論文 - 金井　隆典

Relevance of pepsinogen, gastrin, and endoscopic atrophy in the diagnosis of autoimmune gastritis

Kishikawa H., Nakamura K., Ojiro K., Katayama T., Arahata K., Takarabe S., Sasaki A., Miura S., Hayashi Y., Hoshi H., Kanai T., Nishida J.

Scientific Reports （Scientific Reports）  12 （ 1 ）  2022年12月

　概要を見る

Simple objective modalities are required for evaluating suspected autoimmune gastritis (AIG). This cross-sectional study aimed to examine whether pepsinogen, gastrin, and endoscopic findings can predict AIG. The diagnostic performance of endoscopic findings and serology in distinguishing AIG was evaluated. AIG was diagnosed in patients (N = 31) with anti-parietal cell antibody and/or intrinsic factor antibody positivity and histological findings consistent with AIG. Non-AIG patients (N = 301) were seronegative for anti-parietal cell antibodies. Receiver operating characteristic curve analysis of the entire cohort (N = 332) identified an endoscopic atrophic grade cutoff point of O3 on the Kimura–Takemoto classification (area under the curve [AUC]: 0.909), while those of pepsinogen-I, I/II ratio, and gastrin were 20.1 ng/mL (AUC: 0.932), 1.8 (AUC: 0.913), and 355 pg/mL (AUC: 0.912), respectively. In severe atrophy cases (≥ O3, N = 58, AIG/control; 27/31), the cutoff values of pepsinogen-I, I/II ratio, and gastrin were 9.8 ng/mL (AUC: 0.895), 1.8 (AUC: 0.86), and 355 pg/mL (AUC: 0.897), respectively. In conclusion, endoscopic atrophy is a predictor of AIG. High serum gastrin and low pepsinogen-I and I/II ratio are predictors even in the case of severe atrophy, suggesting their usefulness when the diagnosis of AIG is difficult or as serological screening tests.

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Efficacy and safety of low-dose rifabutin-based 7-day triple therapy as a third- or later-line Helicobacter pylori eradication regimen

Inokuchi K., Mori H., Matsuzaki J., Hirata K., Harada Y., Saito Y., Suzuki H., Kanai T., Masaoka T.

Helicobacter （Helicobacter）  27 （ 4 ）  2022年08月

ISSN  10834389

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Background: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. Materials and Methods: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. Results: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%–99% and 92.7%, 95% CI: 86%–100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. Conclusions: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

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AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study

Matsuoka K., Watanabe M., Ohmori T., Nakajima K., Ishida T., Ishiguro Y., Kanke K., Kobayashi K., Hirai F., Watanabe K., Mizusawa H., Kishida S., Miura Y., Ohta A., Kajioka T., Hibi T., Motoya S., Maemoto A., Fujiya M., Ashida T., Goto M., Matsumoto T., Suzuki Y., Hamahata Y., Nakagawa T., Kato N., Kato J., Endo Y., Suzuki R., Matsuda K., Ohmiya N., Katsushima S., Hosomi S., Tarumi K.i., Watanabe C., Saito M., Yokoyama Y., Inaba T., Sakata Y., Hongo H., Shibuya T., Kawakami K., Kakuta Y., Irisawa A., Yoshimura N., Fukuda K., Shirai T., Ichikawa H., Nagata J., Suzuki T., Yokoyama K., Tomidokoro T., Kojima Y., Yamada M., Yamamoto H., Yamamoto T., Horiki N., Obata H., Inoue S., Tanaka S., Toyokawa T., Kunihiro M., Hisabe T., Ogata S., Takeshima F., Matsushima K., Matsuhashi N., Sakuraba H., Iwabuchi M., Tsuchiya A., Uchiyama K., Kanai T., Nakamura M., Yokoyama T., Hida N., Mitsuyama K., Osada T., Hiraoka S., Tsuzuki T., Masuo T., Hokari R., Kobayashi T., Saruta M., Araki M., Araki H., Shimizu M., Kikuchi M., Nishikawa T., Takedatsu H., Aoyagi K., Ochiai T., Toda N., Mizokami Y., Nagahori M., Matsueda K., Kino H., Kanamori A., Suzuki T., Sakurai T., Kudo M.

