133 results on '"Ileitis chemically induced"'
Search Results
2. Chemotherapy-induced ileitis associated or not with colitis in digestive oncology patients: An AGEO multicentre study.
- Author
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Jenvrin A, Perret A, Palmieri LJ, Soularue E, Broudin C, Rance B, Taieb J, and Gallois C
- Subjects
- Humans, Irinotecan, Diarrhea chemically induced, Diarrhea complications, Ileitis chemically induced, Ileitis diagnosis, Colitis chemically induced, Neoplasms complications, Antineoplastic Agents adverse effects
- Abstract
Background: The characteristics and management of ileitis induced by chemotherapy in cancer patients are poorly described in the literature., Methods: This retrospective multicentre study enroled patients hospitalized in a digestive oncology unit for a symptomatic chemotherapy-induced ileitis., Results: Forty-three patients were included, with a regimen based on fluoropyrimidine and/or irinotecan in 95% of cases. Five patients were excluded due to the diagnosis of infectious ileitis (Clostridium difficile in 3 patients, Campylobacter jejuni in 1 patient and cytomegalovirus in 1 patient). The most frequently described symptoms were diarrhoea (77% including 54% of grade 3-4 diarrhoea), abdominal pain (58%), fever (51%) and vomiting (56%). An ileo-colonoscopy was performed in 35% of patients and did not show any specific results or severity criteria. The ileitis was complicated by bowel perforation and/or obstruction in 3 patients. Disease progression was favourable in 1-2 weeks in the vast majority of cases, on symptomatic treatment, allowing resumption of the chemotherapy regimen involved in 67% of patients., Conclusion: Chemotherapy-induced ileitis is a rare complication that most often involves fluoropyri-midine- and/or irinotecan-based regimens. In most cases, endoscopic examinations were not contributory and do not seem useful in the event of non-severe symptomatology which most often develops favourably on symptomatic therapy, allowing resumption of the chemotherapy involved., Competing Interests: Declaration of Competing Interest Anaïs Jenvrin, Audrey Perret, Emilie Soularue, Chloé Broudin, Bastien Rance: declare no conflict of interest. Claire Gallois has participated in consulting and/or advisory boards for Servier and Sanofi, and has received support for travel to meetings from Amgen. Julien Taieb has participated in consulting and/or advisory boards for Lilly, Celgene, Shire, Servier, Merck KGaA, Sanofi, Roche Genentech, Pfizer, and Amgen. Lola-Jade Palmieri has participated in consulting and/or advisory boards for Servier, Amgen and has received support for travel to meetings from Merck, Servier., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
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3. Mycophenolate mofetil-associated collagenous ileitis in a kidney transplant recipient: A case report.
- Author
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Wang B, Xi W, and Li H
- Subjects
- Humans, Male, Adult, Diarrhea, Ileitis chemically induced, Ileitis diagnosis, Ileitis therapy, Kidney Transplantation, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Mycophenolic Acid adverse effects, Mycophenolic Acid therapeutic use
- Abstract
We report a case of mycophenolate mofetil-induced collagenous ileitis in a kidney transplant patient. A 38-year-old Chinese man who had received a kidney transplant 3 years earlier was admitted to our department for severe diarrhea and rapid weight loss. Infection studies were negative, and tumors were ruled out, so drug-induced factors were suspected. He had been taking mycophenolate mofetil for immunosuppression, which was then suspended, and he had a rapid resolution of diarrhea. Pathological findings of gastrointestinal endoscopy biopsy showed the presence of thickened collagen bands in the subepithelium of the terminal ileum. This is the first report of collagenous ileitis caused by mycophenolate mofetil in a patient with a kidney transplantation, adding another reversible cause to this rare condition. It is important for clinicians to recognize and treat it promptly.
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- 2023
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4. Curcumin: a potential exogenous additive for the prevention of LPS-induced duck ileitis by the alleviation of inflammation and oxidative stress.
- Author
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Yang H, Yu C, Yin Z, Guan P, Jin S, Wang Y, and Feng X
- Subjects
- Animals, Lipopolysaccharides adverse effects, Ducks metabolism, NF-kappa B metabolism, Tumor Necrosis Factor-alpha metabolism, Interleukin-6 metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Toll-Like Receptor 4 metabolism, Toll-Like Receptor 4 therapeutic use, Inflammation chemically induced, Inflammation drug therapy, Inflammation prevention & control, Oxidative Stress, Curcumin pharmacology, Curcumin therapeutic use, Ileitis chemically induced, Ileitis genetics, Ileitis prevention & control
- Abstract
Background: Lipopolysaccharides (LPS) are the main pathogenic substances in Gram-negative bacteria. The aim of this study was to investigate the preventive effects of dietary curcumin (CUR) on LPS toxicity in the duck ileum. The duck diet was supplemented with CUR (0.5 g kg
-1 ) for 28 days, while the birds were injected with LPS (0.5 mg kg-1 body weight per injection, administered as seven injections in the last week of the experimental period)., Results: LPS significantly decreased the ileal villus-to-crypt ratio in the non-supplemented CUR group. Dietary CUR alleviated LPS-induced morphological damage to the ileum. Moreover, dietary CUR alleviated oxidative stress by increasing the levels of total superoxide dismutase (T-SOD) (P < 0.05) and glutathione S-transferase (GST) (P < 0.05) and decreasing the production of malonic dialdehyde (MDA) (P < 0.05) in control ducks and LPS-challenged ducks. Dietary CUR significantly inhibited the LPS-induced massive production of inflammatory factors (IL-1β, IL-6, and TNF-α) (P < 0.05). CUR induced the inhibition of TLR4 and activation of Nrf2 to reduce the expression of inflammation-related genes (TLR4, NF-κB, IKK, TXNIP, NLRP3, caspase-1, IL-1β, IL-6, and TNF-α). Moreover, dietary CUR ameliorated the decrease in claudin-1 and occludin expression (P < 0.05) and improved ZO-1 expression in the duck ileum (P < 0.05)., Conclusion: In conclusion, dietary CUR has beneficial effects on LPS-induced ileal damage, oxidative damage, and inflammatory response by inhibiting the TLR/NF-κB and activating the Nrf2 signaling pathways in ducks. This study provides valuable information regarding the therapeutic uses of CUR in duck ileitis. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)- Published
- 2023
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5. P2X7 receptor blockade decreases inflammation, apoptosis, and enteric neuron loss during Clostridioides difficile toxin A-induced ileitis in mice.
- Author
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Santos AAQA, Costa DVS, Foschetti DA, Duarte ASG, Martins CS, Soares PMG, Castelucci P, and Brito GAC
- Subjects
- Animals, Apoptosis, Biotin metabolism, Calbindin 2, Choline O-Acetyltransferase metabolism, DNA Nucleotidylexotransferase metabolism, Enterotoxins, Inflammation pathology, Interleukin-6 metabolism, Interleukin-8 metabolism, Mice, Neurons pathology, Purinergic P2X Receptor Antagonists pharmacology, Receptors, Purinergic P2X7, Tumor Necrosis Factor-alpha metabolism, Bacterial Toxins, Clostridioides difficile, Ileitis chemically induced
- Abstract
Background: Clostridioides difficile ( C. difficile ) is the most common pathogen causing health care-associated infections. C. difficile TcdA and TcdB have been shown to activate enteric neurons; however, what population of these cells is more profoundly influenced and the mechanism underlying these effects remain unknown., Aim: To characterize a specific population of TcdA-affected myenteric neurons and investigate the role of the P2X7 receptor in TcdA-induced ileal inflammation, cell death, and the changes in the enteric nervous system in mice., Methods: Swiss mice were used to model TcdA-induced ileitis in ileal loops exposed to TcdA (50 μg/Loop) for 4 h. To investigate the role of the P2X7 receptor, Brilliant Blue G (50 mg/kg, i.p.), which is a nonspecific P2X7 receptor antagonist, or A438079 (0.7 μg/mouse, i.p.), which is a competitive P2X7 receptor antagonist, were injected one hour prior to TcdA challenge. Ileal samples were collected to analyze the expression of the P2X7 receptor (by quantitative real-time polymerase chain reaction and immunohistochemistry), the population of myenteric enteric neurons (immunofluorescence), histological damage, intestinal inflammation, cell death (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling), neuronal loss, and S100B synthesis (immunohistochemistry)., Results: TcdA upregulated ( P < 0.05) the expression of the P2X7 receptor gene in the ileal tissues, increasing the level of this receptor in myenteric neurons compared to that in control mice. Comparison with the control mice indicated that TcdA promoted ( P < 0.05) the loss of myenteric calretinin+ (Calr) and choline acetyltransferase+ neurons and increased the number of nitrergic+ and Calr+ neurons expressing the P2X7 receptor. Blockade of the P2X7 receptor decreased TcdA-induced intestinal damage, cytokine release [interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α], cell death, enteric neuron loss, and S100B synthesis in the mouse ileum., Conclusion: Our findings demonstrated that TcdA induced the upregulation of the P2X7 receptor, which promoted enteric neuron loss, S100B synthesis, tissue damage, inflammation, and cell death in the mouse ileum. These findings contribute to the future directions in understanding the mechanism involved in intestinal dysfunction reported in patients after C. difficile infection., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)
- Published
- 2022
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6. Small intestine neuromuscular dysfunction in a mouse model of dextran sulfate sodium-induced ileitis: Involvement of dopaminergic neurotransmission.
