論文 - 金井　隆典

Focus On Helicobacter pylori感染症の治療

正岡 建洋(慶応義塾大学 医学部内科学(消化器)), 山根 剛, 鈴木 秀和, 金井 隆典

内科 （(株)南江堂）  116 （ 3 ） 501 - 505 2015年09月

共著,  ISSN  0022-1961

A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease.

Kanai T, Mikami Y, Hayashi A

J Gastroenterol 50 （ 9 ） 928 - 39 2015年09月

共著, 査読有り

　概要を見る

Intestinal immune homeostasis is regulated by gut microbiota, including beneficial and pathogenic microorganisms. Imbalance in gut bacterial constituents provokes host proinflammatory responses causing diseases such as inflammatory bowel disease (IBD). The development of next-generation sequencing technology allows the identification of microbiota alterations in IBD. Several studies have shown reduced diversity in the gut microbiota of patients with IBD. Advances in gnotobiotic technology have made possible analysis of the role of specific bacterial strains in immune cells in the intestine. Using these techniques, we have shown that Clostridium butyricum as a probiotic induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response gene 88 pathway to prevent acute experimental colitis. In this review, we focus on the new approaches for the role of specific bacterial strains in immunological responses, as well as the potential of bacterial therapy for IBD treatments.

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【生物学的製剤が拓くIBD診療の新時代】 生物学的製剤は中止できるか

中里 圭宏(慶応義塾大学 医学部内視鏡センター), 長沼 誠,金井 隆典

Mebio 32 （ 8 ） 64 - 70 2015年08月

共著,  ISSN  0910-0474

Association of visceral fat area, smoking, and alcohol consumption with reflux esophagitis and Barrett's esophagus in Japan

Matsuzaki Juntaro, Suzuki Hidekazu, Kobayakawa Masao, Inadomi John M., Takayama Michiyo, Makino Kanako, Iwao Yasushi, Sugino Yoshinori, Kanai Takanori

PLoS ONE 10 （ 7 ）  2015年07月

　概要を見る

<p>Background: Central obesity has been suggested as a risk factor for gastroesophageal reflux disease. The aim of this study was to evaluate the association of visceral fat area and other lifestyle factors with reflux esophagitis or Barrett's esophagus in Japanese population. Methods: Individuals who received thorough medical examinations including the measurement of visceral fat area by abdominal computed tomography were enrolled. Factors associated with the presence of reflux esophagitis, the severity of reflux esophagitis, or the presence of Barrett's esophagus were determined using multivariable logistic regression models. Results: A total of 2608 individuals were eligible for the analyses. Visceral fat area was associated with the presence of reflux esophagitis both in men (odds ratio, 1.21 per 50 cm2; 95% confident interval, 1.01 to 1.46) and women (odds ratio, 2.31 per 50 cm2; 95% confident interval, 1.57 to 3.40). Current smoking and serum levels of triglyceride were also associated with the presence of reflux esophagitis in men. However, significant association between visceral fat area and the severity of reflux esophagitis or the presence of Barrett's esophagus was not shown. In men, excessive alcohol consumption on a drinking day, but not the frequency of alcohol drinking, was associated with both the severity of reflux esophagitis (odds ratio, 2.13; 95% confident interval, 1.03 to 4.41) and the presence of Barrett's esophagus (odds ratio, 1.71; 95% confident interval, 1.14 to 2.56). Conclusion: Visceral fat area was independently associated with the presence of reflux esophagitis, but not with the presence of Barrett's esophagus. On the other hand, quantity of alcohol consumption could play a role in the development of severe reflux esophagitis and Barrett's esophagus in Japanese population Copyright:</p>

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Current status of alcoholic liver diseases in Japan

Horie Yoshinori, Ebinuma Hirotoshi, Kikuchi Masahiro, Nakamoto Nobuhiro, Kanai Takanori