The Lancet Gastroenterology and Hepatology （The Lancet Gastroenterology and Hepatology）  7 （ 7 ） 648 - 657 2022年07月

ISSN  24681253

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Background: AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6–10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (<4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment. Findings: Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73−6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug. Interpretation: AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis. Funding: EA Pharma and Kissei Pharmaceutical. Translation: For the Japanese translation of the abstract see Supplementary Materials section.

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Development of a Deep-Learning Algorithm for Small Bowel-Lesion Detection and a Study of the Improvement in the False-Positive Rate

Hosoe N., Horie T., Tojo A., Sakurai H., Hayashi Y., Kamiya K.J.L.L., Sujino T., Takabayashi K., Ogata H., Kanai T.

Journal of Clinical Medicine （Journal of Clinical Medicine）  11 （ 13 ）  2022年07月

　概要を見る

Deep learning has recently been gaining attention as a promising technology to improve the identification of lesions, and deep-learning algorithms for lesion detection have been actively developed in small-bowel capsule endoscopy (SBCE). We developed a detection algorithm for abnormal findings by deep learning (convolutional neural network) the SBCE imaging data of 30 cases with abnormal findings. To enable the detection of a wide variety of abnormal findings, the training data were balanced to include all major findings identified in SBCE (bleeding, angiodysplasia, ulceration, and neoplastic lesions). To reduce the false-positive rate, “findings that may be responsible for hemorrhage” and “findings that may require therapeutic intervention” were extracted from the images of abnormal findings and added to the training dataset. For the performance evaluation, the sensitivity and the specificity were calculated using 271 detectable findings in 35 cases. The sensitivity was calculated using 68,494 images of non-abnormal findings. The sensitivity and specificity were 93.4% and 97.8%, respectively. The average number of images detected by the algorithm as having abnormal findings was 7514. We developed an image-reading support system using deep learning for SBCE and obtained a good detection performance.

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Th17 cells in the liver: balancing autoimmunity and pathogen defense

Taniki N., Nakamoto N., Chu P.S., Ichikawa M., Teratani T., Kanai T.

Seminars in Immunopathology （Seminars in Immunopathology）  44 （ 4 ） 509 - 526 2022年07月

ISSN  18632297

　概要を見る

In addition to carcinogenesis, T helper 17 (Th17) cells (a subtype of CD4 + T lymphocytes) are involved in the acute, chronic, and cirrhotic phases of liver diseases; however, their role in the development and progression of liver diseases remains unclear. It is difficult to elucidate the role of Th17 cells in liver diseases due to their dichotomous nature, i.e., plasticity in terms of pathogenic or host protective function depending on environmental and time phase factors. Moreover, insufficient depletion of Th17 cells by inhibiting the cytokines and transcription factors involved in their production causes difficulties in analyzing their specific role in vitro and in vivo murine models, partially due to complex interaction. This review summarizes the recent progress in understanding the plasticity and function of hepatic Th17 cells and type 3 cytokines.

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A successful case of endoscopic submucosal dissection using the water pressure method for early gastric cancer with severe fibrosis

Miyazaki K., Kato M., Kanai T., Yahagi N.

VideoGIE （VideoGIE）  7 （ 6 ） 219 - 222 2022年06月

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Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer

Toshimitsu K., Takano A., Fujii M., Togasaki K., Matano M., Takahashi S., Kanai T., Sato T.