- Author
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Cerantola S, Faggin S, Caputi V, Bosi A, Banfi D, Rambaldo A, Porzionato A, Di Liddo R, De Caro R, Savarino EV, Giaroni C, and Giron MC
- Subjects
- Animals, Dextran Sulfate toxicity, Disease Models, Animal, Dopamine, Dopamine Antagonists, Humans, Intestine, Small metabolism, Male, Mice, RNA, Messenger genetics, Receptors, Dopamine D1 metabolism, Synaptic Transmission physiology, Drinking Water, Ileitis chemically induced, Inflammatory Bowel Diseases
- Abstract
Aims: Anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and preclinical models of IBD. Thus, we aimed to evaluate the impact of dextran sodium sulfate (DSS)-induced ileitis on enteric dopaminergic pathways., Materials and Methods: Male C57/Bl6 mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and were then switched to regular drinking water for 3 days. To measure ileitis severity inflammatory cytokines (IL-1β, TNFα, IL-6) levels were assessed. Changes in ileal muscle tension were isometrically recorded following: 1) cumulative addition of dopamine on basal tone (0.1-1000 μM); ii) 4-Hz electric field stimulation (EFS) in the presence of 30 μM dopamine with/without 10 μM SCH-23390 (dopamine D1 receptor (D1R) antagonist) or 10 μM sulpiride (D2R antagonist). Immunofluorescence distribution of the neuronal HuC/D protein, glial S100β marker, D1R, and dopamine transporter (DAT) were determined in longitudinal-muscle-myenteric plexus whole-mounts (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR., Key Findings: DSS caused an inflammatory process in the small intestine associated to dysmotility and altered barrier permeability, as suggested by decreased fecal output and enhanced stool water content. DSS treatment caused a significant increase of DAT and D1R myenteric immunoreactivity as well as of D1R and D2R mRNA levels, accompanied by a significant reduction of dopamine-mediated relaxation, involving primarily D1-like receptors., Significance: Mouse ileitis affects enteric dopaminergic neurotransmission mainly involving D1R-mediated responses. These findings provide novel information on the participation of dopaminergic pathways in IBD-mediated neuromuscular dysfunction., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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7. A quinazoline-based bromodomain inhibitor, CN210, ameliorates indomethacin-induced ileitis in mice by inhibiting inflammatory cytokine expression.
- Author
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Noguchi T, Hidaka K, Kobayashi S, Matsumoto K, Yoshioka M, Hu X, Maloney DJ, Yang SM, and Kato S
- Subjects
- Animals, Cytokines biosynthesis, E1A-Associated p300 Protein metabolism, Ileitis chemically induced, Male, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, NF-kappa B physiology, Peroxidase metabolism, Phosphoproteins metabolism, Quinazolines pharmacology, RAW 264.7 Cells, Anti-Inflammatory Agents pharmacology, Cytokines antagonists & inhibitors, Ileitis drug therapy, Indomethacin adverse effects, Proteins antagonists & inhibitors
- Abstract
Inhibitors of bromodomain and extra-terminal motif (BET) proteins are emerging epigenetic therapeutics that suppress gene expressions that drive cancer and inflammation. The present study examined anti-inflammatory effects of a quinazoline-based BET inhibitor, CN210, in a murine ileitis model. CN210 was given orally 30 min before and 24 h after a subcutaneous administration of indomethacin. Macroscopic and histological evidences of ileitis, mucosal myeloperoxidase (MPO) activity and cytokine expressions were evaluated 48 h after the indomethacin administration. To further characterize the anti-inflammatory pathways modulated by CN210, its effects on RAW264 cells treated with lipopolysaccharide (LPS) were investigated. Competitive ligand binding and docking studies of CN210 to CREB-binding protein (CBP) and p300 were also performed. Oral administration of CN210 significantly reduced the severity of ileitis, normalized both proinflammatory MPO activity and concomitant cytokine expressions induced by indomethacin administration. Furthermore, CN210 attenuated the expression of cytokines and reversed the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPK) induced by LPS. Competitive ligand binding assays showed that CN210 bound to the bromodomains of two paralogous histone acetyltransferases, CBP and p300, in addition to the bromodomains of BET proteins. Docking studies of CN210 to the bromodomains of CBP and p300 showed a similarity to the binding mode of SGC-CBP30, a specific CBP/p300 inhibitor. CN210 ameliorates indomethacin-induced ileitis by inhibiting the expression of inflammatory cytokines through the attenuation of NF-κB and MAPK pathways. CN210 thus represents a new mode of therapy for non-steroidal anti-inflammatory drug-induced ileitis and inflammatory bowel disease., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
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8. Deoxycholic acid enhancement of lymphocyte migration through direct interaction with the intestinal vascular endothelium.
- Author
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Shibuya N, Higashiyama M, Akita Y, Shirakabe K, Ito S, Nishii S, Mizoguchi A, Inaba K, Tanemoto R, Sugihara N, Hanawa Y, Wada A, Horiuchi K, Yoshikawa K, Kurihara C, Okada Y, Watanabe C, Komoto S, Tomita K, Saruta M, and Hokari R
- Subjects
- Animals, Bile Acids and Salts adverse effects, Bile Acids and Salts pharmacology, Cholic Acids adverse effects, Cholic Acids pharmacology, Disease Models, Animal, Ileum blood supply, Ileum drug effects, Ileum immunology, Ileum physiopathology, Intercellular Adhesion Molecule-1 biosynthesis, Intercellular Adhesion Molecule-1 immunology, Intravital Microscopy, Male, Mice, Mice, Inbred C57BL, Microvessels drug effects, Microvessels immunology, Rats, Rats, Wistar, Sphingosine-1-Phosphate Receptors antagonists & inhibitors, Splanchnic Circulation immunology, Vascular Cell Adhesion Molecule-1 biosynthesis, Vascular Cell Adhesion Molecule-1 immunology, Cell Movement drug effects, Cell Movement immunology, Deoxycholic Acid adverse effects, Deoxycholic Acid pharmacology, Endothelium, Vascular drug effects, Endothelium, Vascular immunology, Endothelium, Vascular physiopathology, Ileitis chemically induced, Ileitis immunology, Ileitis physiopathology, Intestine, Small blood supply, Intestine, Small drug effects, Intestine, Small immunology, Intestine, Small physiopathology, Lymphocytes drug effects, Lymphocytes immunology
- Abstract
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-α4β1 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., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)
- Published
- 2021
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9. A case of persistent iron deficiency anemia in a kidney transplant recipient.
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Sacco M, Bruno M, Deabate MC, De Angelis CG, and Pennazio M
- Subjects
- Diabetic Nephropathies therapy, Humans, Ileum pathology, Male, Middle Aged, Single-Balloon Enteroscopy, Ulcer pathology, Anemia, Iron-Deficiency etiology, Ileitis chemically induced, Kidney Transplantation adverse effects, Mycophenolic Acid adverse effects
- Abstract
Competing Interests: Declaration of Competing Interest The authors have NO conflict of interest to disclose.
- Published
- 2020
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10. Nod2 Protects the Gut From Experimental Colitis Spreading to Small Intestine.
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Al Nabhani Z, Berrebi D, Martinez-Vinson C, Montcuquet N, Madre C, Roy M, Ogier-Denis E, Dussaillant M, Cerf-Bensussan N, Zouali H, Daniel F, Barreau F, and Hugot JP
- Subjects
- Animals, Cecum metabolism, Cecum pathology, Colitis chemically induced, Colitis metabolism, Colitis pathology, Crohn Disease metabolism, Crohn Disease pathology, Duodenitis chemically induced, Duodenitis metabolism, Duodenitis pathology, Duodenum metabolism, Duodenum pathology, Gene Expression, Humans, Ileitis chemically induced, Ileitis metabolism, Ileitis pathology, Ileum metabolism, Ileum pathology, Interferon-gamma metabolism, Interleukin-12 metabolism, Intestinal Mucosa pathology, Mice, Mice, Knockout, Nod2 Signaling Adaptor Protein metabolism, Trinitrobenzenesulfonic Acid, Tumor Necrosis Factor-alpha metabolism, Colitis genetics, Duodenitis genetics, Ileitis genetics, Intestinal Mucosa metabolism, Nod2 Signaling Adaptor Protein genetics, RNA, Messenger metabolism
- Abstract
Background and Aims: Nucleotide oligomerization domain 2 [NOD2] mutations are key risk factors for Crohn's disease [CD]. NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the exact roles of NOD2 in CD and other NOD2-associated disorders remain poorly known., Methods: We initially observed that NOD2 expression was increased in epithelial cells away from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation, and cytokines expression were examined in the small bowel of wild-type [WT], Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulphonic acid [TNBS]., Results: In WT mice, Nod2 upregulation upstream to rectal injury was associated with pro-inflammatory cytokine expression but no overt histological inflammatory lesions. Conversely, in Nod2-deficient mice the inflammation spread from colitis to ileum and duodenum., Conclusions: Nod2 protects the gut from colitis spreading to small intestine., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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11. Cutaneous Vasculitis with Gut Involvement During Secukinumab Treatment for Psoriatic Arthritis.
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Chelli C, Loget J, Vanhaecke C, Durlach A, Gagneux-Lemoussu L, Soriano C, and Viguier M
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- C-Reactive Protein analysis, Colitis diagnostic imaging, Diarrhea chemically induced, Female, Humans, IgA Vasculitis chemically induced, Ileitis diagnostic imaging, Middle Aged, Necrosis, Skin pathology, Tomography, X-Ray Computed, Vasculitis, Leukocytoclastic, Cutaneous diagnosis, Antibodies, Monoclonal, Humanized adverse effects, Arthritis, Psoriatic drug therapy, Colitis chemically induced, Ileitis chemically induced, Vasculitis, Leukocytoclastic, Cutaneous chemically induced
- Published
- 2020
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12. Effects of Bifidobacterium infantis on cytokine-induced neutrophil chemoattractant and insulin-like growth factor-1 in the ileum of rats with endotoxin injury.
