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1.
J Hepatobiliary Pancreat Sci ; 30(7): e46-e48, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36448320

RESUMO

Endoscopic ultrasonography rendezvous (EUS-RV) is useful in cases of difficult deep biliary cannulation. However, in malignant extrahepatic bile duct strictures (MEHBDS), transduodenal routes are challenging and the transgastric approach often requires fistula dilation. We report a case of resectable MEHBDS in which transgastric puncture from the antrum of the stomach as EUS-RV was useful.


Assuntos
Ductos Biliares Extra-Hepáticos , Colestase , Humanos , Endossonografia , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/cirurgia , Cateterismo , Ductos Biliares Extra-Hepáticos/diagnóstico por imagem , Ductos Biliares Extra-Hepáticos/cirurgia , Colestase/diagnóstico por imagem , Colestase/etiologia , Colestase/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Ultrassonografia de Intervenção , Drenagem
2.
J Gastroenterol Hepatol ; 37(9): 1768-1775, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35877196

RESUMO

BACKGROUND AND AIM: The functions of basophils have not been elucidated until recently because of their rarity. However, with recent developments in basophil-specific antibodies and basophil-deficient animals, the roles of basophils in various diseases related to chronic inflammation have been clarified. In this study, we aimed to investigate the roles of basophils in human ulcerative colitis (UC) and oxazolone (OXA) colitis using genetically engineered Mcpt8DTR mice. METHODS: Immunohistochemical staining of human colon specimens was performed to examine the involvement of basophils in the pathogenesis of UC. We examined the correlation between the number of infiltrating basophils and the UC endoscopic index of severity (UCEIS), Mayo score, and Matts score. We also examined the correlation between eosinophil count and basophil infiltration. In murine experiments, we examined whether basophil infiltration was involved in OXA-induced colitis and whether basophil depletion improved inflammation in Mcpt8DTR mice. RESULTS: Colonic basophil infiltration was significantly increased in patients with UC. There were significant correlations between UCEIS, Mayo score, Matts score, and the number of infiltrating basophils. In murine OXA-induced colitis, a significant increase in basophil infiltration was observed. When basophils were depleted by diphtheria toxin in Mcpt8DTR mice, inflammation improved significantly and mRNA expression of some proinflammatory cytokines, including Tnf-α and Ifn-γ decreased significantly. CONCLUSION: Basophil infiltration correlated with endoscopic, clinical, and pathological scores in human UC independently of eosinophil infiltration, and depletion of basophils ameliorated mucosal inflammation in murine OXA-induced colitis, collectively suggesting that basophils exert a proinflammatory role in chronic intestinal inflammation such as UC.


Assuntos
Colite Ulcerativa , Colite , Animais , Basófilos/metabolismo , Basófilos/patologia , Colite/induzido quimicamente , Colite/patologia , Colite Ulcerativa/patologia , Humanos , Inflamação/patologia , Intestinos/patologia , Camundongos , Oxazolona
3.
Dig Dis Sci ; 67(1): 121-133, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33569665

RESUMO

BACKGROUND: Uric acid (UA) has anti- and pro-inflammatory properties. We previously revealed that elevated serum UA levels provide protection against murine small intestinal injury probably via luminal UA secreted in the small intestine. Luminal UA may act as an antioxidant, preventing microbiota vulnerability to oxidative stress. However, whether luminal UA is increased under hyperuricemia and plays a protective role in a dose-dependent manner as well as the mechanism by which luminal UA exerts its protective effects on enteropathy remains unknown. METHODS: Inosinic acid (IMP) (1000 mg/kg, i.p.) was administered to obtain high serum UA (HUA) and moderate serum UA (500 mg/kg IMP, i.p.) mice. UA concentrations and levels of oxidative stress markers in the serum and intestine were measured. Mice received indomethacin (20 mg/kg, i.p.) to evaluate the effects of UA on indomethacin-induced enteropathy. Reactive oxygen species (ROS) on the ileal mucosa were analyzed. The fecal microbiota of HUA mice was transplanted to investigate its effect on indomethacin-induced enteropathy. RESULTS: IMP increased luminal UA dose-dependently, with higher levels of luminal antioxidant markers. Indomethacin-induced enteropathy was significantly ameliorated in both UA-elevated groups, with decreased indomethacin-induced luminal ROS. The microbiota of HUA mice showed a significant increase in α-diversity and a significant difference in ß-diversity from the control. Fecal microbiota transplantation from HUA mice ameliorated indomethacin-induced enteropathy. CONCLUSIONS: The protective role of luminal UA in intestinal injury is likely exerted via oxidative stress elimination and microbiota composition modulation, preferably for gut immunity. Therefore, enhancing anaerobic conditions using antioxidants is a potential therapeutic target.


