Language：English   Publishing type：Research paper (scientific journal)  

Environmental microplastics have emerged as a critical issue in maintaining the planetary ecosystem. In this study, we generated particulate microplastics from polyethylene terephthalate (PM-PET) and investigated their impact in the gut by using mouse models and implementing histological examinations, as well as multi-omics analysis for colonic immune cells and microbiota. As a result, histological approaches showed that chronic and physiological low dose exposure of PM-PET did not affect intestinal pathology and mucin barriers, respectively. Moreover, immunohistochemical analysis demonstrated that the numbers of T cells, B cells, macrophages, and granulocytes were not affected by the exposure to PM-PET. However, RNA-seq analysis revealed that PM-PET had a substantial impact on the transcriptome in gut immune cells and their metabolisms, while 16s rRNA metagenomic analysis showed that the composition of microbiota was modestly affected. These results suggest an unexpected role played by the PM-PET in affecting gut immune homeostasis without detectable inflammation.

DOI： 10.1016/j.isci.2023.106474

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PubMed

Language：Japanese  

This is a case report of fascioliasis that progressed from the hepatic to the biliary phases over 2 years. A woman in her late 60s ate Zingiber mioga from the field, which was followed by abdominal pain that occurred 1 month later. Although CT and MRI studies revealed an increase in blood eosinophils as well as multiple hepatic nodules, they vanished quickly. After 2 years, an MRCP study revealed multiple flat lesions, which were diagnosed as adult fascioliasis. Definitive diagnosis was provided by enzyme-labeled antibody method using fasciola-specific antigen. Triclabendazole was administered once to complete the treatment.

DOI： 10.11405/nisshoshi.120.269

PubMed

J-GLOBAL

Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The significant increase in food allergy incidence is correlated with dietary changes in modernized countries. Here, we investigated the impact of dietary emulsifiers on food allergy by employing an experimental murine model. Mice were exposed to drinking water containing 1.0% carboxymethylcellulose (CMC) or Polysorbate-80 (P80) for 12 weeks, a treatment that was previously demonstrated to induce significant alterations in microbiota composition and function leading to chronic intestinal inflammation and metabolic abnormalities. Subsequently, the ovalbumin food allergy model was applied and characterized. As a result, we observed that dietary emulsifiers, especially P80, significantly exacerbated food allergy symptoms, with increased OVA-specific IgE induction and accelerated type 2 cytokine expressions, such as IL-4, IL-5, and IL-13, in the colon. Administration of an antibiotic regimen completely reversed the emulsifier-induced exacerbated susceptibility to food allergy, suggesting a critical role played by the intestinal microbiota in food allergy and type 2 immune responses.

DOI： 10.3390/nu14234983

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Food allergy (FA) is a common disease in children; thus, a high level of safety is required for its prevention and treatment. Colonic regulatory T cells (Tregs) have been suggested to attenuate FA. We investigated the Treg-inducing ability and anti-FA effects of carotenoids, a pigment contained in vegetables and fruits. METHODS: C57BL/6N mice were fed a diet containing 0.01% (w/w) of lycopene, β-carotene, astaxanthin or lutein for 4 weeks, and the population of colonic Tregs was assessed. Subsequently, to evaluate the Treg-inducing ability of lycopene, splenic naïve CD4+ T cells from BALB/c mice were cultured with anti-CD3/CD28 antibody, TGF-β and lycopene, and the frequencies of Tregs were examined. The effect of 0.1% (w/w) lycopene containing diet on FA was investigated in OVA-induced FA model BALB/c mice. RESULTS: In screening, only lycopene significantly increased the frequency and number of colonic Tregs. Lycopene also increased Treg differentiation in splenic naïve CD4+ T cells. In FA mice, lycopene feeding significantly increased the number of colonic Tregs and attenuated allergic symptoms. The expression levels of IL-4, IL-9 and IL-13 mRNA in colonic mucosa were also significantly reduced by lycopene. IL-9 is known to induce proliferation of mast cells, and we found that lycopene feeding significantly reduced the number of mast cells in the colonic mucosa of FA mice. CONCLUSION: Our results suggest that lycopene, a carotenoid present in many common foods on the market, may have the potential to induce colonic Tregs and suppress FA symptoms.

DOI： 10.1111/pai.13691

PubMed

J-GLOBAL

Language：English   Publishing type：Research paper (scientific journal)  

CD4+ T cells share common developmental pathways with CD8+ T cells, and upon maturation, CD4+ T conventional T (Tconv) cells lack phenotypic markers that distinguish these cells from FoxP3+ T regulatory cells. We developed a tamoxifen-inducible ThPOKCreERT2.hCD2 line with Frt sites inserted on either side of the CreERT2-hCD2 cassette, and a Foxp3Ametrine-FlpO strain, expressing Ametrine and FlpO in Foxp3+ cells. Breeding these mice resulted in a CD4conviCreERT2-hCD2 line that allows for the specific manipulation of a gene in CD4+ Tconv cells. As FlpO removes the CreERT2-hCD2 cassette, CD4+ Treg cells are spared from Cre activity, which we refer to as allele conditioning. Comparison with an E8IiCreERT2.GFP mouse that enables inducible targeting of CD8+ T cells, and deletion of two inhibitory receptors, PD-1 and LAG-3, in a melanoma model, support the fidelity of these lines. These engineered mouse strains present a resource for the temporal manipulation of genes in CD4+ T cells and CD4+ Tconv cells.

DOI： 10.1016/j.immuni.2021.08.029

PubMed

J-GLOBAL

J-GLOBAL

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Gut microbiota and their metabolites are instrumental in regulating intestinal homeostasis. However, early-life microbiota associated influences on intestinal development remain incompletely understood. Here we demonstrate that co-housing of germ-free (GF) mice with specific-pathogen free (SPF) mice at weaning (exGF) results in altered intestinal gene expression. Our results reveal that one highly differentially expressed gene, erythroid differentiation regulator-1 (Erdr1), is induced during development in SPF but not GF or exGF mice and localizes to Lgr5+ stem cells and transit amplifying (TA) cells. Erdr1 functions to induce Wnt signaling in epithelial cells, increase Lgr5+ stem cell expansion, and promote intestinal organoid growth. Additionally, Erdr1 accelerates scratch-wound closure in vitro, increases Lgr5+ intestinal stem cell regeneration following radiation-induced injury in vivo, and enhances recovery from dextran sodium sulfate (DSS)-induced colonic damage. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage.

