論文 - 金井　隆典

Analysis of risk factors for immune-related adverse events in various solid tumors using real-world data

Shimozaki K., Sukawa Y., Sato Y., Horie S., Chida A., Tsugaru K., Togasaki K., Kawasaki K., Hirata K., Hayashi H., Hamamoto Y., Kanai T.

Future Oncology （Future Oncology）  17 （ 20 ） 2593 - 2603 2021年07月

ISSN  14796694

　概要を見る

The aim of this study was to determine the risk factors for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. The authors conducted a retrospective study in which patients with malignant melanoma, non-small-cell lung cancer, gastric cancer or renal cell carcinoma who received anti-PD-1/PD-L1 antibodies were included. Of 247 patients, 118 developed a total of 182 irAEs. In the multivariate Fine-Gray regression analysis, serum albumin level ≥3.6 g/dl (hazard ratio: 1.62; 95% CI: 1.10-2.39; p = 0.015) and history of Type I hypersensitivity reactions (hazard ratio: 1.48; 95% CI: 1.02-2.14; p = 0.037) were significantly associated with the development of irAEs. High serum albumin levels and history of Type I hypersensitivity reactions are risk factors for irAEs.

• Access to Document (DOI)

Rikkunshito as a Therapeautic Agent for Functional Dyspepsia and its Prokinetic and Non-Prokinetic Effects

Inokuchi K., Masaoka T., Kanai T.

Frontiers in Pharmacology （Frontiers in Pharmacology）  12 2021年06月

　概要を見る

Prokinetics is one of the therapeutic agents for functional and motility disorders of the stomach. However, its efficacy is limited. Kampo medicine is a unique medical system that was developed in Japan. In Kampo medicine, herbal medicine is prescribed based on the patient’s condition. Therefore, even for functional and motility disorders of the stomach, some herbal medicines are considered as a therapeutic option. Recently, there has been an increase in evidence for the efficacy or the mechanism of herbal medicine for functional and motility disorders of the stomach. Among these, rikkunshito is a well-studied herbal medicine that could be used as an alternative to prokinetics. In this review, we discuss the possibilities of rikkunshito for functional dyspepsia with its prokinetic and non-prokinetic effects and provide an overview of their current use with a focus on their therapeutic mechanism.

• Access to Document (DOI)

Clinical, Endoscopic, and Pathological Characteristics of Immune Checkpoint Inhibitor-Induced Gastroenterocolitis

Hayashi Y., Hosoe N., Takabayashi K., Limpias Kamiya K.J.L., Tsugaru K., Shimozaki K., Hirata K., Fukuhara K., Fukuhara S., Mutaguchi M., Sujino T., Sukawa Y., Hamamoto Y., Naganuma M., Takaishi H., Shimoda M., Ogata H., Kanai T.

Digestive Diseases and Sciences （Digestive Diseases and Sciences）  66 （ 6 ） 2129 - 2134 2021年06月

ISSN  01632116

• Access to Document (DOI)

Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study

Shinzaki S., Matsuoka K., Tanaka H., Takeshima F., Kato S., Torisu T., Ohta Y., Watanabe K., Nakamura S., Yoshimura N., Kobayashi T., Shiotani A., Hirai F., Hiraoka S., Watanabe M., Matsuura M., Nishimoto S., Mizuno S., Iijima H., Takehara T., Naka T., Kanai T., Matsumoto T.

Journal of Gastroenterology （Journal of Gastroenterology）  56 （ 6 ） 560 - 569 2021年06月

ISSN  09441174

　概要を見る

Background: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD). Methods: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn’s disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC. Results: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426). Conclusions: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.

• Access to Document (DOI)

Long-Term Observation of Cyclosporine as Second-Line Therapy in Adults for Severe Acute Autoimmune Hepatitis

Noguchi F., Chu P.s., Taniki N., Yoshida A., Morikawa R., Yamaguchi A., Ikura A., Yamataka K., Hoshi H., Usui S., Ebinuma H., Saito H., Kanai T., Nakamoto N.