Acta Hepatologica Japonica 56 （ 7 ） 366 - 368 2015年07月

ISSN  0451-4203

　概要を見る

<p>A nationwide survey of liver cirrhosis (LC) was un- dertaken by asking major hospitals in Japan to provide information on the number of patients with LC admit- ted in 2012 along with information related to etiology including alcohol history. Etiological agents were as fol- lows: hepatitis B virus (10.5％), hepatitis C virus (47.1％), and alcohol (24.6％). Of LC cases, 30.6％ were alcohol- related (ethanol intake &gt;60 g day). Among alcoholic LC (Al-LC) patients, mean age was older in the present study in 2012 compared with the data for 2007-2008. Our survey revealed that the prevalence of Al-LC has been rapidly increasing in Japan. Moreover, age was identified as risk factors for development of Al-LC.</p>

Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells

Kashiwagi Ikkou, Morita Rimpei, Schichita Takashi, Komai Kyoko, Saeki Keita, Matsumoto Makoto, Takeda Kiyoshi, Nomura Masatoshi, Hayashi Atsushi, Kanai Takanori, Yoshimura Akihiko

Immunity 43 （ 1 ） 65 - 80 2015年07月

ISSN  1074-7613

　概要を見る

<p>Colonization with a mixture of Clostridium species has been shown to induce accumulation of induced regulatory T (iTreg) cells in the colon. Transforming growth factor-β (TGF-β) is an essential factor for iTreg cell induction; however, the relationship between Clostridium species and TGF-β remains to be clarified. Here we demonstrated that a gram-positive probiotic bacterial strain, Clostridium butyricum (C. butyricum), promoted iTreg cell generation in the intestine through induction of TGF-β1 from lamina propria dendritic cells (LPDCs). C. butyricum-mediated TGF-β1 induction was mainly Toll-like receptor 2 (TLR2) dependent, and the ERK-AP-1 kinase pathway played an important role. In addition, the autocrine TGF-β-Smad3 transcription factor signal was necessary for robust TGF-β expression in DCs, whereas Smad2 negatively regulated TGF-β expression. Smad2-deficient DCs expressed higher concentrations of TGF-β and were tolerogenic for colitis models. This study reveals a novel mechanism of TGF-β induction by Clostridia through a cooperation between TLR2-AP-1 and TGF-β-Smad signaling pathways.</p>

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Crohn’s disease in which the patient developed aortitis during treatment with adalimumab

Kiyohara Hiroki, Hisamatsu Tadakazu, Matsuoka Katsuyoshi, Naganuma Makoto, Kameda Hideto, Seta Noriyuki, Takeuchi Tsutomu, Kanai Takanori

Internal Medicine 54 （ 14 ） 1725 - 1732 2015年07月

ISSN  0918-2918

　概要を見る

<p>A 23-year-old woman developed aortitis during treatment with adalimumab (ADA) for ileocolic Crohn’s disease (CD). The patient complained of a high fever, abdominal pain, diarrhea, hematochezia and arthralgia. Although the ADA therapy resulted in immediate symptom improvement, after six weeks, she again complained of a low-grade fever and abdominal pain, whereas the CD-related symptoms did not worsen. Contrast-enhanced computed tomography revealed thoracoabdominal aortitis, and we therefore started treatment with prednisolone, which immediately improved the fever and abdominal pain. We subsequently tapered the dose of prednisolone and resumed the administration of ADA in order to maintain the CD remission. No further episodes of aortitis relapse were noted after restarting ADA, and the CD currently remains in remission. This is the first report of the onset of aortitis during ADA therapy for CD.</p>

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本邦におけるアルコール性肝硬変の実態

堀江義則 海老沼浩利 菊池真大 中本伸宏 金井 隆典

肝臓 56 （ 7 ） 366 - 368 2015年07月

共著,  ISSN  0451-4203

Computer-aided prediction of long-term prognosis of patients with ulcerative colitis after cytoapheresis therapy

Takayama Tetsuro, Okamoto Susumu, Hisamatsu Tadakazu, Naganuma Makoto, Matsuoka Katsuyoshi, Mizuno Shinta, Bessho Rieko, Hibi Toshifumi, Kanai Takanori

