volume: 18 Issue: 7 Pages: 3470-3470
  • DOI: 10.3390/ijerph18073470
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Postoperative delirium after reconstructive surgery for oral tumor: a retrospective clinical study (2020)
  • Author(s): Ishibashi-Kanno N, Takaoka S, Nagai H, Okubo-Sato M, Fukuzawa S, Uchida F, Yamagata K, Yanagawa T, Bukawa H
  • Journal Title: Int J Oral Maxi Surg Volume: 49 Issue: 9 Pages: 1143-1148
  • DOI: 10.1016/j.ijom.2020.01.018
  • Peer Reviewed
• [Journal Article] Gender difference in development of steatohepatitis in <i>p62/Sqstm1 and Nrf2</i> double-knockout mice (2020)
  • Author(s): Watahiki T, Okada K, Warabi E, Nagaoka T, Suzuki H, Ishige K, Yanagawa T, Takahashi S, Mizokami Y, Tokushige K, Ariizumi SI, Yamamoto M, Shoda J
  • Journal Title: Experimental Animals Volume: 69 Issue: 4 Pages: 395-406
  • DOI: 10.1538/expanim.20-0028
  • NAID: 130007938666
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Progressive reduction in skeletal muscle mass to visceral fat area ratio is associated with a worsening of the hepatic conditions of non-alcoholic fatty liver disease (2019)
  • Author(s): Shida T, Oshida N, Oh S, Okada K, Shoda J
  • Journal Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Volume: 12 Pages: 495-503
  • DOI: 10.2147/dmso.s185705
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Urinary Levels of Titin-N Fragment, a Skeletal Muscle Damage Marker, are Increased in Subjects with Nonalcoholic Fatty Liver Disease (2019)
  • Author(s): Oshida Natsumi、Shida Takashi、Oh Sechang、Kim Taeho、Isobe Tomonori、Okamoto Yoshikazu、Kamimaki Takashi、Okada Kosuke、Suzuki Hideo、Ariizumi Shun-ichi、Yamamoto Masakazu、Shoda Junichi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 19498-19498
  • DOI: 10.1038/s41598-019-56121-7
  • NAID: 120007132916
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Is Lymph Node Ratio a Prognostic Factor for Patients With Oral Squamous Cell Carcinoma? (2019)
  • Author(s): K. Yamagata、S．Fukuzawa、N．Kanno、F．Uchida、T．Yanagawa、H．Bukawa
  • Journal Title: J Oral Maxillofac Surg Volume: 19 Pages: 30112-0
  • Peer Reviewed / Open Access
• [Journal Article] Association between p62 expression and clinicopathological characteristics in oral leukoplakia. (2019)
  • Author(s): T. Yoshida, T. Terabe, H. Nagai, F. Uchida, S. Hasegawa, T. Nagao, S. Miyabe, N. Ishibashi‐Kanno, K. Yamagata, E. Warabi, M. Gosho, T. Yanagawa, H. Bukawa
  • Journal Title: Clinical and Experimental Dental Research Volume: 5 Issue: 4 Pages: 389-397
  • DOI: 10.1002/cre2.193
  • NAID: 120007133181
  • Peer Reviewed / Open Access
• [Journal Article] A small number of residual teeth after the mandibular resection of oral cancer is associated with titanium reconstruction plate exposure. (2019)
  • Author(s): H. Hirohata, T. Yanagawa, S. Takaoka, K. Yamagata, K. Sasaki, Y. Shibuya, F. Uchida, S. Fukuzawa, K. Tabuchi, S. Hasegawa, N. Ishibashi‐Kanno, M. Sekido, H. Bukawa
  • Journal Title: Clinical and Experimental Dental Research Volume: 5 Issue: 5 Pages: 469-475
  • DOI: 10.1002/cre2.208