DOI： 10.1038/s41467-019-14258-z

PubMed

Other Link： http://www.nature.com/articles/s41467-019-14258-z

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Functional dyspepsia (FD) is associated with poor health-related quality of life. Recent evidence suggests that the main pathogenesis suspect is the gut mucosa-associated microbiota (MAM). However, little is known about the MAM in FD subjects. The aim of this study was to clarify the relationship between upper gastrointestinal symptoms in FD and the characteristics of the gastrointestinal MAM. SUMMARY: Five mucosa samples from the upper gut (intraoral, mid-esophagus, gastric body, gastric antrum, and descending portion of the duodenum) were collected with a brush under endoscopic examination from FD and healthy control subjects. MAM profiles of each sample were analyzed by 16S-rRNA -V3-V4 gene sequences. Questionnaire was used to assess gastrointestinal symptoms in FD. Between FD and healthy control subjects, although the comparison of MAM α-diversity showed no significant differences, the structure of MAM (β-diversity) was clearly different. Only the phylum Firmicutes was increased in FD compared to healthy control subjects in all sites of the upper gut. At the genus level, Streptococcus was significantly increased in all sites in the upper gut in FD. The relative abundance of Streptococcus was positively correlated with upper gastrointestinal symptoms in each upper gut group. Furthermore, the relative abundance of OTU 90 was positively correlated with upper gastrointestinal symptoms in all sites in the upper gut in FD. Key Messages: Streptococcus is a bacterium strongly correlated with upper gastrointestinal symptoms in FD.

DOI： 10.1159/000504090

PubMed

J-GLOBAL

Language：English   Publishing type：Research paper (scientific journal)  

Gut microbiota and their metabolites are instrumental in regulating homeostasis at intestinal and extraintestinal sites. However, the complex effects of prenatal and early postnatal microbial exposure on adult health and disease outcomes remain incompletely understood. Here, we showed that mice raised under germ-free conditions until weaning and then transferred to specific pathogen-free (SPF) conditions harbored altered microbiota composition, augmented inflammatory cytokine and chemokine expression, and were hyper-susceptible to colitis-associated tumorigenesis later in adulthood. Increased number and size of colon tumors and intestinal epithelial cell proliferation in recolonized germ-free mice were associated with augmented intratumoral CXCL1, CXCL2, and CXCL5 expression and granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation. Consistent with these findings, CXCR2 neutralization in recolonized germ-free mice completely reversed the exacerbated susceptibility to colitis-associated tumorigenesis. Collectively, our findings highlight a crucial role for early-life microbial exposure in establishing intestinal homeostasis that restrains colon cancer in adulthood.

DOI： 10.1158/2326-6066.CIR-18-0444

PubMed

Language：Japanese   Publisher：京都府立医科大学附属北部医療センター  

Tolvaptanは肝性腹水の治療に非常に有用な薬剤だが、日常臨床ではしばしば無効例を経験する。本研究ではTolvaptanへの反応性について、治療前後の腹水、肝予備能、血液生化学的検査の変化を検討したところ、Tolvaptanへの反応性は、腎機能、肝予備能に規定されることがわかった。またTolvaptan無効例でもアルブミン補充や腹水濾過再静注(CART)を併用することで、治療効果の改善を認めた。本研究は少数例の検討であり、今後症例の集積が必要である。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J06575&link_issn=&doc_id=20190701050003&doc_link_id=http%3A%2F%2Fid.nii.ac.jp%2F1327%2F00002233%2F&url=http%3A%2F%2Fid.nii.ac.jp%2F1327%2F00002233%2F&type=%8B%9E%93s%95%7B%97%A7%88%E3%89%C8%91%E5%8Aw%81F%8B%9E%93s%95%7B%97%A7%88%E3%89%C8%91%E5%8Aw%83%8A%83%7C%83W%83g%83%8A_%8Bk%88%E4&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80238_3.gif

Language：English   Publishing type：Research paper (scientific journal)  

Interleukin (IL)-2 is expressed during T cell activation and induces the proliferation and differentiation of T cells. CD4+Foxp3+ regulatory T cells (Tregs) constitutively express the high affinity IL-2 receptor (CD25/IL-2Rα) and rapidly respond to IL-2 to elaborate numerous suppressive mechanisms that limit immune-mediated pathologies. Accumulating evidence supports the concept that an aberrant balance between Tregs and Teff contribute to the pathology of intestinal inflammation and that the IL-2/Treg axis is a potential pathway to exploit for the treatment of inflammatory bowel disease (IBD). Here, we show that treatment of mice with IL-2/IL-2 antibody (JES6-1) immunocomplex during DSS-induced colitis induced Foxp3+ Treg expansion, but also potently stimulated GATA3+ type 2 innate lymphoid cell (ILC2) proliferation and high-level expression of IL-5. Furthermore, IL-2/JES6-1 treatment resulted in massive eosinophil accumulation and activation in the inflamed colon, and afforded only modest protection from colitis. In light of these findings, we observed that combined IL-2/JES6-1 and anti-IL-5 mAb treatment was most effective at ameliorating DSS-induced colitis compared to either treatment alone and that this regimen allowed for Foxp3+ Treg expansion without concomitant eosinophilia. Collectively, our findings provide insight into how blockade of IL-5 may aid in optimizing IL-2 immunotherapy for the treatment of intestinal inflammation.

DOI： 10.3389/fimmu.2019.00459

PubMed

DOI： 10.3164/jcbn.17-133

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36γ is a potent inducer of IL-23 both in vitro and in vivo. IL-36γ-induced IL-23 required Notch2-dependent (CD11b+CD103+) dendritic cells (DCs), but not Batf3-dependent (CD11b-CD103+) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36γ-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36γ could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36γ, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.

DOI： 10.1073/pnas.1718902115

PubMed

DOI： 10.1111/ajt.14477

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36 gamma signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-kappa Bp50 in CD4(+) T cells to potently inhibit Foxp3-expressing induced regulatory T cell (T-reg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway. Consistent with these findings, mice deficient in IL-36 gamma were protected from Th cell-driven intestinal inflammation and exhibited increased colonic T-reg cells and diminished Th9 cells. Our findings thus reveal a fundamental contribution for the IL-36/IL-36R axis in regulating the T-reg-Th9 cell balance with broad implications for Th cell-mediated disorders, such as inflammatory bowel diseases and particularly ulcerative colitis.

DOI： 10.1038/mi.2017.21

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Specific components of the intestinal microbiota are capable of influencing immune responses such that a mutualistic relationship is established. In mice, colonization with segmented filamentous bacteria (SFB) induces T-helper-17 (Th17) cell differentiation in the intestine, yet the effector functions of interleukin (IL)-17A in response to SFB remain incompletely understood. Here we report that colonization of mice with SFB-containing microbiota induced IL-17A-and CXCR2-dependent recruitment of neutrophils to the ileum. This response required adaptive immunity, as Rag-deficient mice colonized with SFB-containing microbiota failed to induce IL-17A, CXCL1 and CXCL2, and displayed defective neutrophil recruitment to the ileum. Interestingly, neutrophil depletion in wild-type mice resulted in significantly augmented Th17 responses and SFB expansion, which correlated with impaired expression of IL-22 and antimicrobial peptides. These data provide novel insight into a dynamic IL-17A-CXCR2-neutrophil axis during acute SFB colonization and demonstrate a central role for neutrophils in limiting SFB expansion.