Hepatology （Hepatology）  73 （ 6 ） 2594 - 2597 2021年06月

ISSN  02709139

• Access to Document (DOI)

Current status of colon capsule endoscopy

Hosoe N., Limpias Kamiya K.J.L., Hayashi Y., Sujino T., Ogata H., Kanai T.

Digestive Endoscopy （Digestive Endoscopy）  33 （ 4 ） 529 - 537 2021年05月

ISSN  09155635

　概要を見る

While both the annual incidence and mortality of colorectal cancer are slowly but steadily decreasing in the United States, the incidence of such malignancy is increasing in Japan. Thus, controlling colorectal cancer in Japan is a major concern. In 2006, colon capsule endoscopy was first introduced by Eliakim et al. First-generation colon capsule endoscopy had a moderate sensitivity for detecting polyps of more than 6 mm. Thus, second-generation colon capsule endoscopy was developed to achieve higher sensitivity. Colonoscopy is the gold standard tool for colorectal cancer surveillance. With an improvement in the imaging function, the performance of second-generation colon capsule endoscopy is almost as satisfactory as that of colonoscopy. Certain situations, such as incomplete colonoscopy and contraindication for use of sedation, can benefit from colon capsule endoscopy. Colon capsule endoscopy requires a more extensive bowel preparation than colonoscopy and computed tomography colonography because it requires laxatives not only for bowel cleansing but also for promoting the excretion of the capsule. Another problem with colon capsule endoscopy includes the burden of reading and interpretation and overlook of the lesions. Currently, the development of automatic diagnosis of colon capsule endoscopy using artificial intelligence is still under progress. Although the available guidelines do not support the use of colon capsule endoscopy for inflammatory bowel disease, the possible application of colon capsule endoscopy is ulcerative colitis. This review article summarizes and focuses on the current status of colon capsule endoscopy for colorectal cancer screening and the possibility for its applicability on inflammatory bowel disease.

• Access to Document (DOI)

Oncogenic KRAS–expressing organoids with biliary epithelial stem cell properties give rise to biliary tract cancer in mice

Kasuga A., Semba T., Sato R., Nobusue H., Sugihara E., Takaishi H., Kanai T., Saya H., Arima Y.

Cancer Science （Cancer Science）  112 （ 5 ） 1822 - 1838 2021年05月

ISSN  13479032

　概要を見る

Biliary tract cancer (BTC) arises from biliary epithelial cells (BECs) and includes intrahepatic cholangiocarcinoma (IHCC), gallbladder cancer (GC), and extrahepatic cholangiocarcinoma (EHCC). Although frequent KRAS mutations and epigenetic changes at the INK4A/ARF locus have been identified, the molecular pathogenesis of BTC is unclear and the development of corresponding anticancer agents remains inadequate. We isolated epithelial cell adhesion molecule (EpCAM)–positive BECs from the mouse intrahepatic bile duct, gallbladder, and extrahepatic bile duct, and established organoids derived from these cells. Introduction of activated KRAS and homozygous deletion of Ink4a/Arf in the cells of each organoid type conferred the ability to form lethal metastatic adenocarcinoma with differentiated components and a pronounced desmoplastic reaction on cell transplantation into syngeneic mice, indicating that the manipulated cells correspond to BTC–initiating cells. The syngeneic mouse models recapitulate the pathological features of human IHCC, GC, and EHCC, and they should therefore prove useful for the investigation of BTC carcinogenesis and the development of new therapeutic strategies. Tumor cells isolated from primary tumors formed organoids in three-dimensional culture, and serial syngeneic transplantation of these cells revealed that their cancer stem cell properties were supported by organoid culture, but not by adherent culture. Adherent culture thus attenuated tumorigenic activity as well as the expression of both epithelial and stem cell markers, whereas the expression of epithelial-mesenchymal transition (EMT)–related transcription factor genes and mesenchymal cell markers was induced. Our data show that organoid culture is important for maintenance of epithelial cell characteristics, stemness, and tumorigenic activity of BTC–initiating cells.

• Access to Document (DOI)

Factors predicting major complications, mortality, and recovery in percutaneous endoscopic gastrostomy

Limpias Kamiya K.J.L., Hosoe N., Takabayashi K., Hayashi Y., Fukuhara S., Mutaguchi M., Nakamura R., Kawakubo H., Kitagawa Y., Ogata H., Kanai T.