Nature Chemical Biology （Nature Chemical Biology）  18 （ 6 ） 605 - 614 2022年06月

ISSN  15524450

　概要を見る

Precision oncology presumes an accurate prediction of drug response on the basis of the molecular profile of tumors. However, the extent to which patient-derived tumor organoids recapitulate the response of in vivo tumors to a given drug remains obscure. To gain insights into the pharmacobiology of human colorectal cancer (CRC), we here created a robust drug screening platform for patient-derived colorectal organoids. Application of suspension culture increased organoid scalability, and a refinement of the culture condition enabled incorporation of normal and precursor organoids to high-throughput drug screening. Drug screening identified bromodomain and extra-terminal (BET) bromodomain protein inhibitor as a cancer-selective growth suppressor that targets genes aberrantly activated in CRC. A multi-omics analysis identified an association between checkpoint with forkhead and ring finger domaines (CHFR) silencing and paclitaxel sensitivity, which was further validated by gene engineering of organoids and in xenografts. Our findings highlight the utility of multiparametric validation in enhancing the biological and clinical fidelity of a drug screening system. [Figure not available: see fulltext.]

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Texture and color enhancement imaging in combination with indigo carmine dye spraying to highlight the border of flat ulcerative colitis–associated neoplasia

Takabayashi K., Kato M., Sugimoto S., Yahagi N., Kanai T.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy）  95 （ 6 ） 1273 - 1275 2022年06月

ISSN  00165107

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Heterogeneity of ILC2s in the Intestine; Homeostasis and Pathology

Sunaga S., Tsunoda J., Teratani T., Mikami Y., Kanai T.

Frontiers in Immunology （Frontiers in Immunology）  13 2022年05月

　概要を見る

Group 2 innate lymphoid cells (ILC2s) were identified in 2010 as a novel lymphocyte subset lacking antigen receptors, such as T-cell or B-cell receptors. ILC2s induce local immune responses characterized by producing type 2 cytokines and play essential roles for maintaining tissue homeostasis. ILC2s are distributed across various organs, including the intestine where immune cells are continuously exposed to external antigens. Followed by luminal antigen stimulation, intestinal epithelial cells produce alarmins, such as IL-25, IL-33, and thymic stromal lymphopoietin, and activate ILC2s to expand and produce cytokines. In the context of parasite infection, the tuft cell lining in the epithelium has been revealed as a dominant source of intestinal IL-25 and possesses the capability to regulate ILC2 homeostasis. Neuronal systems also regulate ILC2s through neuropeptides and neurotransmitters, and interact with ILC2s bidirectionally, a process termed “neuro-immune crosstalk”. Activated ILC2s produce type 2 cytokines, which contribute to epithelial barrier function, clearance of luminal antigens and tissue repair, while ILC2s are also involved in chronic inflammation and tissue fibrosis. Recent studies have shed light on the contribution of ILC2s to inflammatory bowel diseases, mainly comprising ulcerative colitis and Crohn’s disease, as defined by chronic immune activation and inflammation. Modern single-cell analysis techniques provide a tissue-specific picture of ILC2s and their roles in regulating homeostasis in each organ. Particularly, single-cell analysis helps our understanding of the uniqueness and commonness of ILC2s across tissues and opens the novel research area of ILC2 heterogeneity. ILC2s are classified into different phenotypes depending on tissue and phase of inflammation, mainly inflammatory and natural ILC2 cells. ILC2s can also switch phenotype to ILC1- or ILC3-like subsets. Hence, recent studies have revealed the heterogeneity and plasticity of ILC2, which indicate dynamicity of inflammation and the immune system. In this review, we describe the regulatory mechanisms, function, and pathological roles of ILC2s in the intestine.

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Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios⁺ Tregs in the gut

Yoshimatsu Y., Sujino T., Miyamoto K., Harada Y., Tanemoto S., Ono K., Umeda S., Yoshida K., Teratani T., Suzuki T., Mikami Y., Nakamoto N., Sasaki N., Takabayashi K., Hosoe N., Ogata H., Sawada K., Imamura T., Yoshimura A., Kanai T.