DOI： 10.1038/mi.2016.80

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PubMed

DOI： 10.1016/j.jcmgh.2015.12.009

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

IL-1 family members are central mediators of host defense. In this article, we show that the novel IL-1 family member IL-36 gamma was expressed during experimental colitis and human inflammatory bowel disease. Germ-free mice failed to induce IL-36 gamma in response to dextran sodium sulfate (DSS)-induced damage, suggesting that gut microbiota are involved in its induction. Surprisingly, IL-36R-deficient (Il1rl2(-/-)) mice exhibited defective recovery following DSS-induced damage and impaired closure of colonic mucosal biopsy wounds, which coincided with impaired neutrophil accumulation in the wound bed. Failure of Il1rl2(-/-) mice to recover from DSS-induced damage was associated with a profound reduction in IL-22 expression, particularly by colonic neutrophils. Defective recovery of Il1rl2(-/-) mice could be rescued by an aryl hydrocarbon receptor agonist, which was sufficient to restore IL-22 expression and promote full recovery from DSS-induced damage. These findings implicate the IL-36/IL-36R axis in the resolution of intestinal mucosal wounds.

DOI： 10.4049/jimmunol.1501312

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PubMed

DOI： 10.1007/978-1-4939-3603-8_16

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

The microbiota that populate the mammalian intestine are critical for proper host physiology, yet simultaneously pose a potential danger. Intestinal antigen-presenting cells, namely macrophages and dendritic cells (DCs), are integral components of the mucosal innate immune system that maintain coexistence with the microbiota in face of this constant threat. Intestinal macrophages and DCs integrate signals from the microenvironment to orchestrate innate and adaptive immune responses that ultimately Lead to durable tolerance of the microbiota. Tolerance is not a default response, however, because macrophages and DCs remain poised to vigorously respond to pathogens that breach the epithelial barrier. In this review, we summarize the salient features of macrophages and DCs in the healthy and inflamed intestine and discuss how signals from the microbiota can influence their function.

DOI： 10.1016/j.ajpath.2015.02.024

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Regulatory CD4(+) T (T-reg) cells are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. The immunoregulatory function of T-reg cells is especially important in the intestine where the mucosa is exposed to a diverse array of foreign antigensincluding those derived from food and commensal bacteria. T-reg cells are enriched in the intestinal lamina propria and provide a crucial function in promoting tolerance to enteric antigens while modulating tissue inflammation. Correspondingly, T-reg cell dysfunction is associated with a breakdown in intestinal tolerance and the induction of aberrant immune responses that may contribute to the pathogenesis of inflammatory bowel disease. This review will provide a brief overview of T-reg cell biology with a focus on Foxp3(+) T-reg and type 1 regulatory (Tr1) cells and summarize the evidence for defective T-reg cells in experimental and human inflammatory bowel disease. The potential application of T-reg cells as a treatment for inflammatory bowel disease will also be discussed in the context of T-reg infusion therapy and the in vivo induction/expansion of intestinal T-reg cells.

DOI： 10.1097/MIB.0000000000000343

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The microbiota that populates the mammalian intestine consists of hundreds of trillions of bacteria that are separated from underlying immune cells by a single layer of epithelial cells. The intestinal immune system effectively tolerates components of the microbiota that provide benefit to the host while remaining poised to eliminate those that are harmful. Antigen presenting cells, especially macrophages and dendritic cells, play important roles in maintaining intestinal homeostasis via their ability to orchestrate appropriate responses to the microbiota. Paramount to elucidating intestinal macrophage- and dendritic cell-mediated functions is the ability to effectively isolate and identify these cells from a complex cellular environment. In this review, we summarize methodology for the isolation and phenotypic characterization of macrophages and DCs from the mouse intestine and discuss how this may be useful for gaining insight into the mechanisms by which mucosal immune tolerance is maintained. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jim.2015.03.023

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Aim: Non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly used in clinical medicine, cause erosion, ulcers, and bleeding in the gastrointestinal tract. No effective agent for the prevention and treatment of small intestinal injury by NSAIDs has been established. This study investigates the effects of agaro-oligosaccharides (AGOs) on NSAID-induced small intestinal injury in mice.
Methods: Mice were treated with indomethacin, an NSAID, to induce intestinal injury. The respective degrees of mucosal injury of mice that received AGO and control mice were compared. Heme oxygenase-1 (HO-1) expression using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were measured. The expression of keratinocyte chemoattractant (KC) was measured using qRT-PCR and enzyme-linked immunosorbent assay.
Results: AGO administration induced HO-1 expression in mouse small intestinal mucosa. Induction was observed mainly in F4/80 positive macrophages. The increased ulcers score, myeloperoxidase activity, and KC expression by indomethacin were inhibited by AGO administration. Conversely, HO inhibitor cancelled AGO-mediated prevention of intestinal injury. In mouse peritoneal macrophages, AGOs enhanced HO-1 expression and suppressed lipopolysaccharide-induced KC expression. Furthermore, AGOs enhanced the expressions of alternatively activated macrophage markers arginase-1, mannose receptor-1, and chitinase 3-like 3.
Conclusions: Results suggest that oral administration of AGOs prevents NSAID-induced intestinal injury.

DOI： 10.1111/jgh.12373

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGOs). Recently, it has been demonstrated that AGOs induce heme oxygenase-1 (HO-1) expression in macrophages and that they might lead to anti-inflammatory property. Nevertheless, the molecular mechanism of AGO-mediated HO-1 induction remains unknown, as does AGOs' ability to elicit anti-inflammatory activity in vivo. This study was undertaken to uncover the mechanism of AGO-mediated HO-1 induction and to investigate the therapeutic effect of AGOs on intestinal inflammation. METHODS: Mice were treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. The respective degrees of mucosal injury of mice that had received AGO and control mice were compared. We investigated HO-1 expression using Western blotting, quantitative real-time PCR (qRT-PCR), and immunohistochemistry. The expression of tumor necrosis factor-α (TNF-α) was measured using qRT-PCR and enzyme-linked immunosorbent assay. RESULTS: AGO administration induced HO-1 expression in colonic mucosa. The induction was observed mainly in F4/80 positive macrophages. Increased colonic damage and myeloperoxidase activity after TNBS treatment were inhibited by AGO administration. TNBS treatment induced TNF-α expression, and AGO administration suppressed induction. However, HO inhibitor canceled AGO-mediated amelioration of colitis. In RAW264 cells, AGOs enhanced HO-1 expression time-dependently and concentration-dependently and suppressed lipopolysaccharide-induced TNF-α expression. Furthermore, agarotetraose-mediated HO-1 induction required NF-E2-related factor 2 function and phosphorylation of c-jun N-terminal kinase. CONCLUSIONS: We infer that AGO administration inhibits TNBS-induced colitis in mice through HO-1 induction in macrophages. Consequently, oral administration of AGOs might be an important therapeutic strategy for inflammatory bowel disease.