PLoS ONE 10 （ 6 ）  2015年06月

　概要を見る

<p>Cytoapheresis (CAP) therapy is widely used in ulcerative colitis (UC) patients with moderate to severe activity in Japan. The aim of this study is to predict the need of operation after CAP therapy of UC patients on an individual level using an artificial neural network system (ANN). Ninety UC patients with moderate to severe activity were treated with CAP. Data on the patients' demographics, medication, clinical activity index (CAI) and efficacy of CAP were collected. Clinical data were divided into training data group and validation data group and analyzed using ANN to predict individual outcomes. The sensitivity and specificity of predictive expression by ANN were 0.96 and 0.97, respectively. Events of admission, operation, and use of immunomodulator, and efficacy of CAP were significantly correlated to the outcome. Requirement of operation after CAP therapy was successfully predicted by using ANN. This newly established ANN strategy would be used as powerful support of physicians in the clinical practice.</p>

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Recognition of and recent issues in hereditary diffuse gastric cancer

Sugimoto Shinya, Komatsu Hirokazu, Morohoshi Yuichi, Kanai Takanori

Journal of Gastroenterology 50 （ 8 ） 831 - 843 2015年06月

ISSN  0944-1174

　概要を見る

<p>In East Asian countries, gastric cancer incidence is high, but detection rates for germline CDH1 mutations that cause hereditary diffuse gastric cancers (HDGCs) are low. Consequently, screens and genetic testing for HDGC are often considered unimportant. Since the first germline truncating CDH1 mutations in Japanese patients were reported, some HDGC cases have been reported, and some of these involve large germline rearrangements and de novo mutation of CDH1. New methods for mutation detection—such as multiplex ligation-dependent probe amplification, array comparative genomic hybridization, and exome sequencing—have become available, as have new experimental models, including novel gene-knockout mice and gastric organoids. Because of these advances, searches for candidate genes (e.g., CTNNA1, MAP3K6) and our understanding of HDGC pathogenesis have improved in recent years; moreover, there have been substantial changes in the field since the current HDGC consensus guidelines were released. This review focuses on recent issues and advances in the study of HDGC. For example, lobular breast cancer cases and de novo occurrences of DGC are unlikely to meet the existing criteria for genetic testing, but current evidence indicates that some such cases may be good candidates for genetic testing. It is important to recognize that HDGC is a syndrome and that lobular breast cancer can be the first manifestation of this syndrome. CDH1 testing, including analyses of large genomic rearrangements, should be recommended even in countries where few HDGC cases have been reported.</p>

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【microbiome(腸内細菌)と肝胆膵領域の新世紀】 なぜ今腸内細菌か?　ヒト腸内細菌と消化管疾患

中本伸宏金井 隆典

肝・胆・膵 70 （ 6 ） 827-833 2015年06月

ISSN  0389-4991

新しい消化器疾患動物モデル(第18回)　動物モデルの問題点と工夫　炎症性腸疾患モデル

筋野 智久(慶応義塾大学 医学部消化器内科), 金井 隆典

分子消化器病 12 （ 2 ） 178 - 184 2015年06月

共著,  ISSN  1348-995X

　概要を見る

炎症性腸疾患(IBD)、とくに潰瘍性大腸炎(UC)、クローン病(CD)はいまだに病態の解明がなされていない。遺伝、環境、腸内細菌など複合的な要因により病態が引き起こされると考えられている。しかし、いまだに完全にヒトIBDと同様の病態を示すモデルはなく、さまざまな大腸炎動物モデルを知り、必要に応じて使い分ける必要がある。近年無菌マウスシステムが確立され、腸内細菌が宿主の免疫系を教育することが判明してきた。さらにCRISPR/Cas9を利用した新しい遺伝子改変システムが今後広範に利用されるであろう。(著者抄録)