JGH Open （JGH Open）  5 （ 5 ） 590 - 598 2021年05月

　概要を見る

Background and Aim: Percutaneous endoscopic gastrostomy (PEG) has been used in patients with dysphagia and inadequate food intake via an oral route. Despite being a procedure with a high success rate, complications and death have been reported. The aim was to identify the factors related to major complications and mortality, as well as PEG removal prognostic factors due to improvement of their general condition. Methods: Patient characteristics, comorbidities, laboratory data, concomitant medication, sedation, and indication for PEG placement were collected. Major complications, mortality, and PEG removal factors were assessed. Results: A total of 388 patients were enrolled. There were 15 (3.9%) cases of major complications, with major bleeding being the most frequent in 6 (1.5%) patients. Corticosteroids were the independent variable associated with major complications (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.71–20; P = <0.01). Advanced cancer (hazard ratio [HR] 0.5; 95% CI 0.3–1; P = 0.05), albumin (HR 0.6; 95% CI 0.4–0.9; P = <0.01), and C-reactive protein (CRP) (HR 1.1; CI 1–1.2; P = 0.01) were considered risk factors for mortality. Previous pneumonia (HR 0.4; CI 0.2–0.9; P = 0.02) was a factor for permanent use of a PEG; however, oncological indication (HR 8.2; CI 3.2–21; P = <0.01) was factors for PEG withdrawal. Conclusions: Chronic corticosteroid users potentially present with major complications. Low albumin levels and elevated CRP were associated with death. Previous aspiration pneumonia was a factor associated with permanent use of PEG; however, patients with oncological indication were the most benefited.

• Access to Document (DOI)

Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells

Teratani T., Tomita K., Wada A., Sugihara N., Higashiyama M., Inaba K., Horiuchi K., Hanawa Y., Nishii S., Mizoguchi A., Tanemoto R., Ito S., Okada Y., Kurihara C., Akita Y., Narimatsu K., Watanabe C., Komoto S., Oike Y., Miura S., Hokari R., Kanai T.

Hepatology Research （Hepatology Research）  51 （ 5 ） 580 - 592 2021年05月

ISSN  13866346

　概要を見る

Aim: We recently reported that lipoprotein lipase (LPL)-mediated free cholesterol (FC) accumulation in hepatic stellate cells (HSCs) augmented liver fibrosis in non-alcoholic steatohepatitis (NASH). The aim of the present study was to explore the role of angiopoietin-like protein 4 (Angptl4), an LPL inhibitor, in the pathogenesis of liver fibrosis in NASH. Methods: Angptl4-deficient or wild-type mice were used to investigate the role of Angptl4 in the pathogenesis of NASH induced by feeding a methionine- and choline-deficient diet. We also examined the effect of Angptl4 on FC accumulation in HSCs, and the subsequent activation of HSCs, using Angptl4-deficient HSCs. Results: In the NASH model, Angptl4-deficient mice had significantly aggravated liver fibrosis and activated HSCs without enhancement of hepatocellular injury, liver inflammation, or liver angiogenesis. FC levels were significantly higher in HSCs from Angptl4-deficient mice than in those from wild-type mice. Treatment with Angptl4 reversed low-density lipoprotein-induced FC accumulation in HSCs through the inhibition of LPL. The Angptl4 deficiency-induced FC accumulation in HSCs suppressed HSC expression of the transforming growth factor-β (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-β-induced activation in vivo and in vitro. Conclusions: Angptl4 plays an important role in the pathogenesis of FC accumulation in HSCs. In addition, regulation of FC levels in HSCs by Angptl4 plays a critical role in the pathogenesis of liver fibrosis in NASH. Thus, Angptl4 could represent a novel therapeutic option for NASH.

• Access to Document (DOI)

Endoscopic diagnosis for colorectal sessile serrated lesions

Nishizawa T., Yoshida S., Toyoshima A., Yamada T., Sakaguchi Y., Irako T., Ebinuma H., Kanai T., Koike K., Toyoshima O.