DOI： 10.1007/s00535-012-0719-4

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Although non-steroidal anti-inflammatory drugs can induce intestinal injury, the mechanisms are not fully understood, and treatment has yet to be established. Heme oxygenase-1 (HO-1) has recently gained attention for anti-inflammatory and cytoprotective effects. This study aimed to investigate the effects of hemin, an HO-1 inducer, on indomethacin-induced enteritis in mice. METHODS: Enteritis was induced by single subcutaneous administration of indomethacin (10 mg/kg) in male C57BL/6 mice. Hemin (30 mg/kg) was administered by intraperitoneal administration 6 h before indomethacin administration. Mice were randomly divided into four groups: (i) sham + vehicle; (ii) sham + hemin; (iii) indomethacin + vehicle; or (iv) indomethacin + hemin. Enteritis was evaluated by measuring ulcerative lesions. Myeloperoxidase activity was measured as an index of neutrophil accumulation. The mRNA expression of inflammatory cytokines and chemokines, such as tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and keratinocyte chemoattractant, were analyzed by real-time polymerase chain reaction. RESULTS: The area of ulcerative lesions, myeloperoxidase activity, and mRNA expression of inflammatory cytokines and chemokines were significantly increased in mice administrated with indomethacin compared with vehicle-treated sham mice. Development of intestinal lesions, increased levels of myeloperoxidase activities, and mRNA expressions of inflammatory cytokines and chemokines were significantly suppressed in mice treated with hemin compared with vehicle-treated mice. Protective effects of hemin were reversed by co-administration of tin protoporphyrin, an HO-1 inhibitor. CONCLUSIONS: Induction of HO-1 by hemin inhibits indomethacin-induced intestinal injury through upregulation of HO-1. Pharmacological induction of HO-1 may offer a novel therapeutic strategy to prevent indomethacin-induced small intestinal injury.

DOI： 10.1111/jgh.12074

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1), which plays an important role in the protection of cells and tissues against acute and chronic inflammation. However, the role of Bach1 in the gastrointestinal mucosal defense system remains little understood. HO-1 supports the suppression of experimental colitis and localizes mainly in macrophages in colonic mucosa. This study was undertaken to elucidate the Bach1/HO-1 system's effects on the pathogenesis of experimental colitis.
Methods: This study used C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice in which colonic damage was induced by the administration of an enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Subsequently, they were evaluated macroscopically, histologically, and biochemically. Peritoneal macrophages from the respective mice were isolated and analyzed. Then, wild-type mice were injected with peritoneal macrophages from the respective mice. Acute colitis was induced similarly.
Results: TNBS-induced colitis was inhibited in Bach1-deficient mice. TNBS administration increased the expression of HO-1 messenger RNA and protein in colonic mucosa in Bach1-deficient mice. The expression of HO-1 mainly localized in F4/80-immunopositive and CD11b-immunopositive macrophages. Isolated peritoneal macrophages from Bach1-deficient mice highly expressed HO-1 and also manifested M2 macrophage markers, such as Arginase-1, Fizz-1, Ym1, and MRC1. Furthermore, TNBS-induced colitis was inhibited by the transfer of Bach1-deficient macrophages into wild-type mice.
Conclusions: Deficiency of Bach1 ameliorated TNBS-induced colitis. Bach1-deficient macrophages played a key role in protection against colitis. Targeting of this mechanism is applicable to cell therapy for human inflammatory bowel disease. (Inflamm Bowel Dis 2013;19:740-753)

DOI： 10.1097/MIB.0b013e3182802968

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: The pathogenesis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal lesions remains unclear, although it is considered to be quite different from that of upper gastrointestinal tract ulcers due to the absence of acid and the presence of bacteria and bile in the small intestine. The aim of this study was to characterize specific gene expression profiles of intestinal mucosa in indomethacin-induced small intestinal injury, and to investigate the effects of rebamipide on the expression of these genes. METHODS: Intestinal injury was induced in male Wistar rats by subcutaneous administration of indomethacin. Total RNA of the intestinal mucosa was extracted 24 h after indomethacin administration, gene expression was investigated using microarray analysis, and the identified genes were confirmed by real-time polymerase chain reaction (PCR). In addition, we investigated whether the treatment with rebamipide altered the expression of these identified genes. RESULTS: The administration of indomethacin induced small intestine injuries, and these lesions were significantly inhibited by the treatment with rebamipide. Microarray analysis showed that the genes for several matrix metalloproteinases (MMPs) and several chemokine-related genes were significantly upregulated, and metallothionein 1a (MT1a) was downregulated in the intestinal mucosa after administration of indomethacin. The expressions of these genes were reversed by the treatment with rebamipide. CONCLUSION: These data suggest that MMPs, chemokines, and MT1a may play an important role in the intestinal mucosal injury induced by indomethacin. In particular, the inhibition of MMP genes and chemokine-related genes by rebamipide may be important for the therapeutic effect against NSAIDs-induced small intestinal injury.

DOI： 10.1111/j.1440-1746.2012.07275.x

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Serpin B1 is a monocyte neutrophil elastase (NE) inhibitor and is one of the most efficient inhibitors of NE. In the present study, we investigated the role of serpin B1 in the pathogenesis of ulcerative colitis by using clinical samples and an experimental model. The colonic expression of serpin B1 was determined by real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistological studies in both normal and inflamed mucosa from patients with ulcerative colitis. Serpin B1 mRNA expression was determined by real-time PCR in the mouse dextran sodium sulfate (DSS)-induced colitis model. Young adult mouse colonic epithelial (YAMC) cells were used to determine the role of serpin B1. Serpin B1 gene transfected YAMC cells were treated with H(2)O(2) to measure cell viability. The expression of NE was determined in YAMC cells treated with H(2)O(2). NE-silenced YAMC cells were also treated with H(2)O(2) and then measured for viability. Upregulated expression of serpin B1 in colonic mucosa was confirmed from patients with active ulcerative colitis. Immunohistochemical studies showed that serpin B1 expression was localized not only in inflammatory infiltration cells but also in epithelial cells. Serpin B1 mRNA expression was also increased in colonic mucosa of mouse DSS-induced colitis. Serpin B1-transfected YAMC cells were resistant against the treatment of H(2)O(2). H(2)O(2) treatment significantly induced NE in YAMC cells, and NE-silenced YAMC cells were also resistant against the treatment of H(2)O(2). These results suggest that serpin B1 may be a novel marker of active ulcerative colitis and may play an important role in the pathogenesis of inflammatory bowel disease.

DOI： 10.1152/ajpgi.00292.2011

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BTB and CNC homologue 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). This study hypothesized that Bach1 plays an important role in the indomethacin-induced apoptosis in the case of small-intestinal mucosal injury. Eight-week-old male C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice were included in this study. Mucosal injuries induced by subcutaneously administering indomethacin were evaluated macroscopically, histologically and biochemically. Indomethacin-induced injuries were improved in Bach1-deficient mice. Immunohistochemistry showed an increase in the number of HO-1-positive cells, which were mainly F4/80 positive macrophages, in Bach1-deficient mice. Indomethacin administration increased the expression of HO-1 mRNA and protein in the small intestine in Bach1-deficient mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining showed that the extent of apoptosis was suppressed in Bach1-deficent mice. In conclusion, deficiency of the Bach1 gene inhibited apoptosis and thus suppressed mucosal injury, indicating that Bach1 is a novel therapeutic target for indomethacin-induced intestinal injury.