Assuntos
Transplante de Microbiota Fecal/métodos , Microbioma Gastrointestinal , Indometacina/farmacologia , Intestino Delgado , Ácido Úrico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Enteropatias/induzido quimicamente , Enteropatias/metabolismo , Enteropatias/microbiologia , Enteropatias/terapia , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fatores de Proteção , Espécies Reativas de Oxigênio/análise , Resultado do Tratamento , Ácido Úrico/sangue , Ácido Úrico/metabolismo
4.
J Gastroenterol ; 56(9): 829-842, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34213612

RESUMO

BACKGROUND: Yeasts are a type of fungi thought to have probiotic functions. In this study, we isolated a novel probiotic yeast (Zygosaccharomyces sapae strain I-6) from Miso (a traditional Japanese fermented food). We examined its effects on phenotypic changes in intestinal dendritic cells (DCs), and evaluated its anti-inflammatory effects in dextran sulfate sodium (DSS)-induced colitis. METHODS: A single colony was selected from homogenized Miso, based on its ability to produce interleukin (IL)-10 in CD11c+ bone marrow DCs (BMDCs) in vitro. The anti-inflammatory effects of strain I-6 on CD11c+ BMDCs and CD11c+ CD103+ DCs were analyzed in mouse mesenteric lymph nodes in vitro and in a DSS mouse model. RESULTS: The IL-10 concentrations in the co-culture BMDC supernatants treated with I-6 were dramatically higher than in those treated with Saccharomyces cerevisiae (Sc). IL-10 production is mediated by both TLR2 and Dectin-1. ß-Glucan extracted from I-6 also induced higher levels of IL-10 production in BMDCs than ß-glucan from Sc. The number of mesenteric lymph node CD11c+ CD103+ DCs was significantly increased by I-6 administration, compared with Sc administration. Strain I-6 showed strong anti-inflammatory effects on DSS-induced colitis compared to Sc. Moreover, the adoptive transfer of I-6-treated BMDCs showed anti-inflammatory effects on DSS-induced colitis in mice without oral administration of I-6 cells. CONCLUSIONS: Strain I-6 induced phenotypic changes in intestinal CD11c+ DCs characterized by high IL-10 production and exerted strong anti-inflammatory effects on DSS-induced colitis. Traditional Japanese fermented foods may be a valuable source of probiotic yeasts for effective IBD therapy and treatment.


Assuntos
Células Dendríticas/efeitos dos fármacos , Interleucina-10/genética , Probióticos/administração & dosagem , Alimentos de Soja/microbiologia , Animais , Modelos Animais de Doenças , Interleucina-10/metabolismo , Japão , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/uso terapêutico
5.
J Gastroenterol Hepatol ; 36(9): 2523-2530, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33783040