肝星細胞遊離コレステロール代謝調節による肝線維化新規治療法開発に関する研究

冨田 謙吾(防衛医科大学校 消化器内科), 寺谷 俊昭, 穂苅 量太,金井 隆典

臨床薬理の進歩  （ 36 ） 32 - 43 2015年06月

ISSN  0914-4366

　概要を見る

肝星細胞遊離コレステロール(Ch)代謝調節による肝線維化新規治療法開発について検討した。C57BL/6バックグラウンドの9週齢雄性ACAT1欠損マウスおよび野生型マウスを用いた。ACAT1がマウス肝星細胞の主要なアイソザイムで、ACAT2発現はほとんど認めなかった。ACAT1欠損が肝星細胞活性化に及ぼす影響が、遊離Ch蓄積に依存することを示唆した。CCL肝線維化モデルで、TLR4シグナルが欠損した状態では、ACAT1欠損は肝線維化進展に影響を及ぼさなかった。TLR4シグナルが欠損した状態でも、ACAT1欠損により肝星細胞の遊離Ch蓄積が有意に増強したが、CE蓄積には影響しなかった。TLR4シグナルが欠損している状態では、ACAT1欠損による反応性の増強は認めなかった。遊離Ch蓄積により増強したTLR4シグナルが、ACAT1欠損による肝線維化の増悪に重要な役割を果たすことが示唆された。

【ベーチェット病の最近の知見】 ベーチェット病の腸管病変

久松 理一(杏林大学 医学部第三内科), 長沼 誠, 金井 隆典

リウマチ科 53 （ 6 ） 565 - 570 2015年06月

ISSN  0915-227X

糞便微生物移植の臨床応用

金井 隆典

日本医事新報  （ 4756 ） 49 2015年06月

ISSN  0385-9215

Genotype-associated differential NKG2D expression on CD56+CD3+ lymphocytes predicts response to pegylated-interferon/ribavirin therapy in chronic hepatitis C

Chu Po Sung, Ebinuma Hirotoshi, Nakamoto Nobuhiro, Sugiyama Kazuo, Usui Shingo, Wakayama Yuko, Taniki Nobuhito, Yamaguchi Akihiro, Shiba Shunsuke, Yamagishi Yoshiyuki, Wakita Takaji, Hibi Toshifumi, Saito Hidetsugu, Kanai Takanori

PLoS ONE 10 （ 5 ）  2015年05月

　概要を見る

<p>Hepatitis C virus (HCV) genotype 1 infections are significantly more difficult to eradicate with PEG-IFN/ribavirin therapy, compared to HCV genotype 2. The aim of this work is to investigate the difference of immunological impairments underlying this phenomenon. Pretreatment NKG2D expression on peripheral CD56+CD3+ lymphocytes and CD56+CD3-NK cells from cases of chronic hepatitis C were analyzed and assessed by treatment effect. Two strains of HCV were used to co-incubate with immune cells in vitro. NKG2D expression on peripheral CD56+CD3+ lymphocytes, but not NK cells, was significantly impaired in genotype 1 infection, compared to genotype 2. When peripheral blood mononuclear cells from healthy donors were co-incubated with TNS2J1, a genotype 1b/2a chimera strain, or with JFH1, a genotype 2a strain, genotype-specific decrease of NKG2D on CD56+CD3+ lymphocytes, but not NK cells, was observed. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes significantly correlated with reduction in serum HCV RNA levels from week 0 to week 4, and predicted treatment response. Ex vivo stimulation of peripheral CD56+CD3+ lymphocytes showed NKG2D expression-correlated IFN-γ production. In conclusion, Decreased NKG2D expression on CD56+CD3+ lymphocytes in chronic HCV genotype 1 infection predicts inferior treatment response to PEG-IFN/ribavirin therapy compared to genotype 2.</p>

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Combination therapy with infliximab and thiopurine compared to infliximab monotherapy in maintaining remission of postoperative crohn's disease

Sakuraba Atsushi, Okamoto Susumu, Matsuoka Katsuyoshi, Sato Toshiro, Naganuma Makoto, Hisamatsu Tadakazu, Iwao Yasushi, Ogata Haruhiko, Kanai Takanori, Hibi Toshifumi