- Author
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Wang W, Sun M, Zheng YL, Sun LY, and Qu SQ
- Subjects
- Animals, Chemokine CXCL1 immunology, Disease Models, Animal, Endotoxins toxicity, Humans, Ileitis chemically induced, Ileitis pathology, Ileum drug effects, Ileum immunology, Ileum pathology, Insulin-Like Growth Factor I immunology, Intestinal Mucosa drug effects, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Male, RNA, Messenger metabolism, Rats, Rats, Wistar, Bifidobacterium longum subspecies infantis, Chemokine CXCL1 metabolism, Ileitis therapy, Insulin-Like Growth Factor I metabolism, Probiotics administration & dosage
- Abstract
Background: The digestive tract is the maximal immunizing tissue in the body, and mucosal integrity and functional status of the gut is very important to maintain a healthy organism. Severe infection is one of the most common causes of gastrointestinal dysfunction, and the pathogenesis is closely related to endotoxemia and intestinal barrier injury. Bifidobacterium is one of the main probiotics in the human body that is involved in digestion, absorption, metabolism, nutrition, and immunity. Bifidobacterium plays an important role in maintaining the intestinal mucosal barrier integrity. This study investigated the protective mechanism of Bifidobacterium during ileal injury in rats., Aim: To investigate the effects of Bifidobacterium on cytokine-induced neutrophil chemoattractant (CINC) and insulin-like growth factor 1 (IGF-1) in the ileum of rats with endotoxin injury., Methods: Preweaning rats were randomly divided into three groups: Control (group C), model (group E) and treatment (group T). Group E was intraperitoneally injected with lipopolysaccharide (LPS) to create an animal model of intestinal injury. Group T was intragastrically administered Bifidobacterium suspension 7 d before LPS. Group C was intraperitoneally injected with normal saline. The rats were killed at 2, 6 or 12 h after LPS or physiological saline injection to collect ileal tissue samples. The expression of ileal CINC mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR), and expression of ileal IGF-1 protein and mRNA was detected by immunohistochemistry and RT-PCR, respectively., Results: The ileum of rats in Group C did not express CINC mRNA, ileums from Group E expressed high levels, which was then significantly decreased in Group T ( F = 23.947, P < 0.05). There was no significant difference in CINC mRNA expression at different times ( F = 0.665, P > 0.05). There was a high level of IGF-1 brown granules in ileal crypts and epithelial cells in Group C, sparse staining in Group E, and dark, dense brown staining in Group T. There was a significant difference between Groups C and E and Groups E and T ( P < 0.05). There was no significant difference in IGF-1 protein expression at different times ( F = 1.269, P > 0.05). IGF-1 mRNA expression was significantly different among the three groups ( P < 0.05), though not at different times ( F = 0.086, P > 0.05)., Conclusion: Expression of CINC mRNA increased in the ileum of preweaning rats with endotoxin injury, and exogenous administration of Bifidobacterium reduced CINC mRNA expression. IGF-1 protein and mRNA expression decreased in the ileum of preweaning rats with endotoxin injury, and exogenous administration of Bifidobacterium prevented the decrease in IGF-1 expression. Bifidobacterium may increase IGF-1 expression and enhance intestinal immune barrier function in rats with endotoxin injury., Competing Interests: Conflict-of-interest statement: No conflict of interest exists.
- Published
- 2019
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13. Porcine lactoferrin-derived peptide LFP-20 modulates immune homoeostasis to defend lipopolysaccharide-triggered intestinal inflammation in mice.
- Author
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Zong X, Cao X, Wang H, Zhao J, Lu Z, Wang F, and Wang Y
- Subjects
- Animals, Cytokines metabolism, Disease Models, Animal, Ileitis chemically induced, Ileum immunology, Lipopolysaccharides, Lymphocyte Activation drug effects, Macrophages immunology, Mice, Neutrophils immunology, Anti-Inflammatory Agents pharmacology, Homeostasis drug effects, Ileitis immunology, Immunity, Active drug effects, Lactoferrin pharmacology
- Abstract
The performance of immune system is vital for defending the body from pathogens, and it plays a crucial role in health homoeostasis. In a previous study, we have shown that LFP-20, a twenty-amino acid antimicrobial peptide in the N terminus of porcine lactoferrin, modulated inflammatory response in colitis. Here, we further investigated the effects of LFP-20 on immune homoeostasis to elucidate the mechanism of its anti-inflammation action. A lipopolysaccharide (LPS)-triggered systemic inflammatory response mice model was established. On the basis of observed mucosal lesions and apoptosis in small intestine, we found increased macrophage and neutrophil infiltration in ileum after LPS stimulation. Expectedly, LFP-20 pre-treatment attenuated the LPS-mediated immune disorders in ileum. Moreover, the flow cytometry results indicated pre-treatment with LFP-20 sustained the balance of CD3+CD8+ T cells, B cells and natural killer cells in LPS-triggered immune disturbance. Simultaneously, we demonstrated LFP-20 modulated the secretion of both activated Th1-related IL-12p70, interferon-γ, TNF-α and Th2-related IL-4, IL-5 and IL-6. Furthermore, we found LFP-20 facilitated a balanced Th1 and Th2 response, which triggered cellular defence mechanisms and induced B cells to produce opsonising antibodies belonging to certain IgG subclasses to defend against LPS stimulation. Collectively, our study indicated pre-treatment with LFP-20 could defend against LPS-triggered systemic inflammatory response in mice via modulating immune homoeostasis.
- Published
- 2019
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14. Mesenteric Lymphatic Alterations Observed During DSS Induced Intestinal Inflammation Are Driven in a TLR4-PAMP/DAMP Discriminative Manner.
- Author
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Stephens M, Liao S, and von der Weid PY
- Subjects
- Animals, Colitis chemically induced, Dextran Sulfate, Disease Models, Animal, HEK293 Cells, Humans, Ileitis chemically induced, Lymphangiogenesis immunology, Mice, Inbred C57BL, Toll-Like Receptors genetics, Colitis immunology, Ileitis immunology, Lymph Nodes immunology, Lymphatic Vessels immunology, Mesentery immunology, Toll-Like Receptors immunology
- Abstract
Background: Inflammatory bowel disease (IBD) is characterized by both acute and chronic phase inflammation of the gastro-intestinal (GI) tract that affect a large and growing number of people worldwide with little to no effective treatments. This is in part due to the lack of understanding of the disease pathogenesis and also the currently poorly described involvement of other systems such as the lymphatics. During DSS induced colitis, mice also develop a severe inflammation of terminal ileum with many features similar to IBD. As well as inflammation within the ileum we have previously demonstrated lymphatic remodeling within the mesentery and mesenteric lymph nodes of DSS-treated mice. The lymphatic remodeling includes lymphangiogenesis, lymphatic vessel dilation and leakiness, as well as cellular infiltration into the surrounding tissue and peripheral draining lymph nodes. Methods: Intestinal inflammation was induced in C57BL/6 mice by administration of 2.5% DSS in drinking water for 7 days. Mice were treated with TLR4 blocker C34 or Polymyxin-B (PMXB) daily from days 3 to 7 of DSS treatment via I.P. injection, and their therapeutic effects on disease activity and lymphatic function were examined. TLR activity and subsequent effect on lymphangiogenesis, lymphadenopathy, and mesenteric lymph node cellular composition were assessed. Results: DSS Mice treated with TLR4 inhibitor, C34, had a significantly improved disease phenotype characterized by reduced ileal and colonic insult. The change correlated with significant reduction in colonic and mesenteric inflammation, resolved mesenteric lymphangiectasia, and CD103
+ DC migration similar to that of healthy control. PMXB treatment however did not resolve inflammation within the colon or associated mesenteric lymphatic dysfunction but did however prevent lymphadenopathy within the MLN through alteration of CCL21 gradients and CD103+ DC migration. Conclusions: TLR4 appears to mediate several changes within the mesenteric lymphatics, more specifically it is shown to have different outcomes whether stimulation occurs through pathogen derived factors such as LPS or tissue derived DAMPs, a novel phenomenon.- Published
- 2019
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15. Two Cases of Capecitabine-Induced Ileitis in Patients Treated with Radiochemotherapy to the Pelvis and Review of the Literature.
- Author
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Nicosia L, Russo I, De Sanctis V, Minniti G, Valeriani M, and Osti MF
- Subjects
- Adenocarcinoma diagnostic imaging, Adenocarcinoma pathology, Aged, Anti-Bacterial Agents therapeutic use, Biopsy, Chemoradiotherapy adverse effects, Chemoradiotherapy methods, Colonoscopy, Female, Hand-Foot Syndrome diagnosis, Hand-Foot Syndrome etiology, Humans, Ileitis diagnosis, Ileitis therapy, Middle Aged, Neoadjuvant Therapy adverse effects, Neoadjuvant Therapy methods, Rectal Neoplasms diagnostic imaging, Rectal Neoplasms pathology, Rectum diagnostic imaging, Rectum pathology, Tomography, X-Ray Computed, Adenocarcinoma therapy, Antimetabolites, Antineoplastic adverse effects, Capecitabine adverse effects, Ileitis chemically induced, Rectal Neoplasms therapy
- Published
- 2018
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16. [Aphthous mouth ulcers as an initial manifestation of sécukinumab-induced inflammatory bowel disease].
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Grimaux X, Leducq S, Goupille P, Aubourg A, Miquelestorena-Standley E, and Samimi M
- Subjects
- Adult, Antibodies, Monoclonal, Humanized, Colitis chemically induced, Female, Humans, Ileitis chemically induced, Inflammatory Bowel Diseases diagnosis, Spondylarthritis drug therapy, Antibodies, Monoclonal adverse effects, Inflammatory Bowel Diseases chemically induced, Oral Ulcer chemically induced
- Abstract
Background: Secukinumab, a humanized monoclonal antibody targeting interleukin 17A, has been associated with the development of inflammatory bowel diseases. We report a case of a female patient developing recurrent oral ulcers prior to inflammatory bowel disease induced by secukinumab. The patient had developed similar oral ulcers 6 years earlier while on tocilizumab (targeting IL6R), suggesting an immunological link between the two episodes., Patients and Methods: A 36-year-old female patient had refractory spondylarthrosis. In 2010, she had presented oral aphthous ulcers during treatment with tocilizumab. In 2011, tocilizumab was stopped and the ulcers resolved. In 2016, secukinumab was introduced and led to recurrence of oral aphthous ulcers followed by ileitis-pancolitis. Corticosteroids and ustekinumab resulted in partial remission., Discussion: The patient developed inflammatory bowel disease during treatment with secukinumab, preceded by recurrent oral aphthous ulcers. She had presented similar oral ulcers 6 years earlier while on a treatment targeting IL6R. IL6 is a pleiotropic cytokine that may activate the Th17 pathway. Thus, tocilizumab could have induced an "anti-IL17-like" effect, accounting for the occurrence of oral aphthous ulcers, possibly related to mild inflammatory bowel disease., Conclusion: The occurrence of oral ulcers during treatment with secukinumab may herald inflammatory bowel disease. In patients with a previous history of recurrent aphthous stomatitis, especially where induced by previous biologics, consideration must be given to the risk-benefit ratio of prescribing an anti-IL17 antibody., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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17. Hepatic portal venous gas due to polystyrene sulfonate-induced enteritis.
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Kubo T, Yamashita K, Yokoyama Y, Hirayama D, Shirata T, Mitsuhashi K, Onodera K, Yamamoto E, Nosho K, Yamano H, Kubo T, Sugita S, Hasegawa T, and Nakase H
- Subjects
- Aged, Biopsy, Colitis complications, Colitis diagnostic imaging, Colitis pathology, Colonoscopy, Humans, Hyperkalemia drug therapy, Ileitis complications, Ileitis diagnostic imaging, Ileitis pathology, Male, Tomography, X-Ray Computed, Chelating Agents adverse effects, Colitis chemically induced, Gases, Ileitis chemically induced, Polystyrenes adverse effects, Portal Vein diagnostic imaging
- Abstract
A 78-year-old man with acute right lower abdominal pain and nausea was referred to our hospital. Computed tomography (CT) demonstrated hepatic portal venous gas and a thickened wall of the terminal ileum, and colonoscopy demonstrated ulcers and erosions of the ileocecal region. Histological examination of biopsy samples revealed basophilic crystals consistent with the component of calcium polystyrene sulfonate (CPS). This patient started taking CPS 2 months prior for chronic hyperkalemia. The symptoms resolved soon after ceasing CPS, and subsequent imaging studies confirmed the disappearance of the portal venous gas and ileocolitis.