RESUMO

BACKGROUND AND AIM: The small intestine plays a central role in gut immunity, and enhanced lymphocyte migration is involved in the pathophysiology of various enteropathy. Bile acid (BA) is closely related to lipid metabolism and gut microbiota and essential for gut homeostasis. However, the effects of BA on gut immunity have not been studied in detail, especially on the small intestine and lymphocyte migration. Therefore, we aimed to investigate the effect of BA on small intestinal lymphocyte microcirculation. METHODS: The effect of deoxycholic acid (DCA), taurocholic acid (tCA), or cholic acid (CA) on the indomethacin (IND)-induced small intestinal enteropathy in mice was investigated. Lymphocyte movements were evaluated after exposure to BA using intravital microscopy. The effects of BA on surface expression of adhesion molecules on the vascular endothelium and lymphocytes through BA receptors were examined in vitro. RESULTS: IND-induced small intestinal enteropathy was histologically aggravated by DCA treatment alone. The expression of adhesion molecules ICAM-1 and VCAM-1 was significantly enhanced by DCA. Exposure to DCA increased lymphocyte adhesion in the microvessels of the ileum, which was partially blocked by anti-α4ß1 integrin antibody in vivo. The expression of ICAM-1 and VCAM-1 was significantly enhanced by DCA in vitro, which was partially suppressed by the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist. The S1PR2 antagonist significantly ameliorated IND-induced and DCA-exaggerated small intestinal injury. CONCLUSION: DCA exacerbated IND-induced small intestinal enteropathy. DCA directly acts on the vascular endothelium and enhances the expression levels of adhesion molecules partially via S1PR2, leading to enhanced small intestinal lymphocyte migration.


Assuntos
Movimento Celular , Ácido Desoxicólico , Endotélio Vascular , Ileíte , Intestino Delgado , Linfócitos , Animais , Ácidos e Sais Biliares/efeitos adversos , Ácidos e Sais Biliares/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Ácidos Cólicos/efeitos adversos , Ácidos Cólicos/farmacologia , Ácido Desoxicólico/efeitos adversos , Ácido Desoxicólico/farmacologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Ileíte/induzido quimicamente , Ileíte/imunologia , Ileíte/fisiopatologia , Íleo/irrigação sanguínea , Íleo/efeitos dos fármacos , Íleo/imunologia , Íleo/fisiopatologia , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/imunologia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/imunologia , Intestino Delgado/fisiopatologia , Microscopia Intravital , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Ratos , Ratos Wistar , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Circulação Esplâncnica/imunologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/imunologia
6.
Microcirculation ; 28(5): e12694, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33742518

RESUMO

INTRODUCTION: Innate lymphoid cells (ILCs) are abundant in the intestinal mucosa, forming boundaries externally. Herein, ILCs were directly obtained from intestinal lymph using a lymph fistula rat model and analyzed under physiological and pathological conditions. METHODS: Thoracic duct (TD) lymphocytes were collected by cannulation with/without preceded mesenteric lymphadenectomy, which were comparable to lymphocytes flowing through mesenteric lymphatic vessels (MLVs) or TD, respectively. The collected ILCs were classified according to gene transcription factors and analyzed by flow cytometry. The effect of IL-25 or indomethacin was studied. RESULTS: The proportion of total ILCs in the MLVs (MLV-ILCs) was significantly higher than that in TD (TD-ILCs, 0.01% vs. 0.003%, respectively). Physiologically, there were several significant differences in the MLV-ILCs compared with TD-ILCs, including the proportion of ILC2 (42.3% vs. 70.9%) and ILC3 (33.3% vs. 13.8%), and the proportion of α4-integrin-positive cells (36.8% vs. 0.3%). IL-25 significantly increased the proportion of MLV-ILC2 after 3 days. Indomethacin-induced intestinal injury increased the proportion of MLV-ILC3 in the early phase within 12 h. CONCLUSION: Intestinal ILCs were found to migrate through MLVs. The altered mobilization of MLV-ILCs after stimuli suggests that ILCs play an important role in regulating the immune responses at the secondary lymph nodes.


Assuntos
Imunidade Inata , Linfócitos , Animais , Indometacina , Inflamação , Mucosa Intestinal , Linfonodos , Ratos
7.
Dig Dis Sci ; 66(2): 577-586, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32249373