Digestion 91 （ 3 ） 233 - 238 2015年05月

ISSN  0012-2823

　概要を見る

<p>Background and Aims: Infliximab is an efficacious agent used for the induction and maintenance of remission in Crohn's disease (CD), and recent studies suggested that it may also prevent the recurrence of this disease after surgery. The present study was performed to assess the efficacy and safety of infliximab in the postoperative setting, and to identify whether combination treatment with thiopurines had any additional beneficial effect as compared to mono-therapy. Methods: We performed a retrospective cohort study to compare the efficacy of infliximab mono-therapy and combination treatment with a thiopurine in preventing recurrence after surgery. Results: Forty-one patients who received infliximab as maintenance treatment following surgery from May 2002 to April 2010 were identified. Twenty-four were naive to infliximab, and 17 who underwent surgery during infliximab treatment were continued on it following surgery. The median follow-up period was 27 months (range 12-66 months). All patients continued infliximab as maintenance treatment, but 10 required dose intensification due to clinical recurrence. Kaplan-Meier analysis demonstrated that the use of concomitant thiopurine was correlated with the continuation of infliximab treatment at an 8-week interval (log-rank test p = 0.018). The rate of adverse event was 9.8% with no patient experiencing severe adverse reactions. Conclusion: Infliximab appears to be safe and it prevented clinical recurrence after surgery. Concomitant thiopurine use predicted response toward continuation of therapy at an 8-week interval. Prospective controlled studies to assess the efficacy of combination treatment in the postoperative setting are warranted.</p>

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A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response in inflammatory bowel disease.

金井 隆典

J Gastroenterol 2015年05月

共著

A breakthrough in probiotics

Kanai Takanori, Mikami Yohei, Hayashi Atsushi

Journal of Gastroenterology 50 （ 9 ） 928 - 939 2015年05月

ISSN  0944-1174

　概要を見る

<p>Intestinal immune homeostasis is regulated by gut microbiota, including beneficial and pathogenic microorganisms. Imbalance in gut bacterial constituents provokes host proinflammatory responses causing diseases such as inflammatory bowel disease (IBD). The development of next-generation sequencing technology allows the identification of microbiota alterations in IBD. Several studies have shown reduced diversity in the gut microbiota of patients with IBD. Advances in gnotobiotic technology have made possible analysis of the role of specific bacterial strains in immune cells in the intestine. Using these techniques, we have shown that Clostridium butyricum as a probiotic induces interleukin-10-producing macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response gene 88 pathway to prevent acute experimental colitis. In this review, we focus on the new approaches for the role of specific bacterial strains in immunological responses, as well as the potential of bacterial therapy for IBD treatments.</p>

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【腸内細菌フローラと疾患】 炎症性腸疾患と腸内細菌の関わり

南木康作,金井 隆典

Medical Science Digest 41 （ 4 ） 154 - 157 2015年04月

ISSN  1347-4340

　概要を見る

ヒトの腸管内には無数の細菌が腸内細菌叢を形成しており、宿主の免疫系に多大な影響を与えている。これまでの研究で、炎症性腸疾患は遺伝的素因、免疫学的機序の異常とともに腸内細菌を含んだ環境因子が関連した多因子疾患であることが示唆されている。近年、次世代シーケンサーを用いた腸内細菌の解析により、炎症性腸疾患と腸内細菌叢の乱れ、すなわちdysbiosisが関連していることが明らかになってきた。dysbiosisが腸炎を惹起することが示唆されており、また特定の細菌が腸炎の惹起・制御に関与していることも明らかとなってきた。これらの知見から腸内細菌に着目し働きかけることで腸炎を改善させる治療に期待が集まってきている。近年、dysbiosisを強力に是正する治療として糞便微生物移植が注目されており、炎症性腸疾患の新たな治療として世界中で臨床試験が開始されている。(著者抄録)