World Journal of Gastroenterology （World Journal of Gastroenterology）  27 （ 13 ） 1321 - 1329 2021年04月

ISSN  10079327

　概要を見る

BACKGROUND Hyperplastic polyps are considered non-neoplastic, whereas sessile serrated lesions (SSLs) are precursors of cancer via the ''serrated neoplastic pathway''. The clinical features of SSLs are tumor size (> 5 mm), location in the proximal colon, coverage with abundant mucus called the ''mucus cap'', indistinct borders, and a cloud-like surface. The features in magnifying narrow-band imaging are varicose microvascular vessels and expanded crypt openings. However, accurate diagnosis is often difficult. AIM To develop a diagnostic score system for SSLs. METHODS We retrospectively reviewed consecutive patients who underwent endoscopic resection during colonoscopy at the Toyoshima endoscopy clinic. We collected data on serrated polyps diagnosed by endoscopic or pathological examination. The significant factors for the diagnosis of SSLs were assessed using logistic regression analysis. Each item that was significant in multivariate analysis was assigned 1 point, with the sum of these points defined as the endoscopic SSL diagnosis score. The optimal cut-off value of the endoscopic SSL diagnosis score was determined by receiver-operating characteristic curve analysis. RESULTS Among 1288 polyps that were endoscopically removed, we analyzed 232 diagnosed as serrated polyps by endoscopic or pathological examination. In the univariate analysis, the location (proximal colon), size (> 5 mm), mucus cap, indistinct borders, cloud-like surface, and varicose microvascular vessels were significantly associated with the diagnosis of SSLs. In the multivariate analysis, size (> 5 mm; P = 0.033), mucus cap (P = 0.005), and indistinct borders (P = 0.033) were independently associated with the diagnosis of SSLs. Size > 5 mm, mucus cap, and indistinct borders were assigned 1 point each and the sum of these points was defined as the endoscopic SSL diagnosis score. The receiver-operating characteristic curve analysis showed an optimal cut-off score of 3, which predicted pathological SSLs with 75% sensitivity, 80% specificity, and 78.4% accuracy. The pathological SSL rate for an endoscopic SSL diagnosis score of 3 was significantly higher than that for an endoscopic SSL diagnosis score of 0, 1, or 2 (P < 0.001). CONCLUSION Size > 5 mm, mucus cap, and indistinct borders were significant endoscopic features for the diagnosis of SSLs. Serrated polyps with these three features should be removed during colonoscopy.

• Access to Document (DOI)

An organoid-based organ-repurposing approach to treat short bowel syndrome

Sugimoto S., Kobayashi E., Fujii M., Ohta Y., Arai K., Matano M., Ishikawa K., Miyamoto K., Toshimitsu K., Takahashi S., Nanki K., Hakamata Y., Kanai T., Sato T.

Nature （Nature）  592 （ 7852 ） 99 - 104 2021年04月

ISSN  00280836

　概要を見る

The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro1, but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging2. Here we generate a functional small intestinalized colon (SIC) by replacing the native colonic epithelium with ileum-derived organoids. We first find that xenotransplanted human ileum organoids maintain their regional identity and form nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer further reveals an essential role for luminal mechanistic flow in the formation of villi. We then develop a rat SIC model by repositioning the SIC at the ileocaecal junction, where the epithelium is exposed to a constant luminal stream of intestinal juice. This anatomical relocation provides the SIC with organ structures of the small intestine, including intact vasculature and innervation, villous structures, and the lacteal (a fat-absorbing lymphatic structure specific to the small intestine). The SIC has absorptive functions and markedly ameliorates intestinal failure in a rat model of SBS, whereas transplantation of colon organoids instead of ileum organoids invariably leads to mortality. These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment.

• Access to Document (DOI)

A significant association of non-obese non-alcoholic fatty liver disease with osteosarcopenic obesity in females 50 years and older

Kashiwagi K., Takayama M., Ichikawa H., Takaishi H., Iwao Y., Kanai T.