RESUMO

BACKGROUND: Adherence to medications is important to maintain disease under control and to prevent complications in pregnant patients with ulcerative colitis (UC). To evaluate the incidence of non-adherence during pregnancy and its effect on relapse and pregnancy outcomes, we conducted a multicenter prospective study using a patient self-reporting system without physician interference. METHODS: Sixty-eight pregnant UC women were recruited from 17 institutions between 2013 and 2019. During the course of pregnancy, questionnaires were collected separately from patients and physicians, to investigate the true adherence to medications, disease activity, and birth outcomes. Multivariable logistic regression analysis was performed to identify the risk factors for the relapse or adverse pregnancy outcomes. RESULTS: Of 68 pregnancy, 15 adverse pregnancy outcomes occurred in 13 patients. The rate of self-reported non-adherence was the greatest to mesalamines in the first trimester, which was significantly higher than physicians' estimate (p = 0.0116), and discontinuation was observed in 42.1% of non-adherent group. Logistic regression analysis revealed non-adherence as an independent risk factor for relapse [odds ratio (OR) 7.659, 95% CI 1.928-30.427, p = 0.038], and possibly for adverse pregnancy outcome (OR 8.378, 95% CI 1.350-51.994, p = 0.023). Among the subgroup of patients treated with oral mesalamine alone, the non-adherence was confirmed to be an independent risk factor for relapse (p = 0.002). CONCLUSION: Non-adherence to mesalamine was underestimated by physicians in pregnant UC patients and contributed to disease relapse and possibly on pregnancy outcomes. Preconceptional education regarding safety of medications and risk of self-discontinuation is warranted.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Adesão à Medicação , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Exacerbação dos Sintomas , Aborto Espontâneo/diagnóstico , Aborto Espontâneo/epidemiologia , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/diagnóstico , Feminino , Humanos , Recém-Nascido , Mesalamina/uso terapêutico , Gravidez , Complicações na Gravidez/diagnóstico , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/epidemiologia , Estudos Prospectivos
8.
Hepatol Res ; 51(5): 580-592, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33247991

RESUMO

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-ß (TGF-ß) pseudoreceptor, bone morphogenetic protein, and activin membrane-bound inhibitor, and sensitized HSCs to TGF-ß-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.

9.
J Gastroenterol Hepatol ; 35(1): 110-117, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31359491

RESUMO

BACKGROUND AND AIM: Dietary emulsifiers are widely used in processed foods and officially approved as safe for intake. However, recent studies have demonstrated that some emulsifiers alter the colonic microbiota, leading to colonic low-grade inflammation, in mice. The effect of dietary emulsifiers on small-intestinal microbiota, which is important for gut immunity, has not been studied. We aimed to investigate the effect of a representative dietary emulsifier, polysorbate-80 (P80), on the small-intestinal microbiota in normal mice. METHODS: Some mice were pretreated with P80 for 8 weeks with or without indomethacin administration on the last 2 days, and intestinal damage was evaluated histologically. The ileal and colonic microbiota composition was assessed using 16S rRNA polymerase chain reaction. RESULTS: Polysorbate-80 increased the Gammaproteobacteria abundance and decreased the α-diversity in the small intestine. No decrease in α-diversity was observed in the colon. P80 pretreatment exacerbated the indomethacin-induced small-intestinal lesions and significantly increased the interleukin-1ß expression. Culture of ileal content on deoxycholate hydrogen sulfide lactose agar showed that P80 significantly increased the colonies of the sulfide-producing bacteria Proteus spp. (genetically identified as Proteus mirabilis). Antibiotic pretreatment abolished the P80-induced aggravation of indomethacin-induced ileitis. Motility assay in semisolid agar showed that adding 0.02% P80 to the agar significantly increased the diameter of P. mirabilis colonies but not that of Escherichia coli colonies. CONCLUSIONS: Polysorbate-80 enhances the vulnerability of the small intestine to indomethacin-induced injury by inducing ileal dysbiosis. Direct enhancement of the motility of specific flagellated microbiota by P80 might be related to dysbiosis and intestinal injury.


Assuntos
Disbiose , Emulsificantes/efeitos adversos , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/microbiologia , Polissorbatos/efeitos adversos , Animais , Humanos , Camundongos
10.
Clin Gastroenterol Hepatol ; 18(5): 1102-1111.e5, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394288

RESUMO

BACKGROUND & AIMS: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). METHODS: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. RESULTS: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). CONCLUSION: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).