- Published
- 2018
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18. Severe inflammatory ileitis resulting in ileal perforation in association with combination immune checkpoint blockade for metastatic malignant melanoma.
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Suwaidan AA, Richards CJ, Boyle K, and Faust G
- Subjects
- Antineoplastic Agents adverse effects, Female, Humans, Ileitis complications, Intestinal Perforation therapy, Middle Aged, Treatment Outcome, Drug Therapy, Combination adverse effects, Ileitis chemically induced, Intestinal Perforation chemically induced, Ipilimumab adverse effects, Melanoma drug therapy, Vulvar Neoplasms drug therapy
- Abstract
Immune checkpoint inhibitors have become standard of care in metastatic malignant melanoma management. Despite superior effectiveness to chemotherapy, significant immune-related adverse events (irAE) may occur, particularly if used in combination. Gastrointestinal irAEs were reported with different patterns of involvement. Here, we report the case of a patient who had ileal perforation as a complication of terminal ileitis, without colitis, induced by combination immune checkpoint blockade., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2018
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19. Acute small intestinal inflammation results in persistent lymphatic alterations.
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Rehal S, Stephens M, Roizes S, Liao S, and von der Weid PY
- Subjects
- Animals, Antigens, CD metabolism, Cell Movement, Dendritic Cells metabolism, Dendritic Cells pathology, Dextran Sulfate, Disease Models, Animal, Ileitis chemically induced, Ileitis metabolism, Ileum metabolism, Integrin alpha Chains metabolism, Intestinal Mucosa metabolism, Lymph Nodes metabolism, Lymphangiectasis, Intestinal chemically induced, Lymphangiectasis, Intestinal metabolism, Lymphatic Vessels metabolism, Male, Mice, Inbred C57BL, Time Factors, Ileitis pathology, Ileum pathology, Intestinal Mucosa pathology, Lymph Nodes pathology, Lymphangiectasis, Intestinal pathology, Lymphangiogenesis, Lymphatic Vessels pathology
- Abstract
Inflammatory bowel disease (IBD) has a complex pathophysiology with limited treatments. Structural and functional changes in the intestinal lymphatic system have been associated with the disease, with increased risk of IBD occurrence linked to a history of acute intestinal injury. To examine the potential role of the lymphatic system in inflammation recurrence, we evaluated morphological and functional changes in mouse mucosal and mesenteric lymphatic vessels, and within the mesenteric lymph nodes during acute ileitis caused by a 7-day treatment with dextran sodium sulfate (DSS). We monitored whether the changes persisted during a 14-day recovery period and determined their potential consequences on dendritic cell (DC) trafficking between the mucosa and lymphoid tissues. DSS administration was associated with marked lymphatic abnormalities and dysfunctions exemplified by lymphangiectasia and lymphangiogenesis in the ileal mucosa and mesentery, increased mesenteric lymphatic vessel leakage, and lymphadenopathy. Lymphangiogenesis and lymphadenopathy were still evident after recovery from intestinal inflammation and correlated with higher numbers of DCs in mucosal and lymphatic tissues. Specifically, a deficit in CD103
+ DCs observed during acute DSS in the lamina propria was reversed and further enhanced during recovery. We concluded that an acute intestinal insult caused alterations of the mesenteric lymphatic system, including lymphangiogenesis, which persisted after resolution of inflammation. These morphological and functional changes could compromise DC function and movement, increasing susceptibility to further gastrointestinal disease. Elucidation of the changes in mesenteric and intestinal lymphatic function should offer key insights for new therapeutic strategies in gastrointestinal disorders such as IBD. NEW & NOTEWORTHY Lymphatic integrity plays a critical role in small intestinal homeostasis. Acute intestinal insult in a mouse model of acute ileitis causes morphological and functional changes in mesenteric and intestinal lymphatic vessels. While some of the changes significantly regressed during inflammation resolution, others persisted, including lymphangiogenesis and altered dendritic cell function and movement, potentially increasing susceptibility to the recurrence of gastrointestinal inflammation.- Published
- 2018
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20. Dietary Fiber Pectin Directly Blocks Toll-Like Receptor 2-1 and Prevents Doxorubicin-Induced Ileitis.
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Sahasrabudhe NM, Beukema M, Tian L, Troost B, Scholte J, Bruininx E, Bruggeman G, van den Berg M, Scheurink A, Schols HA, Faas MM, and de Vos P
- Subjects
- Animals, Diet, Western, Disease Models, Animal, Doxorubicin, Esterification, Fatty Acids, Volatile, Female, HEK293 Cells, Hexuronic Acids chemistry, Humans, Ileitis chemically induced, Mice, Mice, Inbred C57BL, Pectins chemistry, Signal Transduction drug effects, Toll-Like Receptor 1 genetics, Toll-Like Receptor 2 genetics, Dietary Fiber therapeutic use, Ileitis therapy, Pectins therapeutic use, Toll-Like Receptor 1 metabolism, Toll-Like Receptor 2 metabolism
- Abstract
Dietary carbohydrate fibers are known to prevent immunological diseases common in Western countries such as allergy and asthma but the underlying mechanisms are largely unknown. Until now beneficial effects of dietary fibers are mainly attributed to fermentation products of the fibers such as anti-inflammatory short-chain fatty acids (SCFAs). Here, we found and present a new mechanism by which dietary fibers can be anti-inflammatory: a commonly consumed fiber, pectin, blocks innate immune receptors. We show that pectin binds and inhibits, toll-like receptor 2 (TLR2) and specifically inhibits the proinflammatory TLR2-TLR1 pathway while the tolerogenic TLR2-TLR6 pathway remains unaltered. This effect is most pronounced with pectins having a low degree of methyl esterification (DM). Low-DM pectin interacts with TLR2 through electrostatic forces between non-esterified galacturonic acids on the pectin and positive charges on the TLR2 ectodomain, as confirmed by testing pectin binding on mutated TLR2. The anti-inflammatory effect of low-DM pectins was first studied in human dendritic cells and mouse macrophages in vitro and was subsequently tested in vivo in TLR2-dependent ileitis in a mouse model. In these mice, ileitis was prevented by pectin administration. Protective effects were shown to be TLR2-TLR1 dependent and independent of the SCFAs produced by the gut microbiota. These data suggest that low-DM pectins as a source of dietary fiber can reduce inflammation through direct interaction with TLR2-TLR1 receptors.
- Published
- 2018
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21. Donkey milk consumption exerts anti-inflammatory properties by normalizing antimicrobial peptides levels in Paneth's cells in a model of ileitis in mice.
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Yvon S, Olier M, Leveque M, Jard G, Tormo H, Haimoud-Lekhal DA, Peter M, and Eutamène H
- Subjects
- Animals, Feces enzymology, Feces microbiology, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome physiology, Ileitis chemically induced, Ileitis pathology, Indole Alkaloids pharmacology, Male, Mice, Mice, Inbred C57BL, Muramidase analysis, Muramidase metabolism, Paneth Cells chemistry, RNA, Messenger analysis, alpha-Defensins genetics, Anti-Infective Agents analysis, Anti-Inflammatory Agents administration & dosage, Equidae, Ileitis metabolism, Milk chemistry, Peptides analysis
- Abstract
Purpose: In this study, we showed the beneficial effects of donkey milk (DM) on inflammatory damages, endogenous antimicrobial peptides levels and fecal microbiota profile in a mice model of Crohn's disease. Nowadays, new strategies of microbiome manipulations are on the light involving specific diets to induce and/or to maintain clinical remission. Interest of DM is explained by its high levels of antimicrobial peptides which confer it anti-inflammatory properties., Methods: C57BL/6 mice were orally administered with or without indomethacin for 5 days and co-treated with vehicle, DM or heated DM during 7 days. Intestinal length and macroscopic damage scores (MDSs) were determined; ileal samples were taken off for microscopic damage (MD), lysozyme immunostaining and mRNA α-defensin assessments. Ileal luminal content and fecal pellets were collected for lysozyme enzymatic activity and lipocalin-2 (LCN-2) evaluations. Fecal microbiota profiles were compared using a real-time quantitative PCR-based analysis., Results: Administration of indomethacin caused an ileitis in mice characterized by (1) a decrease in body weight and intestinal length, (2) a significant increase in MDS, MD and LCN-2, (3) a reduction in both α-defensin mRNA expression and lysozyme levels in Paneth's cells reflected by a decrease in lysozyme activity in feces, and (4) a global change in relative abundance of targeted microbial communities. DM treatment significantly reduced almost of all these ileitis damages, whereas heated DM has no impact on ileitis., Conclusions: DM consumption exerts anti-inflammatory properties in mice by restoring the endogenous levels of antimicrobial peptides which contribute in turn to reduce microbiota imbalance.
- Published
- 2018
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22. Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice.
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Dunkin D, Berin MC, Mondoulet L, Tobar S, Yeretssian G, Tordesillas L, Iuga A, Larcher T, Gillespie V, Benhamou PH, Colombel JF, and Sampson HA
- Subjects
- Animals, Colitis chemically induced, Dextran Sulfate administration & dosage, Disease Models, Animal, Forkhead Transcription Factors genetics, Ileitis chemically induced, Inflammation immunology, Inflammation metabolism, Interleukin-10 metabolism, Intestinal Mucosa pathology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Ovalbumin administration & dosage, Colitis immunology, Ileitis immunology, Immune Tolerance, T-Lymphocytes, Regulatory immunology
- Abstract
Background: Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation., Methods: Epicutaneous tolerance was induced by topical application of ovalbumin (OVA) using a Viaskin patch for 48 hours. In some experiments, a single feed of ovalbumin was used to drive epicutaneous tolerance-induced regulatory T cells (Tregs) to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-β, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T-cell transfer colitis, dextran sodium sulfate (DSS) colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed., Results: Epicutaneous exposure to ovalbumin induced systemic immune tolerance by a TGF-β-dependent, but IL-10 and iFoxp3 Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the dextran sodium sulfate and SAMP-YITFc models and importantly could halt disease in mice already experiencing weight loss in the T-cell transfer model of colitis. This was accompanied by a significant accumulation of LAP and Foxp3 Tregs in the colon., Conclusions: This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.