Clinical Nutrition ESPEN （Clinical Nutrition ESPEN）  42   166 - 172 2021年04月

ISSN  24054577

　概要を見る

Background & aims: Osteosarcopenic obesity (OSO) encompassing obesity, sarcopenia and osteopenia, is due to redistribution or infiltration of fat into muscle and bone. This cross-sectional study evaluated the association between OSO and non-alcoholic fatty liver disease (NAFLD). Methods: Obesity, sarcopenia and osteopenia was defined using the percentage of body fat mass, reduced muscle mass, and the percentage of young adult mean < 80%, measured by dual-energy x-ray absorptiometry, respectively. Non-obese and obese NAFLD was diagnosed by ultrasound and body mass index cut-off point (25 kg/m2). A total of 619 subjects ≥ 50 years who completed health checkups were divided into obesity group including OSO and sarcopenic obesity (SO) alone phenotype, and non-obesity group that did not belong to any phenotype, including standard (St). Results: Overall osteopenia and OSO were detected in only 10% and 1% in males, compared with 45% and 9% in females, respectively. Multivariate analysis for females demonstrated a significant association of OSO with non-obese NAFLD (odds ratio = 3.737, 95% confidence interval = 1.365–10.233, P = 0.010), while the association between SO alone and non-obese NAFLD was equivocal. The OSO phenotype had a significantly higher proportion of slower walking speed and weaker grip strength, compared to the St phenotype. The proportion of OSO increased with age in contrast to constant prevalence of non-obese NAFLD. Conclusion: Non-obese NAFLD had a significant association with OSO in females, independent of plausible confounders. These results suggest that non-obese NAFLD might be an independent risk factor for OSO.

• Access to Document (DOI)

Water pressure method for duodenal endoscopic submucosal dissection (with video)

Kato M., Takatori Y., Sasaki M., Mizutani M., Tsutsumi K., Kiguchi Y., Akimoto T., Mutaguchi M., Nakayama A., Takabayashi K., Maehata T., Kanai T., Yahagi N.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy）  93 （ 4 ） 942 - 949 2021年04月

ISSN  00165107

　概要を見る

Background and Aims: Duodenal endoscopic submucosal dissection (ESD) is considered technically challenging and has a high risk of adverse events. However, we recently made some progress with the ESD technique and device by introducing 2 features: a water pressure (WP) method and a second-generation ESD knife (DualKnife) with a water jet function (DualKnife J). The present study aimed to assess whether these changes improved the clinical outcomes of duodenal ESD. Methods: This was a retrospective observational study. Among all patients who underwent ESD for superficial duodenal epithelial tumors from June 2010 to December 2018, patients in whom a single expert performed the procedure were included in this study. Various factors, including the use of the WP method and ESD devices (DualKnife or DualKnife J) and the treatment phase (early, mid, and late), were analyzed to determine whether they were associated with intraprocedural perforation and procedure time. Treatment phase was assigned by dividing the study population equally into 3 subgroups according to the treatment phase. Results: The procedure time was significantly shorter, and the proportion of patients with intraprocedural perforations was the lowest in the late phase. Multivariate analysis of the use of the WP method revealed that it significantly decreased the intraprocedural perforation rate (odds ratio, 0.39; 95% confidence interval, 0.16-0.96), and analysis of the use of both the WP method (β coefficient, −0.40; P <.01) and the DualKnife J (β coefficient, −0.10; P =.032) revealed they were independently and negatively correlated with procedure time. Conclusion: The present study reveals that the WP method significantly reduced the intraprocedural perforation rate and that both the WP method and the DualKnife J significantly shortened procedure times for duodenal ESD.

• Access to Document (DOI)

Vulnerability to recurrent episodes of acute decompensation/acute-on-chronic liver failure characterizes those triggered by indeterminate precipitants in patients with liver cirrhosis

Hoshi H., Chu P.S., Yoshida A., Taniki N., Morikawa R., Yamataka K., Noguchi F., Kasuga R., Tabuchi T., Ebinuma H., Saito H., Kanai T., Nakamoto N.