Cell Reports （Cell Reports）  39 （ 6 ）  2022年05月

　概要を見る

CD4+Foxp3+ regulatory T cells (Tregs) are essential for homeostasis in the colon, but the mechanism by which local environmental cues determine the localization of colonic Tregs is unclear. Here, we administer indigo naturalis (IN), a nontoxic phytochemical aryl hydrocarbon receptor (AhR) agonist used for treating patients with ulcerative colitis (UC) in Asia, and we show that IN increases Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Interactions between Tregs and MHC class II+ ECs occur mainly near the crypt bottom in the steady state, whereas Tregs dramatically increase and shift toward the crypt top following IN treatment. Moreover, the number of CD25+ T cells is increased near the surface of ECs in IN-treated UC patients compared with that in patients treated with other therapies. We also highlight additional AhR-signaling mechanisms in intestinal ECs that determine the accumulation and localization of Helios+ Tregs in the colon.

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A significant risk of metabolic dysfunction-associated fatty liver disease plus diabetes on subclinical atherosclerosis

Bessho R., Kashiwagi K., Ikura A., Yamataka K., Inaishi J., Takaishi H., Kanai T.

PLoS ONE （PLoS ONE）  17 （ 5 May ）  2022年05月

　概要を見る

Background This cross-sectional study aims to investigate the association between subclinical atherosclerosis and metabolic dysfunction-associated fatty liver disease (MAFLD) or non-alcoholic fatty liver disease (NAFLD), and a synergistic effect of diabetes mellitus (DM) and MAFLD on subclinical atherosclerosis. Methods Of 977 subjects who underwent health checkups with coronary artery calcification (CAC), carotid intima-media thickness, and brachial-ankle pulse wave velocity (ba-PWV), 890 were included in this study. They were classified as MAFLD, NAFLD, or Neither-FLD, and MAFLD was further categorized into three groups by three metabolic disorders (obesity, lean with metabolic dysregulation, DM), according to its new definition: Obesity-MAFLD, Lean-MAFLD and DM-MAFLD. Results In a multivariable analysis, MAFLD and NAFLD were significantly associated with subclinical atherosclerosis, except for an association between ba-PWV and NAFLD. MAFLD had higher odds for CAC than NAFLD (for CAC score > 100, odds ratio (OR) = 2.599, 95% confidence interval (CI) = 1.625–4.157; OR = 1.795, 95%CI = 1.145–2.814, respectively). In a sub-analysis, DM-MAFLD had higher odds for CAC (for CAC score > 100, OR = 5.833, 95% CI = 3.047–11.164) than the other groups of MAFLD, when compared to Neither FLD as a reference. Moreover, DM-MAFLD had a higher level of homeostasis model assessment of insulin resistance and high sensitive C-reactive protein, compared to the other groups of MAFLD. Conclusions MAFLD was significantly associated with subclinical atherosclerosis in the general population. Additionally, DM-MAFLD could be a significant risk factor for cardiovascular disease through insulin resistance and low-grade inflammation and requires careful follow-up or appropriate intervention.

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Advanced endoscopy for the management of inflammatory digestive diseases: Review of the Japan Gastroenterological Endoscopy Society core session

Matsuura M., Matsumoto T., Naito Y., Saitoh Y., Kanai T., Suzuki Y., Tanaka S., Ogata H., Hisamatsu T.

Digestive Endoscopy （Digestive Endoscopy）  34 （ 4 ） 729 - 735 2022年05月

ISSN  09155635

　概要を見る

A series of workshops entitled “Advanced endoscopy in the management of inflammatory digestive disease” was held at the 97th to 100th biannual meeting of the Japan Gastroenterological Endoscopy Society. During these core sessions, research findings concerning various endoscopic practices in the field of inflammatory bowel disease (IBD) were presented, and meaningful discussions were shared on the evolving role and future challenges of endoscopy in IBD. This article reviews these core sessions and discusses current topics on the role of endoscopy, focusing on the diagnosis, disease monitoring, mucosal healing assessments, cancer surveillance, and therapeutic interventions in IBD.