Assuntos
Colite Ulcerativa , Biomarcadores/análise , Colite Ulcerativa/diagnóstico , Colonoscopia , Fezes/química , Humanos , Mucosa Intestinal , Complexo Antígeno L1 Leucocitário , Sangue Oculto , Índice de Gravidade de Doença
11.
Hepatol Commun ; 3(8): 1098-1112, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31388630

RESUMO

Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)-specific LPL-knockout (LplHSC-KO ) mice, LPL-floxed (Lplfl/fl ) mice, or double-mutant toll-like receptor 4-deficient (Tlr4-/- ) LplHSC-KO mice were fed a high-fat/high-cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high-fat/high-cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity-related factors, such as free fatty acid, leptin, and interleukin-6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC-KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL-mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL-mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

12.
Hepatol Res ; 49(11): 1316-1328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31250532

RESUMO

AIM: Chitinase 3-like 1 (CHI3L1), an 18-glycosyl hydrolase-related molecule, is a member of the enzymatically inactive chitinase-like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. METHODS: Chitinase 3-like 1-deficient (Chi3l1-/- ) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline-deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. RESULTS: In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1-/- mice compared to that in wild-type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1-/- mice compared to that in wild-type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1-/- mice. Chitinase 3-like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. CONCLUSIONS: Chitinase 3-like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.

13.
Intern Med ; 58(14): 2019-2023, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918171

RESUMO

We herein present the case of an immunocompetent 63-year-old man who had previously undergone resection of Crohn's disease (CD)-related small intestinal obstruction more than 30 years ago. He had not been receiving any medication for many years, but had recently started to suffer from ileus. A stenosed site of ileo-cecal anastomosis was identified and therefore was surgically resected, which was diagnosed as CD with small intestinal extramedullary plasmacytoma (EMP). The subsequent progression of CD was successfully controlled by anti-TNFα agents without any recurrence of EMP for over 3 years, implying the clinical benefit and safety of the biological therapy. This was the first known case of a patient who received anti-TNFα agents after a resection of small intestinal EMP accompanied with CD.


Assuntos
Antineoplásicos/uso terapêutico , Doença de Crohn/complicações , Fármacos Gastrointestinais/uso terapêutico , Intestino Delgado/fisiopatologia , Plasmocitoma/tratamento farmacológico , Plasmocitoma/etiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/complicações , Plasmocitoma/diagnóstico , Resultado do Tratamento
14.
Gut Liver ; 13(3): 325-332, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602220

RESUMO

Background/Aims: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. Methods: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. Results: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. Conclusions: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS.


Assuntos
Depressão/microbiologia , Disbiose/psicologia , Síndrome do Intestino Irritável/microbiologia , Síndrome do Intestino Irritável/psicologia , Animais , Modelos Animais de Doenças , Microbioma Gastrointestinal , Masculino , Ratos , Ratos Wistar
15.
Intern Med ; 58(3): 369-374, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30210116

RESUMO

We herein report a 44-year-old man suffering from systemic edema due to protein-losing enteropathy (PLE) with superior mesenteric vein (SMV) obstruction and development of collateral veins, which subsequently proved to be a chronic result of thrombosis and a complication of Crohn's disease (CD). PLE was supposedly induced by both intestinal erosion and thrombosis-related lymphangiectasia, which was histologically proven in his surgically-resected ileal stenosis. Elemental diet and anti-TNFα agent improved his hypoalbuminemia after surgery. The rarity of the simultaneous coexistence of SMV obstruction and PLE and the precedence of these complications over typical abdominal symptoms of CD made the clinical course complex.


Assuntos
Doença de Crohn/complicações , Doença de Crohn/fisiopatologia , Veias Mesentéricas/fisiopatologia , Enteropatias Perdedoras de Proteínas/etiologia , Enteropatias Perdedoras de Proteínas/fisiopatologia , Trombose Venosa/fisiopatologia , Adulto , Doença de Crohn/terapia , Humanos , Masculino , Enteropatias Perdedoras de Proteínas/terapia , Resultado do Tratamento , Trombose Venosa/complicações , Trombose Venosa/etiologia , Trombose Venosa/terapia
16.
J Leukoc Biol ; 104(5): 1013-1022, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29901817