PLoS ONE （PLoS ONE）  16 （ 4 April ）  2021年04月

　概要を見る

Background Acute decompensation (AD) of liver cirrhosis (LC) and subsequent acute-on-chronic liver failure (ACLF) are fatal and impair quality of life. Insufficient knowledge of the highly heterogeneous natural history of LC, including decompensation, re-compensation, and possible recurrent decompensation, hinders the development and application of novel therapeutics. Approximately 10%-50% of AD/ACLF is reported to be precipitated by any indeterminate (unidentifiable, cryptogenic, or unknown) acute insults; however, its clinical characteristics are unclear. Methods We conducted a single-center observational study of 2165 consecutively admitted patients with LC from January 2012 to December 2019. A total of 466 episodes of AD/ACLF in 285 patients, including their 285 first indexed AD/ACLF, were extracted for analysis. Stratified analyses of different acute precipitants, classified as indeterminate (AD/ACLFIND), bacterial infection (AD/ACLFBAC), gastrointestinal bleeding, active alcoholism, and miscellaneous, were performed. Results AD/ACLFIND was the leading acute precipitant (28%), followed by AD/ACLFBAC (23%). AD/ ACLFIND showed better survival outcomes than AD/ACLFBAC (P = 0.03); however, hyperbilirubinemia, hyponatremia, or leukocytosis significantly and uniquely characterized subgroups of AD/ACLFIND with comparable or even worse survival outcomes than those of AD/ ACLFBAC. Patients with subsequent AD/ACLF significantly tended to suffer from AD/ACLF with any organ failure in AD/ACLFIND but not in AD/ACLFBAC (P = 0.004, for trend). In competing risk analysis, patients with AD/ACLFIND were significantly more vulnerable to suffer from recurrent episodes of AD/ACLF within 180 days, compared to those triggered by other precipitants (P = 0.04). Conclusions AD/ACLFIND, the leading acute precipitant, also plays a role in subsequent AD/ACLF. An abruptly exacerbating, remitting, and relapsing nature of systemic inflammation underlying AD/ACLF may also be useful for risk estimation.

• Access to Document (DOI)

Monitoring of inflammatory bowel disease ―capsule endoscopy―

Hosoe N., Ogata H., Kanai T.

Journal of Japanese Society of Gastroenterology （Journal of Japanese Society of Gastroenterology）  118 （ 3 ） 221 - 228 2021年03月

ISSN  04466586

• Access to Document (DOI)

Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells

Suzuki M., Sujino T., Chiba S., Harada Y., Goto M., Takahashi R., Mita M., Hamase K., Kanai T., Ito M., Waldor M.K., Yasui M., Sasabe J.

Science Advances （Science Advances）  7 （ 10 ）  2021年03月

　概要を見る

Organisms use l-amino acids (l-aa) for most physiological processes. Unlike other organisms, bacteria chiral-convert l-aa to d-configurations as essential components of their cell walls and as signaling molecules in their ecosystems. Mammals recognize microbe-associated molecules to initiate immune responses, but roles of bacterial d-amino acids (d-aa) in mammalian immune systems remain largely unknown. Here, we report that amino acid chirality balanced by bacteria-mammal cross-talk modulates intestinal B cell fate and immunoglobulin A (IgA) production. Bacterial d-aa stimulate M1 macrophages and promote survival of intestinal naïve B cells. Mammalian intestinal d-aa catabolism limits the number of B cells and restricts growth of symbiotic bacteria that activate T cell–dependent IgA class switching of the B cells. Loss of d-aa catabolism results in excessive IgA production and dysbiosis with altered IgA coating on bacteria. Thus, chiral conversion of amino acids is linked to bacterial recognition by mammals to control symbiosis with bacteria.

• Access to Document (DOI)

Impact of Enteral Nutrition Within 24 Hours Versus Between 24 and 48 Hours in Patients With Severe Acute Pancreatitis: A Multicenter Retrospective Study

Nakashima I., Horibe M., Sanui M., Sasaki M., Sawano H., Goto T., Ikeura T., Takeda T., Oda T., Yasuda H., Ogura Y., Miyazaki D., Kitamura K., Chiba N., Ozaki T., Yamashita T., Koinuma T., Oshima T., Yamamoto T., Hirota M., Moriya T., Shirai K., Izai J., Takeda K., Sekino M., Iwasaki E., Kanai T., Mayumi T.