  • Peer Reviewed / Open Access
• [Journal Article] Progressive reduction in skeletal muscle mass to visceral fat area ratio is associated with a worsening of the hepatic conditions of non-alcoholic fatty liver disease． (2019)
  • Author(s): Shida T, Oshida N, Oh S, Okada K, Shoda J
  • Journal Title: Diabetes Metab Syndr Obes Volume: 12 Pages: 495-503
  • Peer Reviewed
• [Journal Article] Proton Beam Therapy for Ameloblastic Carcinoma of the Maxilla: Report of a Rare Case. (2018)
  • Author(s): K. Yamagata, H. Ishikawa, T. Saito, H. Bukawa
  • Journal Title: J Oral Maxillofac Surg Volume: 77
  • NAID: 120007128214
  • Peer Reviewed
• [Journal Article] 頸動脈洞症候群による失神発作を繰り返した舌がん頸部再発の1例 (2018)
  • Author(s): 山縣 憲司、生井 友農、内田 文彦、菅野 直美、柳川 徹、武川 寛樹
  • Journal Title: 日本口腔科学会誌 Volume: 67 Pages: 23-28
  • NAID: 130006646899
  • Peer Reviewed
• [Journal Article] 妊娠初期および後期に外科治療を行った舌癌の1例 (2018)
  • Author(s): 高岡 昇平、山縣 憲司、伊藤 寛之、内田 文彦、柳川 徹、武川 寛樹
  • Journal Title: 日本口腔科学会誌 Volume: 67 Pages: 41-47
  • NAID: 130006646915
  • Peer Reviewed
• [Journal Article] MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP 2 expression. (2018)
  • Author(s): H. Nagai, S. Hasegawa, F. Uchida, T. Terabe, N. Ishibashi Kanno, K. Kato, K. Yamagata, S. Sakai, S. Kawashiri, H. Sato, T. Yanagawa, H. Bukawa
  • Journal Title: Int J Oncol Volume: 52 Pages: 841-850
  • Peer Reviewed
• [Journal Article] Synaptic-adhesion molecules neurexin 1 and neuroligin 1 as novel prognostic factors in oral squamous cell carcinoma. (2018)
  • Author(s): H. Hirohata, T. Yanagawa, S. Takaoka, F. Uchida, Y. Shibuya, S. Miyabe, K. Tabuchi, Y. Akagi, S. Hasegawa, S. Sakai, Y. Takeuchi, N. Ishibashi-Kanno, K. Yamagata, H. Bukawa
  • Journal Title: J Dents Dent Med Volume: 1 Pages: 111-111
  • Peer Reviewed
• [Journal Article] A rare case of synchronous squamous cell carcinoma on the body of the tongue and malignant lymphoma of the neck. (2018)
  • Author(s): A. Katou, H. Hirohata, F. Uchida, Y. Takeuchi, M. Yamato, K. Yamagata, T. Yanagawa, H. Bukawa
  • Journal Title: J Dents Dent Med Volume: 1 Pages: 110-110
  • Peer Reviewed
• [Journal Article] Deletion of both p62 and Nrf2 spontaneously leads to development of nonalcoholic steatohepatitis. (2018)
  • Author(s): Akiyama K, Warabi E, Okada K, Yanagawa T, Yamagata K, Shoda J
  • Journal Title: Experimental Animals Volume: 67 Pages: 201-218
  • Peer Reviewed
• [Journal Article] Exercise habitation is effective for improvement of periodontal disease status: a prospective intervention study. (2018)
  • Author(s): Omori T, Uchida F, Oh S, So R, Tsujimoto T, Yanagawa T, Sakai S, Shoda J, Tanaka K, Bukawa H
  • Journal Title: Ther Clin Risk Manag Volume: 14 Pages: 565-574
  • Peer Reviewed
• [Journal Article] Skeletal muscle mass to visceral fat area ratio is an important determinant affecting pathophysiology of NAFLD. (2018)
  • Author(s): Shida T, Akiyama K, Oh S, Sawai A, Isobe T, Okamoto Y, Ishige K, Mizokami Y, Yamagata K, Onizawa K, Tanaka H, Iijima H, Shoda J
  • Journal Title: J Gastroenterol Volume: 53 Pages: 535-547