RESUMO

The enhanced recruitment of leukocytes to the inflamed colon is a key feature of ulcerative colitis (UC). The gut-specific adhesion molecules involved in leukocyte recruitment have emerged as recent therapeutic targets. Nicotine absorbed from smoking has been reported to work protectively in UC patients. Our hypothesis is that nicotine may suppress the aberrant leukocyte recruitment and colonic inflammation via the suppression of the overexpressed gut-specific adhesion molecules in the inflamed colon. To test this hypothesis, the severity of colitis and the degree of leukocyte recruitment induced by gut-specific adhesion molecules were assessed in dextran sulfate sodium (DSS) colitis mice (C57BL/6J mice treated with 3% DSS) with or without nicotine treatment. We also studied the in vitro changes in the expression of adhesion molecules by using a vascular endothelial cell line. DSS-induced colitis was accompanied by increases in disease activity index (DAI), histological score, recruitment of leukocytes, and the expression of adhesion molecules, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and VCAM-1. Nicotine treatment significantly attenuated MAdCAM-1 expression, leukocyte recruitment, DAI, and histological score. The expression of ß7-integrin, the ligand for MAdCAM-1, on leukocytes was not affected by nicotine treatment. In vitro study, the TNF-α-enhanced mRNA expression of MAdCAM-1 was reduced by the coadministration of nicotine in a dose-dependent manner, possibly via nicotinic receptor activation. These results supported our hypothesis that nicotine treatment ameliorated colitis through the suppression of MAdCAM-1 expression on the microvessels in the inflamed colon. Further investigation is warranted on the role of nicotine in the treatment of UC.


Assuntos
Moléculas de Adesão Celular/biossíntese , Quimiotaxia de Leucócito/efeitos dos fármacos , Colite/imunologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Moléculas de Adesão Celular/efeitos dos fármacos , Colite/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucoproteínas
17.
J Gastroenterol Hepatol ; 33(11): 1839-1843, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29669163

RESUMO

BACKGROUND AND AIM: Studies on the characteristics of elderly-onset ulcerative colitis (EOUC) and non-elderly-onset ulcerative colitis (NEOUC) have reported conflicting findings. The aim of this study was to compare disease characteristics of EOUC and NEOUC by analyzing the database of the Japanese nationwide inflammatory bowel disease (IBD) registry. METHODS: We analyzed the age of disease onset, sex, disease severity, and disease extent in patients with ulcerative colitis that were newly diagnosed and registered within 1 year between 2004 and 2009 (n = 28 179). We also analyzed the medical treatment, rate of IBD-related surgery, and postoperative complications. We compared them between younger than 65 years old (NEOUC group) and 65 years old or older (EOUC group) patients. RESULTS: A total of 25 401 (90.1%) and 2778 (9.9%) patients were included in the NEOUC and EOUC groups, respectively. In the EOUC group, disease activity was significantly higher, and extent of pathological changes in the colon more extended significantly. Laboratory findings showed that inflammatory markers were elevated significantly in the EOUC group. The proportion of those with IBD-related hospitalization was significantly higher in the EOUC group (54.2% vs 35.7%, P < 0.001). The proportion of patients who were treated with corticosteroids was significantly higher in the EOUC group (36.7% vs 30.8%, P < 0.001). Significantly more number of patients underwent IBD-related surgery in the EOUC group (0.68% vs 0.27%, P < 0.001). CONCLUSION: Elderly patients show higher disease activity, with a higher proportion requiring IBD-related hospitalization and IBD-related surgery, according to the nationwide registry in Japan.


Assuntos
Colite Ulcerativa , Bases de Dados como Assunto , Inquéritos e Questionários , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Feminino , Glucocorticoides/administração & dosagem , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Índice de Gravidade de Doença , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-29336057