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Intracellular metabolic adaptation of intraepithelial CD4⁺CD8αα⁺ T lymphocytes

Harada Y., Sujino T., Miyamoto K., Nomura E., Yoshimatsu Y., Tanemoto S., Umeda S., Ono K., Mikami Y., Nakamoto N., Takabayashi K., Hosoe N., Ogata H., Ikenoue T., Hirao A., Kubota Y., Kanai T.

iScience （iScience）  25 （ 4 ）  2022年04月

　概要を見る

Intestinal intraepithelial lymphocytes (IELs), the first line of defense against microbial and dietary antigens, are classified as natural or induced based on their origin and receptor expression. Induced CD4+CD8αα+TCRβ+ T cells (double positive, DPIELs) originated from CD4+CD8α−TCRβ+ T cells (single positive, SPIELs) increase with aging. However, the metabolic requirements and the metabolic-related genes in IEL development remain unclear. We determined that the intraepithelial compartment is hypoxic in the presence of microbes and DPIELs increased more than natural IELs in this location. Moreover, DPIELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DPIELs adapt to their surrounding oxygen-deprived environment in peripheral tissues by modulating specific genes, including hypoxia-inducible factor, mammalian target of rapamycin complexes (mTORC), phosphorylated ribosomal protein S6 (pS6), and other glycolytic factors. Our findings provide valuable insight into the metabolic properties of IELs.

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Effectiveness and Durability of Ustekinumab Therapy With or Without Immunomodulators for Ulcerative Colitis Patients in Japan

Aoki Y., Sujino T., Kawaguchi T., Sugimoto S., Shimada F., Yoshimatsu Y., Kiyohara H., Nanki K., Mikami Y., Takabayashi K., Hosoe N., Ogata H., Iwao Y., Kanai T.

Crohn's and Colitis 360 （Crohn's and Colitis 360）  4 （ 2 ）  2022年04月

　概要を見る

Background and Aims: The effectiveness and durability of ustekinumab therapy with or without thiopurine immunomodulators (IMs) for ulcerative colitis (UC) in real-world Asian, Japanese patients have not yet been elucidated. Methods: To evaluate the additive effects of IMs on ustekinumab, a retrospective cohort study of UC patients receiving ustekinumab with or without thiopurine IMs, azathioprine or 6-mercaptopurine, was conducted from March 2020 to August 2021. The primary endpoint was clinical remission or response rate at week 8. The secondary endpoints were clinical remission or response rates at weeks 24 and 52, the durability of each treatment, and adverse events. Results: Of the 50 patients with UC treated with ustekinumab, 42 were enrolled. Sixteen patients were treated with a combination of ustekinumab and an IM. The clinical response rates of all patients at weeks 8, 24, and 52 were 53.7%, 63.3%, and 42.9%, respectively. There was no significant difference in the clinical responses or remission rates between the combination therapy and monotherapy groups at weeks 8, 24, and 52. (50.0% vs. 56.0%, P =. 757; 70.0% vs. 60.0%, P =. 702; and 42.9% vs. 42.9%, P = 1.00, respectively). A Kaplan-Meier analysis showed no difference in IM use on the durability of ustekinumab treatment (log-rank test; P =. 955). Conclusions: The response rate for Japanese UC patients is similar to previous reports based on American and European UC patients. There was no significant difference between the ustekinumab monotherapy group and the ustekinumab and IM combination group in the real world.

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Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases

Matsubara Y., Kiyohara H., Teratani T., Mikami Y., Kanai T.

Neuropharmacology （Neuropharmacology）  205 2022年03月

ISSN  00283908

　概要を見る

The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.