- Published
- 2017
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23. Secretion of biologically active pancreatitis-associated protein I (PAP) by genetically modified dairy Lactococcus lactis NZ9000 in the prevention of intestinal mucositis.
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Carvalho RD, Breyner N, Menezes-Garcia Z, Rodrigues NM, Lemos L, Maioli TU, da Gloria Souza D, Carmona D, de Faria AM, Langella P, Chatel JM, Bermúdez-Humarán LG, Figueiredo HC, Azevedo V, and de Azevedo MS
- Subjects
- Animals, Antibiosis, Antigens, Neoplasm pharmacology, Biomarkers, Tumor pharmacology, Disease Models, Animal, Enterococcus faecalis physiology, Fluorouracil, Humans, Ileitis chemically induced, Ileitis drug therapy, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases prevention & control, Intestinal Mucosa metabolism, Intestine, Small immunology, Intestine, Small microbiology, Intestine, Small pathology, Lactococcus lactis metabolism, Listeria monocytogenes physiology, Mice, Mice, Inbred BALB C, Mucositis chemically induced, Mucositis drug therapy, Mucositis microbiology, Pancreatitis-Associated Proteins, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Ileitis prevention & control, Lactococcus lactis genetics, Lactococcus lactis physiology, Lectins, C-Type genetics, Lectins, C-Type metabolism, Mucositis prevention & control
- Abstract
Background: Mucositis is one of the most relevant gastrointestinal inflammatory conditions in humans, generated by the use of chemotherapy drugs, such as 5-fluoracil (5-FU). 5-FU-induced mucositis affects 80% of patients undergoing oncological treatment causing mucosal gut dysfunctions and great discomfort. As current therapy drugs presents limitations in alleviating mucositis symptoms, alternative strategies are being pursued. Recent studies have shown that the antimicrobial pancreatitis-associated protein (PAP) has a protective role in intestinal inflammatory processes. Indeed, it was demonstrated that a recombinant strain of Lactococcus lactis expressing human PAP (LL-PAP) could prevent and improve murine DNBS-induced colitis, an inflammatory bowel disease (IBD) that causes severe inflammation of the colon. Hence, in this study we sought to evaluate the protective effects of LL-PAP on 5-FU-induced experimental mucositis in BALB/c mice as a novel approach to treat the disease., Results: Our results show that non-recombinant L. lactis NZ9000 have antagonistic activity, in vitro, against the enteroinvasive gastrointestinal pathogen L. monocytogenes and confirmed PAP inhibitory effect against Opportunistic E. faecalis. Moreover, L. lactis was able to prevent histological damage, reduce neutrophil and eosinophil infiltration and secretory Immunoglobulin-A in mice injected with 5-FU. Recombinant lactococci carrying antimicrobial PAP did not improve those markers of inflammation, although its expression was associated with villous architecture preservation and increased secretory granules density inside Paneth cells in response to 5-FU inflammation., Conclusions: We have demonstrated for the first time that L. lactis NZ9000 by itself, is able to prevent 5-FU-induced intestinal inflammation in BALB/c mice. Moreover, PAP delivered by recombinant L. lactis strain showed additional protective effects in mice epithelium, revealing to be a promising strategy to treat intestinal mucositis.
- Published
- 2017
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24. Ipilimumab-induced hypophysitis and ileocolitis: Serial pituitary MRI findings.
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Singh D, Hsu CC, Kwan GN, and Bhuta S
- Subjects
- Colitis diagnostic imaging, Humans, Hypophysitis diagnostic imaging, Ileitis diagnostic imaging, Magnetic Resonance Imaging, Male, Middle Aged, Antineoplastic Agents, Immunological adverse effects, Colitis chemically induced, Hypophysitis chemically induced, Ileitis chemically induced, Ipilimumab adverse effects
- Published
- 2017
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25. A novel model for studying ileitis-induced visceral hypersensitivity in goats.
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Tahir AH, Wan J, Shah MK, Janyaro H, Li XJ, and Ding MX
- Subjects
- Animals, Cytokines analysis, Ethanol, Female, Goats, Hypersensitivity etiology, Ileitis chemically induced, Ileitis complications, Ileum metabolism, Ileum physiopathology, Inflammatory Bowel Diseases physiopathology, Male, Peroxidase metabolism, Trinitrobenzenesulfonic Acid, Viscera pathology, Disease Models, Animal, Goat Diseases physiopathology, Hypersensitivity veterinary, Ileitis veterinary, Inflammatory Bowel Diseases veterinary
- Abstract
Background: Visceral hypersensitivity (VH) is a common condition in many gastrointestinal disorders such as inflammatory bowel diseases (IBDs) in human and animals. Most studies often induce Crohn's disease/colitis to investigate VH in small experimental animals. Although farm animals commonly suffer from IBDs, their VH has not been investigated so far. Because goats can suffer from Johne's disease, a naturally occurring Crohn's-like disease, they may be suitable to be used for studying the mechanism underlying VH in common intestinal disorders of large animals. In the present study, 60 healthy goats of either sex were equally divided into a 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) group and saline group. A volume of 1.2 ml of TNBS-ethanol solution (30 mg TNBS in 40 % ethanol) or an equal volume of isotonic saline was injected into the wall of the terminal ileum through laparotomy. The severity of the developing ileitis was determined according to macro- and microscopic pathologic scores and the levels of myeloperoxidase, interleukin-1β, interleukin-6 and tumor necrosis factor-α, and VH was evaluated with visceromotor responses (VMR) to colorectal distension on days 3, 7, 14, 21 and 28. VMRs were assessed with a continuous ramp distention mode with 6 s for each pressure (20, 40, 60, 80 and 100 mmHg)., Results: Compared to the saline group, the TNBS-treated goats showed apparent transmural pathological changes and a significant increase (P < 0.05) in macroscopic and microscopic change scores, and levels of myeloperoxidase, interleukin-1β, interleukin-6 and tumor necrosis factor-α in the ileum, and VMR to colorectal distension. The goats exhibited apparent ileitis at days 3 to 21, and VH at days 7 to 28 following TNBS treatment., Conclusion: This experiment successfully established a reproducible ileitis and VH with administration of TNBS-ethanol solution in the ileal wall of goats. This model is useful for studying the pathogenesis of the IBD and the mechanism underlying VH, and for evaluating the efficacy of new therapeutic regimens.
- Published
- 2016
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26. Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling.
- Author
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Narimatsu K, Higashiyama M, Kurihara C, Takajo T, Maruta K, Yasutake Y, Sato H, Okada Y, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, and Hokari R
- Subjects
- Animals, Cell Migration Assays, Leukocyte, Cell Movement, Cytokines metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Gene Expression drug effects, Ileitis chemically induced, Ileitis immunology, Inflammation Mediators metabolism, Injections, Intraperitoneal, Leukocytes immunology, Lipopolysaccharides administration & dosage, Lipopolysaccharides pharmacology, Mice, RAW 264.7 Cells, RNA, Messenger metabolism, Teichoic Acids administration & dosage, Teichoic Acids pharmacology, Toll-Like Receptor 4 genetics, Anti-Inflammatory Agents, Non-Steroidal toxicity, Ileitis drug therapy, Indomethacin toxicity, Lipopolysaccharides therapeutic use, Signal Transduction drug effects, Teichoic Acids therapeutic use, Toll-Like Receptor 2 agonists, Toll-Like Receptor 4 metabolism
- Abstract
Background and Aim: Few drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Toll-like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)-induced intestinal damage., Methods: LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence-labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P-selectin, MAdCAM-1, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide (LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-α, and interleukin-12p40 were measured., Results: Pretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80(+) macrophages, the level of P-selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner., Conclusion: TLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)
- Published
- 2015
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27. Evidence for a causal link between adaptor protein PDZK1 downregulation and Na⁺/H⁺ exchanger NHE3 dysfunction in human and murine colitis.
- Author
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Yeruva S, Chodisetti G, Luo M, Chen M, Cinar A, Ludolph L, Lünnemann M, Goldstein J, Singh AK, Riederer B, Bachmann O, Bleich A, Gereke M, Bruder D, Hagen S, He P, Yun C, and Seidler U
- Subjects
- Animals, Biopsy, Caco-2 Cells, Carrier Proteins genetics, Colitis chemically induced, Colitis genetics, Colitis pathology, Colon pathology, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dextran Sulfate, Disease Models, Animal, Down-Regulation, Enterocytes pathology, Humans, Ileitis chemically induced, Ileitis genetics, Ileitis pathology, Ileum pathology, Inflammation Mediators metabolism, Interleukin-10 genetics, Interleukin-10 metabolism, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins, Mice, 129 Strain, Mice, Knockout, Microvilli metabolism, RNA Interference, RNA, Messenger metabolism, Retrospective Studies, Sodium-Hydrogen Exchanger 3, Sodium-Hydrogen Exchangers genetics, Transfection, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Carrier Proteins metabolism, Colitis metabolism, Colon metabolism, Enterocytes metabolism, Ileitis metabolism, Ileum metabolism, Intracellular Signaling Peptides and Proteins metabolism, Sodium-Hydrogen Exchangers metabolism
- Abstract
A dysfunction of the Na(+)/H(+) exchanger isoform 3 (NHE3) significantly contributes to the reduced salt absorptive capacity of the inflamed intestine. We previously reported a strong decrease in the NHERF family member PDZK1 (NHERF3), which binds to NHE3 and regulates its function in a mouse model of colitis. The present study investigates whether a causal relationship exists between the decreased PDZK1 expression and the NHE3 dysfunction in human and murine intestinal inflammation. Biopsies from the colon of patients with ulcerative colitis, murine inflamed ileal and colonic mucosa, NHE3-transfected Caco-2BBe colonic cells with short hairpin RNA (shRNA) knockdown of PDZK1, and Pdzk1-gene-deleted mice were studied. PDZK1 mRNA and protein expression was strongly decreased in inflamed human and murine intestinal tissue as compared to inactive disease or control tissue, whereas that of NHE3 or NHERF1 was not. Inflamed human and murine intestinal tissues displayed correct brush border localization of NHE3 but reduced acid-activated NHE3 transport activity. A similar NHE3 transport defect was observed when PDZK1 protein content was decreased by shRNA knockdown in Caco-2BBe cells or when enterocyte PDZK1 protein content was decreased to similar levels as found in inflamed mucosa by heterozygote breeding of Pdzk1-gene-deleted and WT mice. We conclude that a decrease in PDZK1 expression, whether induced by inflammation, shRNA-mediated knockdown, or heterozygous breeding, is associated with a decreased NHE3 transport rate in human and murine enterocytes. We therefore hypothesize that inflammation-induced loss of PDZK1 expression may contribute to the NHE3 dysfunction observed in the inflamed intestine.