DOI： 10.3109/10715762.2011.574287

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The pathogenesis of small intestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin is still unclear. For this reason, there is currently no therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF)-α exert beneficial effects on intestinal lesions in patients with inflammatory bowel disease (IBD). To clarify the participation of TNF-α in NSAID-induced small intestinal damage, we investigated the effects of indomethacin administration in mice with targeted deletion of the TNF-α gene. Indomethacin (10 mg/kg) was administered subcutaneously to male C57BL/6 (wild-type: WT) mice and TNF-α-deficient (TNF-α-/-) mice to induce small intestinal damage. The ulcer score, the tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the expression of keratinocyte chemoattractant (KC) mRNA in the small intestinal mucosa were measured. In addition, we performed a TUNEL assay to evaluate indomethacin-induced apoptosis of intestinal epithelial cells and measured the expression of caspase-3 protein and Bcl-2 mRNA. The ulcer score, MPO activity, and expression of KC mRNA were significantly increased after indomethacin administration. These increases were significantly inhibited in TNF-α-/- mice compared with WT mice. Apoptotic cells were observed by the TUNEL assay in the area of the ulcerative lesion, and they were significantly fewer in TNF-α-/- mice compared with WT mice. The expression of cleaved caspase-3 protein was induced by indomethacin administration, and significantly inhibited in TNF-α-/- mice compared with that of WT mice. The expression level of Bcl-2 mRNA in indomethacin-treated TNF-α-/- mice was significantly higher than that in WT mice. TNF-α plays an important role in the pathogenesis of indomethacin-induced small intestinal damage. These results suggest that TNF-α could become a new therapeutic target for NSAID-induced small intestinal damage.

DOI： 10.3892/ijmm.2011.602

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Heat shock protein (HSP) 47 may play an important role in the pathogenesis of intestinal fibrosis. Daikenchuto (DKT), a traditional Japanese herbal (Kampo) medicine, has been reported to ameliorate intestinal inflammation. The aims of this study were to determine time-course profiles of several parameters of fibrosis in a rat model, to confirm the HSP47-expressing cells in the colon, and finally to evaluate DKT's effects on intestinal fibrosis. Colitis was induced in male Wistar rats weighing 200 g using an enema of trinitrobenzene sulfonic acid (TNBS). HSP47 localization was determined by immunohistochemistry. Colonic inflammation and fibrosis were assessed by macroscopic, histological, morphometric, and immunohistochemical analyses. Colonic mRNA expression of transforming growth factor β1 (TGF-β1), HSP47, and collagen type I were assessed by real time-polymerase chain reaction (PCR). DKT was administered orally once a day from 8 to 14 d after TNBS administration. The colon was removed on the 15th day. HSP47 immunoreactivity was coexpressed with α-smooth muscle actin-positive cells located in the subepithelial space. Intracolonic administration of TNBS resulted in grossly visible ulcers. Colonic inflammation persisted for 6 weeks, and fibrosis persisted for 4 weeks after cessation of TNBS treatment. The expression levels of mRNA and proteins for TGF-β1, HSP47, and collagen I were elevated in colonic mucosa treated with TNBS. These fibrosis markers indicated that DKT treatment significantly inhibited TNBS-induced fibrosis. These findings suggest that DKT reduces intestinal fibrosis associated with decreasing expression of HSP47 and collagen content in the intestine.

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background and Aims: The pathogenesis of enteropathy induced by non-steroidal anti-inflammatory drugs (NSAIDs) is still unclear, and there are no established treatments. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has been associated with the development of chronic inflammatory diseases, including autoimmune diseases. To define the role of IL-17A in small intestinal injury and inflammation, we studied the effects of indomethacin administration in mice with targeted deletions of the IL-17A gene. Methods: Male C57BL/6 (wild-type) and homozygous IL-17A-/- C57BL/6 mice were subjected to this study. Indomethacin (10mg/kg) was subcutaneously administered to induce small-intestinal damage. Indomethacin-induced lesions in the small intestine were evaluated by measuring the injured area and by histopathology. Also assessed were myeloperoxidase (MPO) activity, as an index of neutrophil accumulation, and intestinal mRNA expression for inflammatory cytokines. Results: The area of macroscopic ulcerative lesions, the MPO activity and the mRNA expression of inflammatory-associated chemokines, such as keratinocyte chemoattractant (KC), monocyte chemotactic protein-1 (MCP-1), and granulocyte-colony stimulating factor (G-CSF), were significantly increased in indomethacin-treated groups compared with the sham groups. The development of intestinal lesions by indomethacin was inhibited in IL-17A-/- mice compared with wild-type mice, together with significant suppression of the increased levels of MPO activities and KC, MCP-1, and G-CSF levels. Conclusion: These findings demonstrate that IL-17A contributes to the development of indomethacin-induced small intestinal injury through upregulation of G-CSF, KC, and MCP-1. IL-17A might be a promising new therapeutic target to treat NSAID-induced enteritis. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1746.2010.06496.x

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: To protect the small intestine from mucosal injury induced by nonsteroidal anti-inflammatory drugs is one of the critical issues in the field of gastroenterology. Polaprezinc (PZ), a gastric muco-protecting agent, has been widely used for the treatment of gastric ulcer and gastritis for its unique effects, such as its strong reactive oxygen species (ROS)-quenching effect. The aim of this study was to clarify the mechanism by which indomethacin-induced small intestinal mucosal injury occurs, by using a rat intestinal epithelial cell line (RIE-1). In addition, the protective role of PZ and the possible mechanism of its effect on indomethacin-induced small intestinal injury were investigated. METHODS: Cell death was evaluated by methyl thiazolyl tetrazolium (MTT) assay and a double-staining method with Hoechst33342 dye and propidium iodide. Indomethacin-induced ROS production was evaluated by detecting the oxidation of a redox-sensitive fluorogenic probe, RedoxSensor, and the oxidation of cysteine residues of proteins (protein S oxidation). The activation of cytochrome c, smac/DIABLO, and caspase-3 was assessed by western blotting. In some experiments, PZ or its components, L: -carnosine and zinc, were used. RESULTS: We found that indomethacin caused apoptosis in RIE-1 cells in a dose- and time-dependent manner. Indomethacin also induced ROS production and an increase in the protein S oxidation of RIE-1. Pretreatment of RIE-1 with PZ or zinc sulfate, but not L: -carnosine, significantly reduced the indomethacin-induced apoptosis. PZ prevented ROS production and the increase in protein S-oxidation. PZ inhibited indomethacin-induced cytochrome c and smac/DIABLO release and subsequent caspase-3 activation. CONCLUSIONS: The protective effect of PZ on indomethacin-induced small intestinal injury may be dependent on its ROS-quenching effect.