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Vagus nerve-mediated intestinal immune regulation: Therapeutic implications of inflammatory bowel diseases

Mikami Y., Tsunoda J., Kiyohara H., Taniki N., Teratani T., Kanai T.

International Immunology （International Immunology）  34 （ 2 ） 97 - 106 2022年02月

ISSN  09538178

　概要を見る

The pathophysiology of inflammatory bowel diseases (IBDs) involves immunological, genetic and environmental factors. Through its ability to sense environmental stimuli, the autonomic nervous system plays a key role in the development and persistence of IBDs. The vagus nerve (VN), which contains sensory and motor neurons, travels throughout the body to innervate the gut and other visceral organs in the thoracic and abdominopelvic cavities. Recent studies show that the VN has anti-inflammatory effects via the release of acetylcholine, in what is known as the cholinergic anti-inflammatory pathway (CAIP). In the gut immune system, the CAIP is proposed to be activated directly by signals from the gut and indirectly by signals from the liver, which receives gut-derived bioactive substances via the portal vein and senses the status of the gut. The gut-brain axis and liver-brain-gut reflex arc regulate a wide variety of peripheral immune cells to maintain homeostasis in the gut. Therefore, targeting the neural reflex by methods such as VN stimulation is now under investigation for suppressing intestinal inflammation associated with IBDs. In this review, we describe the role of the VN in the regulation of intestinal immunity, and we discuss novel therapeutic approaches for IBDs that target neuroimmune interactions.

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Endoscopic resection of the rectal mucosal bridge after surgery for Hirschsprung's disease

Iwata K., Kato M., Takabayashi K., Kanai T., Yahagi N.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy）  95 （ 2 ） 392 - 393 2022年02月

ISSN  00165107

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Endoscopic Diagnosis of Biliary Stricture Combined with Digital Cholangioscope: A Case Series

Fukuhara S., Iwasaki E., Kayashima A., Machida Y., Tamagawa H., Kawasaki S., Horibe M., Hori S., Abe Y., Kitago M., Ogata H., Kanai T.

Healthcare (Switzerland) （Healthcare (Switzerland)）  10 （ 1 ）  2022年01月

　概要を見る

The endoscopic diagnosis of biliary tract lesions is applied as a non-invasive method; however, its diagnostic accuracy is not yet high. Moreover, digital cholangioscopy is used for directly visualizing the inside of the bile duct, resulting in a more precise biopsy. We present the case series of the outcomes of diagnosis using digital cholangioscopy in patients who underwent cholangioscopy for the evaluation of biliary stenosis in our department between January 2014 and March 2021. The controls were those who underwent a biopsy for biliary stenosis with conventional endoscopic retrograde cholangiopancreatography (ERCP). Background data for each case were collected, and the clinical outcomes by biopsy were evaluated, focusing on the accuracy of the diagnosis. Cholangioscopy was performed in 15 cases, while a conventional biopsy by ERCP was performed in 172 cases. Nine of 15 cases (60.0%) were diagnosed with cholangiocarcinoma. The number of specimens obtained through conventional ERCP and cholangioscopy was 2.5 ± 1.3 and 3.3 ± 1.5, respectively (p = 0.043). The diagnostic accuracy of conventional ERCP and cholangioscopy were 65.7% (113 of 172 cases) and 100%, respectively, which was significantly higher in the group with cholangioscopy. Digital cholangioscopy is useful when the diagnosis of the biliary stricture using the conventional ERCP method is difficult.