- Published
- 2015
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28. Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus.
- Author
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Buchholz BM, Shapiro RA, Vodovotz Y, Billiar TR, Sodhi CP, Hackam DJ, and Bauer AJ
- Subjects
- Animals, Ileitis chemically induced, Immunologic Factors immunology, Lipopolysaccharides, Male, Mice, Mice, Inbred C57BL, Muscle Cells pathology, Chemokines immunology, Ileitis immunology, Ileitis pathology, Ileus immunology, Ileus pathology, Muscle Cells immunology, Toll-Like Receptor 4 immunology
- Abstract
Myocytes are nonhemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid-onset nonhemopoietic mechanism potently triggers early ileus in a Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)-dependent manner. Moreover, synergistically with hemopoietic cells, nonhemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. We therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. TLR4(+/+), TLR4(-/-), bmTLR4(+/+)/TLR4(-/-) chimera, SM22-Cre(-/-)TLR4(flox/flox), and selective myocyte TLR4-deficient (SM22-Cre(+/-)TLR4(flox/flox)) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal, skeletal, and vascular myocytes, of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to nonhemopoietic TLR4 deficiency, deletion of myocyte TLR4 signaling prevented neither endotoxin-induced suppression of spontaneous jejunal contractility in vitro nor early ileus in vivo at 6 h. Circulating plasma colony-stimulating factor 3 was greatly elevated during endotoxemia, independent of myocyte TLR4 signaling or time. TLR4 activation of myocytes contributed significantly to an early enteric IL-6 mRNA induction and systemic IL-6 release, as well as to a late increase in circulating chemokine (C-X-C motif) ligand 1 (CXCL1) and IL-17. Consequently, inhibition of myocyte TLR4 signaling allowed functional recovery of motility by preventing inflammation-driven late ileus at 24 h. Direct TLR4 activation of myocytes is not responsible for nonhemopoietic-mediated early ileus. However, myocytes are proinflammatory cells that potently drive enteric and systemic inflammation, subsequently fueling late mediator-triggered ileus. Specifically, the myocyte TLR4-dependent inflammatory signature of elevated plasma IL-6, CXCL1, and IL-17 is strongly associated with late rodent ileus., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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29. Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis.
- Author
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Venditti O, De Lisi D, Caricato M, Caputo D, Capolupo GT, Taffon C, Pagliara E, Battisi S, Frezza AM, Onetti Muda A, Tonini G, and Santini D
- Subjects
- Antibodies, Monoclonal therapeutic use, Female, Humans, Ipilimumab, Melanoma drug therapy, Melanoma pathology, Middle Aged, Neoplasm Metastasis, Precision Medicine, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Antibodies, Monoclonal adverse effects, Ileitis chemically induced, Ileitis pathology
- Abstract
Background: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 , a key negative regulator of T-cell activation approved by the Food and Drug Administration as of March 2011 for the treatment of metastatic melanoma. As a result of the up-regulation of the immune system, several immune-mediated adverse effects have been reported including colitis, dermatitis, hepatitis and rarely hypophysitis. The most frequent immune-mediated adverse effects described in literature include gastrointestinal toxicity such as diarrhea, colitis and case of colitis and ileitis., Case Presentation: In this paper we report an interesting case of immune-mediate ileitis without colitis in a 54 years old woman with metastatic melanoma treated with ipilimumab. We also discuss about case management and the possible pathological mechanisms considering also previous reports., Conclusions: The aim of this article is to support further investigations concerning epigenetic and genetic analysis in order to personalize biological therapy and to reduce immune related adverse events observed after ipilimumab administration.
- Published
- 2015
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30. Experimental ileitis alters prostaglandin biosynthesis in mesenteric lymphatic and blood vessels.
- Author
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Rehal S and von der Weid PY
- Subjects
- Animals, Guinea Pigs, Ileitis chemically induced, Ileitis pathology, Intestine, Small pathology, Lymphatic Vessels pathology, Rats, Splanchnic Circulation, Dinoprostone metabolism, Epoprostenol metabolism, Ileitis metabolism, Intestine, Small metabolism, Lymphatic Vessels metabolism, Mesentery metabolism, Mesentery pathology
- Abstract
Prostaglandins are important mediators responsible for many changes that occur during the inflammatory response. Specifically, in inflammatory bowel disease (IBD), prostaglandins are key players in maintenance of blood flow and mucosal defense. In blood vessels, prostaglandins modulate and inhibit transmigration. In lymphatic vessels, on the other hand, prostaglandin E2 (PGE2) and prostacyclin (PGI2) have been shown to potently inhibit lymphatic contractility. Inhibition of lymphatic contractility could impair proper tissue fluid drainage during inflammation, consequently leading to the submucosal oedema observed in IBD. Alterations in production of PGE2 and PGI2 during inflammation could have severe implications on lymphatic and vascular functions within the small intestine. Using the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis guinea pig and rat models, we assessed by quantitative PCR changes in mRNA transcript of enzymes and receptors involved in the production and actions of prostaglandins in mesenteric lymphatic and blood vessels as well as in the affected ileum. Furthermore, we also assessed lymphatic tissue levels of PGE2 and PGI2 during inflammation. We observed significant changes in lymphatic mRNA expression of COX-1, COX-2, MPGES-1, PGIS, EP4 and IP and increases in PGE2 and PGI2 in tissues of TNBS-treated animals. Changes in mRNA in blood vessels from TNBS-treated animals included differences in COX-1, COX-2, MPGES-1, PGIS, EP1, EP2 and IP expression. Prostaglandin metabolites are differentially regulated in both lymphatic and blood vessels during intestinal inflammation., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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31. Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation.
- Author
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Vandenbroucke RE, Vanlaere I, Van Hauwermeiren F, Van Wonterghem E, Wilson C, and Libert C
- Subjects
- Acute Disease, Animals, Disease Models, Animal, Endotoxemia, Enzyme Activation, Female, Gene Expression, Ileitis chemically induced, Ileitis genetics, Ileitis metabolism, Ileum metabolism, Ileum microbiology, Ileum pathology, Inflammation chemically induced, Inflammation genetics, Inflammation mortality, Lipopolysaccharides adverse effects, Lymph Nodes immunology, Lymph Nodes metabolism, Male, Matrix Metalloproteinase 7 deficiency, Matrix Metalloproteinase 7 genetics, Mesentery, Mice, Mice, Knockout, Paneth Cells metabolism, Permeability, Protein Precursors metabolism, Severity of Illness Index, Inflammation metabolism, Matrix Metalloproteinase 7 metabolism
- Abstract
Matrix metalloproteinase 7 (MMP7) is a member of the MMP family. In the small intestine, MMP7 is responsible for activating α-defensins, which are broad-spectrum anti-microbial peptides produced by the Paneth cells. We report that MMP7(-/-) mice are resistant to LPS-induced lethality and that this resistance is correlated with reduced levels of systemic cytokines. LPS induced the upregulation and activation of MMP7 in the small intestine, degranulation of the Paneth cells, and induction of intestinal permeability in MMP7(+/+) mice. In MMP7(-/-) mice, both LPS-induced intestinal permeability and consequent bacterial translocation to the mesenteric lymph nodes were reduced. Based on gene expression analysis and evaluation of intestinal damage, we attribute the protected state of MMP7(-/-) mice to reduced intestinal inflammation. Interestingly, we found that different α-defensins, namely Crp1 (DEFA1) and Crp4 (DEFA4), can stimulate IL-6 release in macrophages and ileum explants in a TLR4 independent way. We conclude that absence of MMP7 protects mice from LPS-induced intestinal permeability and lethality, and suggest that MMP7-activated α-defensins, in addition to their previously recognized bactericidal and anti-inflammatory roles, may exhibit pro-inflammatory activities in the intestine by activating macrophages and amplifying the local inflammatory response in the gut, leading to intestinal leakage and subsequent increase in systemic inflammation.
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- 2014
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32. Five cases of sprue-like enteropathy in patients treated by olmesartan.
- Author
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Théophile H, David XR, Miremont-Salamé G, and Haramburu F
- Subjects
- Aged, Aged, 80 and over, Atrophy chemically induced, Dehydration chemically induced, Diarrhea chemically induced, Endoscopy, Gastrointestinal, Female, Humans, Ileitis pathology, Male, Weight Loss, Angiotensin II Type 1 Receptor Blockers adverse effects, Colitis chemically induced, Duodenum pathology, Ileitis chemically induced, Imidazoles adverse effects, Tetrazoles adverse effects
- Abstract
We describe five cases of sprue-like enteropathy during treatment with olmesartan, an angiotensin II receptor antagonist indicated for the treatment of hypertension. Patients presented severe diarrhoea, significant weight loss or dehydration, with or without intestinal villous atrophy. Clinical signs ceased upon drug discontinuation in all cases; olmesartan was reintroduced in two cases and rechallenge was positive in both. These add to the previously reported cases that led to a label change for olmesartan in the United States. However, all cases were observed in a small gastroenterology unit, which suggests that this adverse effect may not be rare. A preliminary search for the other angiotensin II receptor antagonists in the French pharmacovigilance system found severe diarrhoea and colitis, but no case with villous atrophy. Therefore, in the presence of severe diarrhoea, olmesartan or other angiotensin II receptor antagonists should be discontinued, even if the treatment has been taken for several months or years., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
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33. Breast cancer, DPYD mutations and capecitabine-related ileitis: description of two cases and a review of the literature.