DOI： 10.1007/s00535-010-0213-9

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Carbon monoxide (CO) has been reported to ameliorate colonic inflammation and improve experimental colitis. It is well known that mucosal restitution is important to improve colitis as well as reduction of mucosal inflammation. However, it has not been clear whether CO effects to colonic mucosal restitution or not. In general, colonic myofibroblast (MF) has been reported to play an important role of colonic epithelial cell restitution via constitutive secretion of TGF-β. In this study, we showed CO (supplied by CO-releasing molecule
CORM) treated MF conditioned medium enhanced colonic epithelial cell (YAMC) restitution and we determined gene expression in colonic MF treated with CO using microRNA. The microRNA array suggested that miR-710 was significantly reduced in MF by CO treatment and the target gene of miR-710 is determined to fibroblast growth factor (FGF)15. The CO treated MF conditioned medium which FGF15 expression was silenced extinguished the enhancement effect of epithelial cell restitution. Our findings demonstrate that CO treatment to MF increased FGF15 expression via inhibition of miR-710 and FGF15 enhanced colonic epithelial cell restitution. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.12.035

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). It plays an important role in the feedback regulation of HO-1 expression, which protects cells from various insults including oxidative stress and inflammatory cytokines. However, the role of Bach1 in intestinal inflammation remains unclear. In this study, the role of Bach1 in intestinal mucosal injury was elucidated using 8-week-old female C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice. Intestinal mucosal injuries induced by a single subcutaneous administration of indomethacin were evaluated macroscopically, histologically, and biochemically. Mucosal protein content and chemokine mRNA levels were determined by real-time PCR. Our results showed that the indomethacin-induced intestinal injury was remarkably improved in Bach1-deficient mice. Histological examination showed that the area of injured lesion was decreased in Bach1-deficient mice compared to wild-type mice. Administration of indomethacin induced expression of inflammatory chemokines such as KC, MIP1alpha and MCP1, which was suppressed in Bach1-deficient mice. Myeloperoxidase activity in the intestinal mucosa was also significantly decreased in Bach1-deficient mice. Additionally, Bach1 deficiency enhanced immunopositivity of HO-1 in the intestinal mucosa after indomethacin administration. Disruption of the Bach1 gene thus caused inhibition of mucosal injury, indicating that inhibition of Bach1 may be a novel therapeutic strategy for treating indomethacin-induced intestinal injury.

Scopus

PubMed

Language：Japanese   Publisher：(一社)日本消化器がん検診学会  

総合健診受診者12716名(男性7789名、女性4927名)を対象に、癌と生活習慣、メタボリック症候群(MS)との関係について前向き調査を行い、受診後1年以内に癌と診断された者を健診受診時担癌者とした。その結果、対象者の0.9%・120名(男性87名、女性33名)から癌が報告され、胃癌33名(男性27名、女性6名)、大腸癌27名(男性20名、女性7名)であり、MSは男性13.6%・女性1.2%に認められた。胃癌ではMS(+)0.4%・MS(-)0.3%と差を認めなかったが、大腸癌ではMS(+)0.5%・MS(-)0.2%と有意差を認めた。空腹時高血糖(IFG)(+)では胃癌0.7%、大腸癌0.5%とIFG(-)の胃癌0.2%・大腸癌0.2%より多く認めた。MSの各因子の多変量解析では、胃癌のIFGオッズ比は2.84(P=0.01)と有意であり、大腸癌でもIFGオッズ比は2.58(P=0.037)と有意であった。以上より、胃癌・大腸癌は喫煙・飲酒・コーヒー・運動の四つの生活習慣に有意な関連を認めなかったが、MSは大腸癌において有意な危険因子であり、IFGは胃癌・大腸癌の両者で有意な危険因子であった。

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J04447&link_issn=&doc_id=20080918220002&doc_link_id=10.11404%2Fjsgcs.46.558&url=https%3A%2F%2Fdoi.org%2F10.11404%2Fjsgcs.46.558&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(株)先端医学社  

1991年に提唱された新しい胃炎の概念Sydney Systemに対応する内視鏡診断はいまだに確立されていない。われわれは、Helicobacter pylori(H.pylori)感染による胃粘膜の炎症にもとづく所見-(1)胃底腺粘膜のびまん性発赤、(2)同粘膜の集合細静脈の拡張(点状発赤も含む)、(3)胃体部大彎ひだの腫大・蛇行-を診断指標にして検討した。その結果、上記(1)(2)(3)の順に内視鏡診断成績は、感度94.5%,90.4%,96.7%、特異度83.9%,81.7%,69.2%であった。また、びまん性発赤を定量的に評価するHemoglobin index(IHb)では、感度、特異度とも90%であった。これらの成績は、内視鏡疑診例、IHbのグレーゾーン例を除いたものであるが、H.pyloriの一般診断検査にあまり遜色のない成績である。IHb測定を含めたH.pyloriの内視鏡診断はreal timeに、容易に、しかも経費をかけることなく実施できる有用な診断法である。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J03103&link_issn=&doc_id=20071210410001&doc_link_id=%2Fae6helib%2F2007%2F001106%2F001%2F0520-0526%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae6helib%2F2007%2F001106%2F001%2F0520-0526%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)東京医学社  

Virtual enteroscopyは、軽微な病変を除けば小腸X線造影検査やカプセル内視鏡検査、ダブルバルーン小腸内視鏡検査から得られる情報を一度に入手でき、Crohn病や憩室性疾患、腸閉塞などの診断に有用な検査法である。他の検査法により得られる画像とのfusion画像の作製など、新たな応用も可能であり、また、MDCT機器のバージョンアップなどにより更なる発展も期待できる。Virtual enteroscopyは、小腸X線造影検査、カプセル内視鏡検査やダブルバルーン小腸内視鏡検査とともに、小腸疾患の診断に積極的に導入していかなければならない検査法である。(著者抄録)

Language：Japanese   Publisher：(一社)京都府医師会  

最近3年間に成人のO157感染症を4例(43歳女,21歳女,62歳女,25歳女)経験し,そのうち1例(43歳女)は溶血性尿毒症症候群(HUS)を合併した.4例とも血性下痢で発症し腹部CTで右側大腸腸管壁の著明な壁肥厚を認めた.便培養は陰性であったが,O157-LPS抗体が陽性と判明しO157感染症と診断した.症例1はHUSを合併し,週3回の血液透析を行い救命できた.症例1は抗生物質が便培養検査前に投与されていたこと,便培養検査までに5日を要したことから陰性になった可能性が示唆されたが,症例2,3,4は下痢発症後4日以内の抗生物質投与前に便培養を行っていたが陰性であった.いずれの症例も救急外来を経由しており,検体の採取から培養開始までに24時間以上要したことが原因の一つと考えられた

Language：Japanese   Publishing type：Research paper (scientific journal)  

Scopus

PubMed

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2004&ichushi_jid=J01118&link_issn=&doc_id=20040213030007&doc_link_id=1390282681377715072&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282681377715072&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Language：English  