Pancreas （Pancreas）  50 （ 3 ） 371 - 377 2021年03月

　概要を見る

OBJECTIVES: In patients with severe acute pancreatitis (SAP), early enteral nutrition (EN) is recommended by major clinical practice guidelines, but the exact timing for the initiation of EN is unknown. METHODS: We conducted a post hoc analysis of the database for a multicenter (44 institutions) retrospective study of patients with SAP in Japan. The patients were classified into 3 groups according to the timing of EN initiation after the diagnosis of SAP: within 24 hours, between 24 and 48 hours, and more than 48 hours. The primary outcome was in-hospital mortality. RESULTS: Of the 1094 study patients, 176, 120, and 798 patients started EN within 24 hours, between 24 and 48 hours, and more than 48 hours after SAP diagnosis, respectively. On multivariable analysis, hospital mortality was significantly better with EN within 48 hours than with more than 48 hours (adjusted odds ratio, 0.49; 95% confidence interval, 0.29-0.83; P < 0.001) but did not significantly differ between the groups with EN starting within 24 hours and between 24 and 48 hours (P = 0.29). CONCLUSIONS: Enteral nutrition within 24 hours may not confer any additional benefit on clinical outcomes compared with EN between 24 and 48 hours.

• Access to Document (DOI)

C-C motif chemokine receptor 9 regulates obesity-induced insulin resistance via inflammation of the small intestine in mice

Amiya T., Nakamoto N., Irie J., Taniki N., Chu P.S., Koda Y., Miyamoto K., Yamaguchi A., Shiba S., Morikawa R., Itoh H., Kanai T.

Diabetologia （Diabetologia）  64 （ 3 ） 603 - 617 2021年03月

ISSN  0012186X

　概要を見る

Aims/hypothesis: Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms. Methods: To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks. Results: WT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4+ T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT. Conclusions/interpretation: CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut–VAT–liver axis. Graphical abstract: [Figure not available: see fulltext.]

• Access to Document (DOI)

Role of CC chemokine receptor 9 in the progression of murine and human non-alcoholic steatohepatitis

Morikawa R., Nakamoto N., Amiya T., Chu P.s., Koda Y., Teratani T., Suzuki T., Kurebayashi Y., Ueno A., Taniki N., Miyamoto K., Yamaguchi A., Shiba S., Katayama T., Yoshida K., Takada Y., Ishihara R., Ebinuma H., Sakamoto M., Kanai T.

Journal of Hepatology （Journal of Hepatology）  74 （ 3 ） 511 - 521 2021年03月

ISSN  01688278

　概要を見る

Background & Aims: The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH. Methods: Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9−/− mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH. Results: Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9−/− mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9+CD11b+ inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9−/− mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine. Conclusions: These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH. Lay summary: Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis.

• Access to Document (DOI)

Endoscopic ultrasound-guided sampling for personalized pancreatic cancer treatment

Iwasaki E., Fukuhara S., Horibe M., Kawasaki S., Seino T., Takimoto Y., Tamagawa H., Machida Y., Kayashima A., Noda M., Hayashi H., Kanai T.

Diagnostics （Diagnostics）  11 （ 3 ）  2021年03月

　概要を見る

Pancreatic cancer is the most lethal solid malignancy, and the number of patients with pancreatic cancer is increasing. Systemic chemotherapies are often ineffective for such patients, and there is an urgent need for personalized medicine. Unlike other types of cancer, personalized treatments for pancreatic cancer are still in development. Consequently, pancreatic cancer is less sensitive to anticancer drugs and is often refractory to common treatments. Therefore, advances in personalized medicine for pancreatic cancer are necessary. This review examined advances in personalized medicine for pancreatic cancer, including the use of endoscopic ultrasound (EUS)-guided sampling. EUS-guided sampling is widely used for diagnosing pancreatic tumors and is expected to be applied to sampled tissues. Additionally, there has been an increase in clinical research using EUS-guided sampling. The combination of precision medicine using genomic testing and pharmacological profiles based on high-throughput drug sensitivity testing using patient-derived organoids is expected to revolutionize pancreatic cancer treatment.

• Access to Document (DOI)