- Author
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Mokrim M, Aftimos PG, Errihani H, and Piccart-Gebhart M
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms genetics, Breast Neoplasms pathology, Capecitabine, Carcinoma, Ductal drug therapy, Carcinoma, Ductal genetics, Carcinoma, Ductal pathology, Colitis diagnosis, Contraindications, Deoxycytidine adverse effects, Diagnosis, Differential, Diarrhea chemically induced, Diarrhea diagnosis, Dihydropyrimidine Dehydrogenase Deficiency complications, Female, Fluorouracil adverse effects, Humans, Neoplasm Metastasis, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Antimetabolites, Antineoplastic adverse effects, Breast Neoplasms drug therapy, Deoxycytidine analogs & derivatives, Dihydrouracil Dehydrogenase (NADP) genetics, Fluorouracil analogs & derivatives, Ileitis chemically induced, Mutation
- Abstract
Despite many treatment advances, metastatic breast cancer remains an incurable disease and is the third leading cause of cancer-related deaths in Europe. Capecitabine has become a standard treatment option for metastatic breast cancer, as a single agent or in combination. Hand-foot syndrome and diarrhoea are the most frequently reported side effects, while capecitabine-related ileitis is very rare. Deficiency of dihydropyrimidine dehydrogenase activity leads to severe toxicities after administration of 5-fluorouracil or its prodrugs. We report two cases of patients with metastatic breast cancer who developed ileitis after treatment with capecitabine. One patient had a DPYD gene abnormality.
- Published
- 2014
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34. Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation.
- Author
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Wolfs TG, Kramer BW, Thuijls G, Kemp MW, Saito M, Willems MG, Senthamarai-Kannan P, Newnham JP, Jobe AH, and Kallapur SG
- Subjects
- Amniotic Fluid, Animals, Cell Differentiation, Cell Proliferation, Chorioamnionitis chemically induced, Cytokines genetics, Cytokines metabolism, Disease Models, Animal, Epithelial Cells cytology, Epithelial Cells drug effects, Female, Fetal Diseases chemically induced, Gastrointestinal Diseases embryology, Gastrointestinal Diseases pathology, Gene Expression Regulation, Developmental drug effects, Ileitis chemically induced, Ileitis embryology, Ileitis pathology, Ileum embryology, Ileum pathology, Inflammation chemically induced, Inflammation complications, Inflammation pathology, Intestinal Mucosa cytology, Lipopolysaccharides toxicity, Pneumonia chemically induced, Pneumonia pathology, Pregnancy, Random Allocation, Sheep, T-Lymphocytes, Regulatory, Toll-Like Receptors, Chorioamnionitis pathology, Fetal Diseases etiology, Gastrointestinal Diseases etiology, Pneumonia complications
- Abstract
Intra-amniotic exposure to proinflammatory agonists causes chorioamnionitis and fetal gut inflammation. Fetal gut inflammation is associated with mucosal injury and impaired gut development. We tested whether this detrimental inflammatory response of the fetal gut results from a direct local (gut derived) or an indirect inflammatory response mediated by the chorioamnion/skin or lung, since these organs are also in direct contact with the amniotic fluid. The gastrointestinal tract was isolated from the respiratory tract and the amnion/skin epithelia by fetal surgery in time-mated ewes. Lipopolysaccharide (LPS) or saline (controls) was selectively infused in the gastrointestinal tract, trachea, or amniotic compartment at 2 or 6 days before preterm delivery at 124 days gestation (term 150 days). Gastrointestinal and intratracheal LPS exposure caused distinct inflammatory responses in the fetal gut. Inflammatory responses could be distinguished by the influx of leukocytes (MPO(+), CD3(+), and FoxP3(+) cells), tumor necrosis factor-α, and interferon-γ expression and differential upregulation of mRNA levels for Toll-like receptor 1, 2, 4, and 6. Fetal gut inflammation after direct intestinal LPS exposure resulted in severe loss of the tight junctional protein zonula occludens protein 1 (ZO-1) and increased mitosis of intestinal epithelial cells. Inflammation of the fetal gut after selective LPS instillation in the lungs caused only mild disruption of ZO-1, loss in epithelial cell integrity, and impaired epithelial differentiation. LPS exposure of the amnion/skin epithelia did not result in gut inflammation or morphological, structural, and functional changes. Our results indicate that the detrimental consequences of chorioamnionitis on fetal gut development are the combined result of local gut and lung-mediated inflammatory responses.
- Published
- 2014
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35. Olmesartan-induced enteropathy resembling celiac disease.
- Author
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Khan AS, Peter S, and Wilcox CM
- Subjects
- Aged, Atrophy pathology, Capsule Endoscopy, Celiac Disease diagnosis, Diagnostic Errors, Duodenal Diseases pathology, Female, Humans, Ileitis pathology, Jejunal Diseases pathology, Antihypertensive Agents adverse effects, Duodenal Diseases chemically induced, Ileitis chemically induced, Imidazoles adverse effects, Intestinal Mucosa pathology, Jejunal Diseases chemically induced, Tetrazoles adverse effects
- Published
- 2014
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36. Feed-forward inhibition of CD73 and upregulation of adenosine deaminase contribute to the loss of adenosine neuromodulation in postinflammatory ileitis.
- Author
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Vieira C, Magalhães-Cardoso MT, Ferreirinha F, Silva I, Dias AS, Pelletier J, Sévigny J, and Correia-de-Sá P
- Subjects
- Animals, Female, Male, Rats, Trinitrobenzenesulfonic Acid toxicity, 5'-Nucleotidase metabolism, Adenosine metabolism, Adenosine Deaminase metabolism, Ileitis chemically induced, Ileitis metabolism
- Abstract
Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the "purinome" may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on A(2A) excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5'-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from released ATP, thus contributing to the prolonged inhibition of muscle-bound ecto-5'-nucleotidase/CD73 and to the delay of adenosine formation at the inflamed neuromuscular synapse. On the other hand, depression of endogenous adenosine accumulation may also occur due to enhancement of adenosine deaminase activity. Both membrane-bound and soluble forms of ecto-5'-nucleotidase/CD73 and adenosine deaminase were detected in the inflamed myenteric plexus. These findings provide novel therapeutic targets for inflammatory gut motility disorders.
- Published
- 2014
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37. Dysregulated NOD2 predisposes SAMP1/YitFc mice to chronic intestinal inflammation.
- Author
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Corridoni D, Kodani T, Rodriguez-Palacios A, Pizarro TT, Xin W, Nickerson KP, McDonald C, Ley KF, Abbott DW, and Cominelli F
- Subjects
- Animals, Crohn Disease genetics, Crohn Disease immunology, Crohn Disease pathology, Cytokines genetics, Cytokines immunology, Hematopoietic Stem Cells pathology, Ileitis chemically induced, Ileitis genetics, Ileitis pathology, Mice, Inbred AKR, Mice, Transgenic, Nod2 Signaling Adaptor Protein genetics, Genetic Predisposition to Disease, Hematopoietic Stem Cells immunology, Ileitis immunology, Immunity, Innate, Nod2 Signaling Adaptor Protein immunology
- Abstract
Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular receptor that plays an essential role in innate immunity as a sensor of a component of the bacterial cell wall, muramyl dipeptide (MDP). Crohn's disease (CD)-associated NOD2 variants lead to defective innate immune responses, including decreased NF-κB activation and cytokine production. We report herein that SAMP1/YitFc (SAMP) mice, which develop spontaneous CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and dysregulated NOD2 signaling compared with parental AKR control mice. We show that, unlike in other mouse strains, in vivo administration of MDP does not prevent dextran sodium sulfate-induced colitis in SAMP mice and that the abnormal NOD2 response is specific to the hematopoietic cellular component. Moreover, we demonstrate that MDP fails to enhance intracellular bacterial killing in SAMP mice. These findings shed important light on the initiating molecular events underlying CD-like ileitis.
- Published
- 2013
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38. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation.
- Author
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Liu B, Gulati AS, Cantillana V, Henry SC, Schmidt EA, Daniell X, Grossniklaus E, Schoenborn AA, Sartor RB, and Taylor GA
- Subjects
- Animals, Autophagy, Colitis metabolism, Dextran Sulfate toxicity, Female, GTP-Binding Proteins genetics, Gene Expression Regulation physiology, Ileitis chemically induced, Ileitis metabolism, Inflammation genetics, Inflammation metabolism, Male, Mice, Mice, Knockout, Mitophagy, Paneth Cells metabolism, Colitis chemically induced, GTP-Binding Proteins metabolism, Paneth Cells pathology
- Abstract
Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the immunity-related GTPase (IRG) M (IRGM). IRGs comprise a family of proteins known to confer resistance to intracellular infections through various mechanisms, including regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear. We investigated the involvement of Irgm1, an ortholog of IRGM, in the genesis of murine intestinal inflammation. After dextran sodium sulfate exposure, Irgm1-deficient [Irgm1 knockout (KO)] mice showed increased acute inflammation in the colon and ileum, with worsened clinical responses. Marked alterations of Paneth cell location and granule morphology were present in Irgm1 KO mice, even without dextran sodium sulfate exposure, and were associated with impaired mitophagy and autophagy in Irgm1 KO intestinal cells (including Paneth cells). This was manifested by frequent tubular and swollen mitochondria and increased LC3-positive autophagic structures. Interestingly, these LC3-positive structures often contained Paneth cell granules. These results suggest that Irgm1 modulates acute inflammatory responses in the mouse intestine, putatively through the regulation of gut autophagic processes, that may be pivotal for proper Paneth cell functioning.
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- 2013
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39. Alpha-1-antitrypsin therapy ameliorates acute colitis and chronic murine ileitis.
- Author
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Collins CB, Aherne CM, Ehrentraut SF, Gerich ME, McNamee EN, McManus MC, Lebsack MD, Jedlicka P, Azam T, de Zoeten EF, Dinarello CA, and Rivera-Nieves J
- Subjects
- Acute Disease, Animals, Cell Membrane Permeability, Chronic Disease, Colitis chemically induced, Colitis immunology, Cytokines metabolism, Flow Cytometry, Humans, Ileitis chemically induced, Ileitis immunology, Inflammation etiology, Inflammation prevention & control, Mice, Colitis prevention & control, Dextran Sulfate toxicity, Ileitis prevention & control, alpha 1-Antitrypsin therapeutic use
- Abstract
Background: Fecal alpha-1-antitrypsin (AAT) clearance has been a marker of clinical disease severity in inflammatory bowel diseases (IBDs) for many years. Although AAT deficiency is more often associated with lung and liver pathologies, AAT-deficient patients with concomitant IBD have been shown to develop more aggressive disease and rapid progression to surgery. Although recent studies have highlighted the pleiotropic anti-inflammatory functions of AAT, including reducing proinflammatory cytokine production and suppressing immune cell activation, its potential therapeutic role in IBD has not been described., Methods: The therapeutic potential of human AAT administration was assessed in murine models of IBD including new-onset and established chemically induced colitis and spontaneous chronic murine ileitis. Histological assessment of inflammation, cytokine secretion profiling, and flow cytometric evaluation of inflammatory infiltrate were performed in each model. The effect of AAT on intestinal barrier function was also examined both in vitro and in vivo., Results: AAT attenuated inflammation in small and large intestinal IBD models through reduced secretion of proinflammatory cytokines, inflammatory cell infiltration, and reduced tissue injury. AAT also increased intestinal restitution after chemically induced colitis. AAT significantly decreased intestinal permeability in vitro and in vivo as part of a protective mechanism for both acute and chronic models of IBD., Conclusions: Our findings describe a beneficial role for AAT in IBD models through suppression of cytokine production and enhanced intestinal barrier function. This raises the possibility that AAT supplementation, which has a long history of proven safety, may have a therapeutic effect in human IBD.