BACKGROUND AND OBJECTIVE: Several endoscopic resection methods have been developed as less invasive treatments for superficial non-ampullary duodenal epithelial tumours. This study aimed to compare outcomes of conventional endoscopic mucosal resection and underwater endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumours, including resection depth and rate of the muscularis mucosa contained under the lesion. METHODS: This single-centre retrospective cohort study conducted from January 2009 to December 2021 enrolled patients who underwent conventional endoscopic mucosal resection and underwater endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumours and investigated their clinicopathological outcomes using propensity score matching. RESULTS: Of the 285 superficial non-ampullary duodenal epithelial tumours, 98 conventional endoscopic mucosal resections and 187 underwater endoscopic mucosal resections were included. After propensity score matching, 64 conventional endoscopic mucosal resections and 64 underwater endoscopic mucosal resections were analysed. The R0 resection rate was significantly higher in underwater endoscopic mucosal resection cases than in conventional endoscopic mucosal resection cases (70.3% vs. 50.0%; P = 0.030). In the multivariate analysis, a lesion diameter > 10 mm (odds ratio 7.246; P = 0.001), being in the 1st-50th treatment period (odds ratio 3.405; P = 0.008), and undergoing conventional endoscopic mucosal resection (odds ratio 3.617; P = 0.016) were associated with RX/R1 resection. Furthermore, in underwater endoscopic mucosal resection cases, the R0 rate was significantly higher for lesions diameter ≤10 mm than >10 mm, and was significantly higher in the 51st-treatment period than in the 1st-50th period. Conventional endoscopic mucosal resection and underwater endoscopic mucosal resection cases showed no significant difference in resection depth and muscularis mucosa containing rate. CONCLUSIONS: Underwater endoscopic mucosal resection may be more acceptable than conventional endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumours ≤ 10 mm. A steep early learning curve may be acquired for underwater endoscopic mucosal resection. Large multicentre prospective studies need to be conducted to confirm the effectiveness of underwater endoscopic mucosal resection.

DOI： 10.1093/jjco/hyad145

PubMed

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

Language：English   Publisher：(一社)日本癌学会  

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

Language：Japanese   Publisher：(一社)日本ヘリコバクター学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本胃癌学会  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：English  

OBJECTIVES: Esophagogastroduodenoscopy is important for the detection of curable gastric cancer (GC). However, there are no appropriate surveillance data during routine endoscopic inspections. This study aimed to clarify the risk factors of pT1b- or deeper-GC detection during surveillance endoscopy. METHODS: This was a retrospective, multicenter, cross-sectional study conducted in 15 Japanese hospitals. We retrospectively analyzed patients with GC who had previously undergone surveillance endoscopy at each institution from January 2014 to March 2020. Patients who had undergone gastrectomy, non-infection of Helicobacter pylori (Hp), and those with intervals < 3 months or >10 years from a previous endoscopy were excluded. RESULTS: In total, 1085 patients with GCs detected during surveillance endoscopy were enrolled. The multivariate logistic analysis revealed that current Hp infection (odds ratio [OR], 2.18; 95% confidence interval [CI] 1.50-3.16) and a surveillance interval of >1.5 years (OR, 1.96; 95% CI, 1.35-2.84) were independent risk factors for pT1b- or deeper-GC. The 5-year disease-specific survival (5y-DSS) rate of GC was significantly lower in patients with surveillance interval of >1.5 years than in those with surveillance interval of ≤1.5 years (93.7% vs. 98.3%, P <0.001). Similarly, the 5y-DSS rate of GC was significantly lower in patients with active Hp infection than in those without (93.7% vs. 99.4%, P <0.001). CONCLUSION: In this study, a surveillance interval of >1.5 years and current Hp infection were independent risk factors for detecting pT1b- or deeper-GC. Additionally, these factors were poor prognostic factors of the detected GC during surveillance endoscopy.

DOI： 10.1111/den.14492

PubMed

Language：English  

Small intestinal lipomas are rare, but may cause obscure gastrointestinal bleeding. The endoscopic unroofing technique excises only the upper third of the lipoma and allows both histological confirmation and complete treatment with minimal risk of perforation. We present a rare case of obscure gastrointestinal bleeding caused by a jejunal lipoma. A 75-year-old man on antiplatelet therapy presented to our department with melena and anemia. Computed tomography revealed he had a 45-mm jejunal submucosal tumor with fat attenuation. Endoscopic resection using an endoscopic unroofing technique with double balloon enteroscopy was successfully performed. The tumor was confirmed to be a lipoma.

DOI： 10.1007/s12328-022-01724-3

PubMed

Language：Japanese   Publisher：日本消化器内視鏡学会-近畿支部  

Language：English  

Background/Aims: Several studies have assessed the effect of cool temperature on colonic peristalsis. Transient receptor potential melastatin 8 (TRPM8) is a temperature-sensitive ion channel activated by mild cooling expressed in the colon. We examined the antispasmodic effect of cool temperature on colonic peristalsis in a prospective, randomized, single-blind trial and based on the video imaging and intraluminal pressure of the proximal colon in rats and TRPM8-deficient mice. Methods: In the clinical trial, we randomly assigned a total of 94 patients scheduled to undergo colonoscopy to 2 groups: the mildly cool water (n = 47) and control (n = 47) groups. We used 20 mL of 15°C water for the mildly cool water. The primary outcome was the proportion of subjects with improved peristalsis after treatment. In the rodent proximal colon, we evaluated the intraluminal pressure and performed video imaging of the rodent proximal colon with cool water administration into the colonic lumen. Clinical trial registry website (Trial No. UMIN-CTR; UMIN000030725). Results: In the randomized controlled trial, after treatment, the proportion of subjects with no peristalsis with cool water was significantly higher than that in the placebo group (44.7% vs 23.4%; P < 0.05). In the rodent colon model, cool temperature water was associated with a significant decrease in colonic peristalsis through its suppression of the ratio of peak frequency (P < 0.05). Cool temperature-treated TRPM8-deficient mice did not show a reduction in colonic peristalsis compared with wild-type mice. Conclusion: For the first time, this study demonstrates that cool temperature-dependent suppression of colonic peristalsis may be associated with TRPM8 activation.

DOI： 10.5056/jnm21198

PubMed

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：日本消化器内視鏡学会-近畿支部  

Language：English  

Neuroendocrine carcinoma (NEC) of the esophagus at early-stage is very rare due to its rapidly progression. Here, we reported a case of esophageal NEC at early stage treated with endoscopic submucosal dissection (ESD). A 63-year-old man underwent esophagogastroduodenoscopy (EGD) and a lesion was detected in the thoracic esophagus. The preoperative diagnosis was squamous cell carcinoma (SCC) based on magnifying endoscopy; however, the pathological diagnosis was NEC with an invasion of muscularis mucosa accompanied by lymphovascular invasion. Adjuvant chemoradiotherapy was recommended after ESD; however, the patient did not accept additional treatments. The patient was alive with no recurrence 15 months after ESD. In this case, there were three malignant components among SCC, NEC, and adenocarcinoma with transitional areas among each component in the superficial part of the lesion.