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Potential benefits of immunomodulator use with vedolizumab for maintenance of remission in ulcerative colitis

Naganuma M., Watanabe K., Motoya S., Ogata H., Matsui T., Suzuki Y., Ursos L., Sakamoto S., Shikamura M., Hori T., Fernandez J., Watanabe M., Hibi T., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) （Journal of Gastroenterology and Hepatology (Australia)）  37 （ 1 ） 81 - 88 2022年01月

ISSN  08159319

　概要を見る

Background and Aim: This study aimed to determine the efficacy and safety of vedolizumab treatment with or without concomitant immunomodulator use in Japanese patients with moderate-to-severe ulcerative colitis. Methods: Among enrolled patients in a phase 3 study conducted in Japan (clinicaltrials.gov, NCT02039505), data from patients allocated to 300-mg intravenous vedolizumab for induction and maintenance phases were used for this exploratory analysis. Efficacy endpoints were clinical response, clinical remission, and mucosal healing at week 10 and clinical remission and mucosal healing at week 60, and disease worsening and treatment failure during the maintenance phase. Results: At week 10, the differences in clinical response, clinical remission, and mucosal healing rates between the subgroups (those with concomitant immunomodulator use minus those without) were 0.7 (95% confidence interval: −14.3, 15.7), 3.3 (95% confidence interval: −8.5, 15.2), and 1.8 (95% confidence interval: −13.0, 16.5), respectively. At week 60, the differences in clinical remission and mucosal healing between the subgroups with and without concomitant immunomodulator use were 26.1 (95% confidence interval: −3.5, 55.6) and 29.9 (95% confidence interval: 1.4, 58.4), respectively. The proportions of patients without treatment failure at day 330 of the maintenance phase were 90.7% with concomitant immunomodulator use and 73.7% without. No marked differences in incidence of infections were observed between subgroups. Conclusions: This study suggested the possibility that concomitant immunomodulator use may be beneficial to maintain the clinical efficacy of vedolizumab.

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Development of plasma ghrelin level as a novel marker for gastric mucosal atrophy after Helicobacter pylori eradication

Mori H., Suzuki H., Matsuzaki J., Kameyama K., Igarashi K., Masaoka T., Kanai T.

Annals of Medicine （Annals of Medicine）  54 （ 1 ） 170 - 180 2022年

ISSN  07853890

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Background and aim: The severity of atrophic gastritis is significantly associated with the risk of gastric cancer. Although the current gold standard for assessing the gastric cancer risk is esophagogastroduodenoscopy with a pathological examination, the development of less-invasive biomarkers is warranted for efficient risk stratification of gastric cancer. Serum pepsinogens (PGs) are biomarkers used to predict the extent of gastric mucosal atrophy; however, they are not an accurate reflection of gastric mucosal atrophy after Helicobacter pylori eradication. The present study was conducted to investigate the usefulness of plasma ghrelin levels as a marker for gastric mucosal atrophy, and as a risk stratification marker for gastric cancer, even after H. pylori eradication. Methods: Patients who received H. pylori eradication treatment were enrolled in the study. The severity of gastric mucosal atrophy was evaluated both endoscopically and histologically. Serum pepsinogen and plasma ghrelin levels were measured before and at 1, 12, 24, and 48 weeks after treatment. The study was approved by the Research Ethics Committee of the Keio University School of Medicine (no. 20140102; 8 July 2014). Results: Eighteen patients completed the study protocol. Total and acyl plasma ghrelin levels demonstrated no significant change from before treatment to 48 weeks after eradication; however, there was a significant difference between open-type and closed-type atrophic gastritis. The PG I/II ratio increased significantly from 48 weeks after H. pylori eradication. The severity of the histological intestinal metaplasia scores correlated inversely with plasma total ghrelin levels from before to 48 weeks after H. pylori eradication. Conclusion: Plasma levels of ghrelin correlate well with the level of gastric mucosal atrophy, even after H. pylori eradication.KEY MESSAGES Ghrelin plasma levels are associated with the progression of endoscopic atrophic gastritis, even at 48 weeks after H. pylori eradication. Ghrelin plasma levels are also associated with increased severity of histological intestinal metaplasia 48 weeks after H. pylori eradication. Pepsinogen I/II ratios increased immediately after H. pylori eradication and are inappropriate for assessing atrophic gastritis after H. pylori eradication.

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