  • Peer Reviewed
• [Presentation] 口腔がん患者における炎症性マーカーの予後予測因子としての有用性 (2020)
  • Author(s): 山縣憲司,福澤 智,内田文彦,寺田和浩,井上 裕,生井友農,菅野直美,柳川 徹,廣畠広実,武川寛樹
  • Organizer: 第65回日本口腔外科学会総会・学術大会
• [Presentation] 歯周病に対する運動の影響―口腔内細菌叢および唾液分析 (2020)
  • Author(s): 内田 文彦,廣畠 広実,福澤 智,菅野 直美,山縣 憲司,武川 寛樹
  • Organizer: 第65回日本口腔外科学会総会・学術大会
• [Presentation] 中年肥満男性の歯周病に対する運動療法の効果 口腔内細菌叢とメタゲノムの解析より (2020)
  • Author(s): 内田 文彦,志田 隆史,大森 翔英,呉 世昶,福澤 智,菅野 直美,山縣 憲司,鈴木 英雄,正田 純一,武川 寛樹
  • Organizer: 第74回日本口腔科学会学術集会
• [Presentation] 脂肪酸代謝制御因子p62はマウス脂肪性肝炎を防御する - 組織細胞特異的p62遺伝子レスキューマウスの解析より (2020)
  • Author(s): 岡田浩介，綿引隆久，正田純一
  • Organizer: JDDW2020
• [Presentation] レドックスナノ粒子（RNP）はp62:Nrf2遺伝子二重欠失マウス脂肪性肝炎における線維化を抑止する (2020)
  • Author(s): 綿引隆久，岡田浩介，正田純一
  • Organizer: JDDW2020
• [Presentation] 脂肪酸代謝に着目したマウス脂肪性肝炎におけるp62の役割 (2019)
  • Author(s): 岡田浩介, 石毛和紀，蕨 栄治，正田純一
  • Organizer: 第105回消化器病学会総会
• [Presentation] Lipophagy制御因子p62は，中性脂肪-脂肪酸代謝を介してマウス脂肪性肝炎を防御する (2019)
  • Author(s): 岡田浩介, 石毛和紀，正田純一
  • Organizer: 第55回肝臓学会総会
• [Presentation] D-dimer測定は口腔がん患者の周術期血栓塞栓症の発見に有用である (2019)
  • Author(s): 山縣憲司, 福澤智, 佐藤牧子, 長井宏樹, 内田文彦, 菅野直美, 生井友農, 廣畠広実, 柳川徹, 武川寛樹
  • Organizer: 第64回日本口腔外科学会総会・学術大会
• [Presentation] 骨吸収阻害薬投与前における口腔内スクリーニングの有用性の検討 (2019)
  • Author(s): 武川幸太郎, 福澤 智, 山縣憲司, 菅野直美, 内田文彦, 佐藤牧子, 金子真也, 伊藤寛之, 柳川徹, 武川寛樹
  • Organizer: 第64回日本口腔外科学会総会・学術大会
• [Presentation] 口腔がん患者におけるKhoranaスコアでの血栓リスクの評価について (2019)
  • Author(s): 福澤 智, 山縣憲司, 菅野直美, 内田文彦, 佐藤牧子, 寺田和浩, 飯坂慶人, 井上 裕, 萩原敏之, 武川寛樹
  • Organizer: 第64回日本口腔外科学会総会・学術大会
• [Presentation] 再発転移口腔がんに対する外来パクリタキセル+セツキシマブ療法の意義． (2018)
  • Author(s): 山縣 憲司, 菅野 直美, 寺田 和浩, 木村 愛理, 佐藤 牧子, 長井 宏樹, 福澤 智, 内田 文彦, 柳川 徹, 廣畠 広実, 武川 寛樹
  • Organizer: 第72回日本口腔科学会学術集会
• [Presentation] 顎関節に発症した滑膜性骨軟骨腫症の1例． (2018)
  • Author(s): 佐藤 牧子, 山縣 憲司, 武内 保敏, 三宮 範子, 内田 文彦, 菅野 直美, 柳川 徹, 武川 寛樹
  • Organizer: 第72回日本口腔科学会学術集会
• [Presentation] 当科で入院加療を行った歯性感染症症例の臨床的検討 リウマチ・膠原病症例の特徴およびその他の症例との比較． (2018)
  • Author(s): 生井 友農, 三上 拓朗, 平野 智香子, 高岡 昇平, 佐藤 志興, 山縣 憲司, 柳川 徹, 武川 寛樹
  • Organizer: 第72回日本口腔科学会学術集会
• [Presentation] ビデオレクチャー「ビデオでみる頸部郭清術の基本 ～MRND(MacFee切開)およびSOHND~」 (2018)
  • Author(s): 山縣憲司
  • Organizer: 第６３回日本口腔外科学会総会・学術大会
• [Presentation] 口腔がんにおけるLymph Node Ratio (LNR)の予後不良因子としての有用性． (2018)
  • Author(s): 山縣憲司, 福澤 智，菅野 直美, 木村 愛理, 長井 宏樹, 佐藤 牧子, 内田 文彦, 生井友農，柳川 徹, 武川 寛樹
  • Organizer: 第６３回日本口腔外科学会総会・学術大会
• [Presentation] 骨格筋減少と内臓脂肪増加による体組成異常は非アルコール性脂肪性肝疾患（NAFLD）を悪化させる. (2018)
  • Author(s): 岡田浩介, 志田隆史, 正田純一
  • Organizer: 第104回消化器病学会総会
• [Presentation] 胆嚢癌のリスクファクターは何か？ (2018)
  • Author(s): 正田純一
  • Organizer: 第54回日本胆道学会学術集会
  • Invited
• [Presentation] 非アルコール性脂肪性肝疾患（NAFLD）における骨格筋組成の異常－超音波画像診断装置を用いた解析. (2018)
  • Author(s): 押田夏海，志田隆史，磯辺智範，岡本嘉一，上牧 隆，正田純一
  • Organizer: 第42回肝臓学会東部会
• [Book] 胆と膵（コレステロール胆石とウルソデオキシコール酸） (2019)
  • Author(s): 正田純一
  • Total Pages: 84
  • Publisher: 医学図書出版
• [Book] 消化器疾患診断・治療指針（胆石の形成機序 ） (2018)
  • Author(s): 正田純一
  • Total Pages: 455
  • Publisher: 中山書店
• [Book] 膵・胆道疾患診療の最前線（胆石の形成機序） (2018)
  • Author(s): 正田純一
  • Total Pages: 335
  • Publisher: 中山書店
• [Book] 胆と膵（性差による臨床像の差違―胆石症） (2018)
  • Author(s): 正田純一
  • Total Pages: 90
  • Publisher: 胆と膵