DOI： 10.1007/s12328-022-01595-8

PubMed

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Language：Japanese   Publisher：(一財)日本消化器病学会  

Language：Japanese   Publisher：(一財)日本消化器病学会  

Language：Japanese  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese  

J-GLOBAL

Language：Japanese  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本消化管学会  

Language：Japanese  

J-GLOBAL

J-GLOBAL

J-GLOBAL

Language：English  

INTRODUCTION: Studies have reported the feasibility of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in elderly people with respect to both short- and long-term outcomes. As the elderly population in society increases, the requirement for managing super-elderly patients aged ≥85 years with EGC will also increase. This study aims to identify the long-term clinical outcomes of ESD for clinical T1N0 EGC in patients aged ≥85 years. METHODS: A total of 370 consecutive patients aged ≥85 years with clinical T1N0 EGC who were managed in 11 institutions were reviewed retrospectively. On the basis of treatment strategy, we compared the overall survival (OS) and disease-specific survival (DSS) after performing propensity score-matched analysis between patients undergoing ESD (ESD group) and those not undergoing treatment (conservative treatment group). The potential prognostic factors were also investigated in the propensity score-matched patients. RESULTS: After propensity score matching, we found that the 3-year OS and DSS rates were significantly higher in the ESD group than in the conservative treatment group (OS, 82.2% vs. 50.5%; p < 0.001; DSS, 100% vs. 80.1%; p = 0.008). Furthermore, ESD was identified as a significant factor for prolonged OS, whereas Charlson comorbidity index (CCI) ≥3 and prognostic nutritional index (PNI) <36.2 were associated with reduced OS. CONCLUSION: ESD was associated with improved OS in patients with clinical T1N0 EGC aged ≥85 years compared with the absence of treatment. Furthermore, CCI and PNI were helpful for patient selection.

DOI： 10.1159/000525422

PubMed

J-GLOBAL

J-GLOBAL

J-GLOBAL

J-GLOBAL

Language：Japanese   Publisher：日本消化器内視鏡学会-近畿支部  

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

J-GLOBAL

Language：English  

The visibility and diagnostic accuracy of early gastric cancer (EGC) after Helicobacter pylori (HP) eradication have been reported to improve using image-enhanced endoscopy (IEE) compared with white light imaging (WLI). The present study clarified the appropriate IEE for the detection and diagnosis of EGC in clinical settings. This prospective and cross-sectional study evaluated the visibility of EGC and endoscopic findings of gastric mucosa after successful HP eradication (n = 31) using videos with WLI and IEE. Three endoscopists evaluated high-definition videos in a randomized order. The mean visibility scores (MVSs) on linked color imaging (LCI) for atrophic border, intestinal metaplasia, map-like redness, and EGC were the highest among each modality (3.87 ± 0.34, 3.82 ± 0.49, 3.87 ± 0.50, and 3.35 ± 0.92, respectively). The MVSs with blue laser imaging (BLI) were highest for magnifying view of the demarcation line (DL), microsurface pattern (MSP), and microvascular pattern (MVP) for EGC (3.77 ± 0.49, 3.94 ± 0.25, and 3.92 ± 0.34, respectively). LCI had the highest visibility among findings of gastric mucosa and EGC after HP eradication, and BLI had the highest visibility of MVP, MSP, and DL in magnifying observation. These results suggest that LCI observation in the entire stomach and further magnifying BLI are the best methods for detecting and diagnosing EGCs after HP eradication, respectively.

DOI： 10.3390/jcm10163649

PubMed

Language：English  

BACKGROUND: Long-term outcomes of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) have not been assessed in a large, multicenter cohort. We aimed to evaluate long-term outcomes of ESD for ESCC in a real-world setting. METHODS: We retrospectively recruited 659 patients who underwent ESD for ESCC at ten institutions from January 2007 to December 2015. Of these, 566 patients were analyzed and classified into three groups according to the pathologic invasion depth after ESD: epithelium/lamina propria mucosa (EP/LPM group: 454 patients), muscularis mucosa/submucosa invasion ≤ 200 μm below the inferior margin of the muscularis mucosa (MM/SM1 group: 81 patients), and submucosa invasion > 200 μm below the MM inferior margin (SM2 group: 31 patients). RESULTS: The 5-year overall survival rates in the EP/LPM, MM/SM1, and SM2 groups were 92.6%, 80.0%, and 62.7%, respectively, while the 5-year disease-specific survival rates were 99.7%, 96.9%, and 88.3%, respectively. Multivariate analyses revealed that the invasion depth, Charlson Comorbidity Index (CCI), and prognostic nutritional index (PNI) were independent prognostic factors. Hazard ratios in the MM/SM1 and SM2 groups were 2.25 (95% confidence interval [CI] 1.04-4.83; P = 0.038) and 3.18 (95% CI 1.08-9.34; P = 0.036), respectively, compared to those in the EP/LPM group, while those for patients with a CCI ≥ 3 and PNI ≤ 47.75 were 3.25 (95% CI 1.79-5.89; P < 0.001) and 2.42 (95% CI 1.26-4.65; P = 0.008), respectively. CONCLUSIONS: This study identified that invasion depth, presence of comorbid diseases and preoperative nutritional status are independent prognostic risk factors associated with ESCC patients undergoing ESD.

DOI： 10.1007/s00464-021-08502-1

PubMed

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Language：Japanese  

J-GLOBAL

Language：Japanese   Publisher：京都府立医科大学附属北部医療センター  

症例は36歳男性。主訴は発熱。肝右葉に多発する内部蜂巣状の膿瘍を認めた。経静脈的抗菌療法により炎症は沈静せず膿瘍は増大した。蜂窩織炎成分主体の病変性状によりドレナージ療法は困難と考え、大腿動脈経由に設置した肝動脈リザーバーを用いて抗菌薬動注療法を開始した。17日目に膿瘍の著明な縮小と炎症反応の鎮静化、28日目に膿瘍は消失した。本例のように従来治療が困難な肝膿瘍に対しては、抗菌薬の肝動注療法が有効である可能性があり、治療法の一つとして考慮する価値がある。(著者抄録)

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

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Language：English   Publisher：(NPO)日本免疫学会  

Language：Japanese   Publisher：(一財)日本消化器病学会  

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

Language：Japanese   Publisher：京都府立医科大学附属北部医療センター  

Tolvaptanは肝性腹水の治療に非常に有用な薬剤だが、日常臨床ではしばしば無効例を経験する。本研究ではTolvaptanへの反応性について、治療前後の腹水、肝予備能、血液生化学的検査の変化を検討したところ、Tolvaptanへの反応性は、腎機能、肝予備能に規定されることがわかった。またTolvaptan無効例でもアルブミン補充や腹水濾過再静注(CART)を併用することで、治療効果の改善を認めた。本研究は少数例の検討であり、今後症例の集積が必要である。(著者抄録)

Language：Japanese   Publisher：日本消化器病学会-近畿支部  

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Language：Japanese   Publisher：(公社)日本ビタミン学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Web of Science

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Web of Science

Language：English  

A 68-year-old woman was admitted to the authors' hospital for hepatic encephalopathy. Her laboratory data and computed tomography findings were not suggestive of liver cirrhosis. Superior mesenteric angiography revealed an extrahepatic portal-systemic shunt with a main cause of hepatic encephalopathy. Despite treatment with branched-chain amino acid, lactulose, and kanamycin, hyperammonemia was prolonged, and the portal-systemic shunt was therefore treated with balloon-occluded retrograde transvenous obliteration. After the procedure, hyperammonemia was improved, and there were no signs of recurrent portal-systemic encephalopathy.

PubMed