RESUMO

BACKGROUND AND AIM: Sphingosine-1-phosphate (S1P) receptor 1, a therapeutic target of the S1P1 agonist FTY720, plays a crucial role in lymphocyte migration and is expressed in several cells including naïve T lymphocytes and endothelial cells. 2-Acetyl-4-tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase, exhibits immunomodulatory activity through increasing the S1P concentration in the secondary lymphoid organs, but its effects on colitis remain unclear. This study aimed to clarify how THI affects colitis and migration of naïve T lymphocytes in Peyer's patches (PPs). METHODS: The effect of THI on gut immunity was investigated by analyzing the dextran sulfate sodium (DSS)-induced murine colitis model, lymphocyte components in thoracic duct lymphocytes (TDLs), and microscopic movement of TDLs in PPs. RESULTS: 2-Acetyl-4-tetrahydroxybutyl imidazole ameliorated DSS-induced colitis histologically by causing a significant decrease in colonic lymphocyte infiltration and expression of mucosal pro-inflammatory cytokines. THI suppressed the inflow of naïve T lymphocytes into the thoracic duct. Microscopic observation of PPs in control animals revealed that many TDLs egressed to the stroma and migrated to lymph capillaries after attaching to the high endothelial venules (HEVs). THI or FTY720 treatment in recipient animals blocked lymphocyte egression from the HEVs to the stroma. CONCLUSIONS: This is the first study to clarify the ameliorating effects of THI on DSS-induced colitis. Microscopic observations demonstrated the involvement of HEVs in the egression of S1P-dependent gut-tropic T lymphocytes to lymph capillaries. This S1P lyase inhibitor might become a novel immunosuppressant for inflammatory bowel disease therapy by blocking infiltration of lymphocytes through HEVs into the stroma in PPs.

19.
Clin J Gastroenterol ; 11(2): 145-149, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29204849

RESUMO

Human intestinal spirochetosis (HIS) is a colorectal infection caused by the Brachyspira species of intestinal spirochetes, whose pathogenicity in humans remains unclear owing to the lack of or mild symptoms. We monitored the 5-year clinical course of a woman diagnosed with HIS in whom ulcerative colitis (UC) had been suspected. Following a positive fecal occult blood test, she underwent a colonoscopic examination at a local clinic where she was diagnosed with "right-sided" UC concomitant with incidentally detected HIS, and was referred to our hospital. Colonoscopic, histopathological, and cytological examination revealed localized erosive colitis in the ascending and the right transverse colon concomitant with HIS resembling skip lesions of UC. Initially, we chose the wait-and-watch approach; however, she gradually developed bloody diarrhea. Metronidazole improved her abdominal symptoms, as well as her colonoscopic and histopathological findings, suggesting that HIS was responsible for her colorectal inflammation. This case reveals (1) a possible pro-inflammatory role of HIS, (2) difficulties in diagnosing HIS in chronic proctocolitis, and (3) a possible inclusion of some HIS cases in "UC". HIS could mimic UC and might be included in differential diagnoses for UC. Antibiotic administration is necessary following the detection of HIS, particularly in patients demonstrating an atypical presentation of UC.


Assuntos
Brachyspira , Colite Ulcerativa/diagnóstico , Colite/diagnóstico , Infecções por Bactérias Gram-Negativas/diagnóstico , Idoso , Anti-Infecciosos/uso terapêutico , Colite/tratamento farmacológico , Colite/patologia , Colonoscopia , Diagnóstico Diferencial , Diarreia/microbiologia , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/patologia , Humanos , Metronidazol/uso terapêutico
20.
Intern Med ; 57(1): 37-41, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29033425

RESUMO

We herein describe a 69-year-old man suffering from chronic diarrhea caused by lansoprazole (LPZ)-induced collagenous colitis (CC) accompanied with protein-losing enteropathy (PLE), diagnosed by increased fecal alpha-1 antitrypsin clearance and the findings of leakage from the descending colon to the sigmoid colon on scintigraphy. MR enterocolonography (MREC) was also performed for differentiating digestive diseases, and inflamed findings were observed around the same portion as those on scintigraphy, suggesting that this region was responsible for protein loss in this case. The MREC findings improved after the cessation of LPZ, and hypoalbuminemia also improved simultaneously. This case suggests that MREC may be a new and useful diagnostic tool for CC with PLE.


Assuntos
Colite Colagenosa/induzido quimicamente , Colite Colagenosa/terapia , Diarreia/induzido quimicamente , Lansoprazol/efeitos adversos , Enteropatias Perdedoras de Proteínas/diagnóstico por imagem , Enteropatias Perdedoras de Proteínas/terapia , Idoso , Colite Colagenosa/diagnóstico por imagem , Diarreia/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Enteropatias Perdedoras de Proteínas/etiologia , Doenças Raras/diagnóstico , Doenças Raras/terapia , Resultado do Tratamento
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