- Published
- 2013
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40. Development of a peptidoglycan-polysaccharide murine model of Crohn's disease: effect of genetic background.
- Author
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Reingold L, Rahal K, Schmiedlin-Ren P, Rittershaus AC, Bender D, Owens SR, Adler J, and Zimmermann EM
- Subjects
- Animals, Cecum metabolism, Cecum pathology, Colitis chemically induced, Colitis genetics, Crohn Disease chemically induced, Crohn Disease genetics, Fibrosis chemically induced, Fibrosis genetics, Humans, Ileitis chemically induced, Ileitis genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Nod2 Signaling Adaptor Protein physiology, Peyer's Patches metabolism, Peyer's Patches pathology, Rats, Receptor-Interacting Protein Serine-Threonine Kinase 2, Receptor-Interacting Protein Serine-Threonine Kinases physiology, Colitis pathology, Crohn Disease pathology, Disease Models, Animal, Fibrosis pathology, Ileitis pathology, Peptidoglycan toxicity
- Abstract
The peptidoglycan-polysaccharide (PGPS) model using inbred rats closely mimics Crohn's disease. Our aim was to identify mouse strains that develop ileocolitis in response to bowel wall injection with PGPS. Mouse strains studied included NOD2 knockout animals, RICK/RIP2 knockout animals, and genetically inbred strains that are susceptible to inflammation. Mice underwent laparotomy with intramural injection of PGPS or human serum albumin in the terminal ileum, ileal Peyer's patches, and cecum. Gross abdominal score, cecal histologic score, and levels of pro-fibrotic factor mRNAs were determined 20 to 32 days after laparotomy. PGPS-injected wild-type and knockout mice with mutations in the NOD2 pathway had higher abdominal scores than human serum albumin-injected mice. The RICK knockout animals tended to have higher mean abdominal scores than the NOD2 knockout animals, but the differences were not significant. CBA/J mice were shown to have the most robust response to PGPS, demonstrating consistently higher abdominal scores than other strains. Animals killed on day 26 had an average gross abdominal score of 6.1 ± 1.5, compared with those on day 20 (3.0 ± 0.0) or day 32 (2.8 ± 0.9). PGPS-injected CBA/J mice studied 26 days after laparotomy developed the most robust inflammation and most closely mimicked the PGPS rat model and human Crohn's disease.
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- 2013
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41. Anti-IL-6 antibody treatment but not IL-6 knockout improves intestinal barrier function and reduces inflammation after binge ethanol exposure and burn injury.
- Author
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Zahs A, Bird MD, Ramirez L, Choudhry MA, and Kovacs EJ
- Subjects
- Animals, Bacterial Translocation drug effects, Bacterial Translocation immunology, Binge Drinking immunology, Cytokines metabolism, Ileitis chemically induced, Ileitis physiopathology, Interleukin-6 antagonists & inhibitors, Interleukin-6 deficiency, Mice, Mice, Inbred C57BL, Mice, Knockout, Myosin Light Chains metabolism, Occludin metabolism, Zonula Occludens-1 Protein metabolism, Antibodies pharmacology, Burns physiopathology, Ethanol toxicity, Ileitis prevention & control, Interleukin-6 immunology, Solvents toxicity
- Abstract
Interleukin 6 (IL-6) is an inflammatory cytokine known to be elevated in chronic diseases and after insults such as trauma and infection. Although necessary for the development of B cells and Th17 cells, IL-6, at elevated levels, can also cause tissue damage and lead to a rise in inflammation. Previous work in our laboratory has shown that IL-6 is increased both systemically and in multiple organ systems including the ileum after ethanol exposure and burn injury. As this combined insult causes elevated intestinal morphological damage, tight junction protein localization alterations, and phosphorylated myosin light chain levels, we sought to determine the role of IL-6 in these intestinal responses using a model of binge ethanol exposure and burn injury. Interleukin 6 antibody treatment after the combined insult reduced morphological changes in the ileum, bacterial translocation, and phosphorylated myosin light chain levels relative to either injury alone. Zonula occludens protein 1 and occludin localization was also reestablished in wild-type mice given IL-6 antibody after ethanol and burn. Interleukin 6-knockout mice given ethanol and burn injury also had reduced intestinal damage; however, no changes in bacterial translocation or tight junction protein localization were observed as compared with similarly treated wild-type mice. These data suggest that IL-6 may have a role in intestinal tissue damage observed after the combined insult of binge ethanol exposure and burn injury, although complete loss of IL-6 does not seem to be beneficial in this model. Modulation of IL-6 may present a new option for preventing intestinal damage and associated inflammation after a combined insult of ethanol exposure and burn injury.
- Published
- 2013
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42. Involvement of the NO-cGMP-K(ATP) channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis.
- Author
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Mathias R and von der Weid PY
- Subjects
- ATP-Binding Cassette Transporters metabolism, Animals, Enzyme Inhibitors pharmacology, Glyburide pharmacology, Guanylate Cyclase antagonists & inhibitors, Guinea Pigs, Hypoglycemic Agents pharmacology, Inflammation Mediators metabolism, Nitric Oxide Synthase antagonists & inhibitors, Oxadiazoles pharmacology, Potassium Channels, Inwardly Rectifying metabolism, Quinoxalines pharmacology, Receptors, Drug metabolism, Sulfonylurea Receptors, Trinitrobenzenesulfonic Acid pharmacology, Up-Regulation physiology, Disease Models, Animal, Ileitis chemically induced, Ileitis metabolism, Ileitis physiopathology, KATP Channels metabolism, Lymphatic Vessels metabolism, Lymphatic Vessels physiopathology, Muscle Contraction drug effects, Muscle Contraction physiology, Nitric Oxide metabolism
- Abstract
Mesenteric lymphatic vessels actively transport lymph, immune cells, fat, and other macromolecules from the intestine via a rhythmical contraction-relaxation process called lymphatic pumping. We have previously demonstrated that mesenteric lymphatic pumping was compromised in the guinea pig model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis, corroborating clinical and experimental observations of a dilated and/or obstructed phenotype of these vessels in inflammatory bowel disease. Many mediators released during the inflammatory process have been shown to alter lymphatic contractile activity. Among them, nitric oxide (NO), an inflammatory mediator abundantly released during intestinal inflammation, decreases the frequency of lymphatic contractions through activation of ATP-sensitive potassium (K(ATP)) channels. The objective of this study was to investigate the role of NO and K(ATP) channels in the lymphatic dysfunction observed in the guinea pig model of TNBS-induced ileitis. Using quantitative real-time PCR, we demonstrated that expression of Kir6.1, SUR2B, and inducible NO synthase (iNOS) mRNAs was significantly upregulated in TNBS-treated animals. Pharmacological studies performed on isolated, luminally perfused mesenteric lymphatic vessels showed that the K(ATP) channels blocker glibenclamide, the selective iNOS inhibitor 1400W, and the guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly improved lymphatic pumping in quiescent lymphatic vessels from TNBS-treated animals. Membrane potential measurement with intracellular microelectrodes revealed that vessels from TNBS-treated animals were hyperpolarized compared with their sham counterpart and that the hyperpolarization was significantly attenuated in the presence of glibenclamide and ODQ. Our findings suggest that NO and K(ATP) play a major role in the lymphatic contractile dysfunction that occurred as a consequence of the intestinal inflammation caused by TNBS.
- Published
- 2013
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43. Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis.
- Author
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Bhargava A, Clifton MS, Mhaske P, Liao M, Pothoulakis C, Leeman SE, and Grady EF
- Subjects
- Animals, Blotting, Western, Calcitonin Receptor-Like Protein administration & dosage, Calcitonin Receptor-Like Protein immunology, Goblet Cells drug effects, Male, Mast Cells drug effects, Microscopy, Fluorescence, Mitogen-Activated Protein Kinases metabolism, Mucins metabolism, NF-kappa B metabolism, Neutrophil Infiltration drug effects, Peroxidase metabolism, RNA Interference, RNA, Double-Stranded administration & dosage, RNA, Double-Stranded metabolism, Rats, Rats, Sprague-Dawley, Statistics, Nonparametric, Tumor Necrosis Factor-alpha metabolism, Bacterial Toxins toxicity, Calcitonin Receptor-Like Protein metabolism, Enterotoxins toxicity, Ileitis chemically induced, Ileitis drug therapy, RNA, Double-Stranded pharmacology, Signal Transduction drug effects
- Abstract
Enteritis caused by Clostridium difficile toxin (Tx) is a nosocomial disease of increasing clinical concern, but the local mediators of C. difficile TxA inflammation are unknown. The potent vasodilator calcitonin gene-related peptide mediates neurogenic inflammation via the calcitonin receptor-like receptor (CLR). Here we examined the ileum-specific effects of reducing CLR on TxA ileitis by local preinjection of double-stranded RNAs. Treatment with CLR dsRNA for 7 d decreased CLR immunoreactivity, whereas treatment with non-CLR dsRNA did not. Subsequent injection of TxA in the same location increased CLR in rats treated with non-CLR dsRNA but not in rats treated with CLR dsRNA, documenting that local injection of dsRNA is effective in preventing the increase in CLR immunoreactivity in response to local TxA. After non-CLR dsRNA pretreatment, TxA induced robust intestinal secretion, myeloperoxidase activity, and histopathologic indications of inflammation including epithelial damage, congestion, neutrophil infiltration, loss of mucin from goblet cells, and increase in mast cell numbers. After CLR dsRNA pretreatment, TxA-induced changes in intestinal secretion and histopathologic inflammation were improved, including normal mucin staining and fewer resident mast cells. Loss of CLR prevented TxA-mediated activation of NF-κB and concomitant increases in pERK1/2 and TNF-α mRNA. Locally produced CLR plays a proinflammatory role in TxA ileitis via MAPK signaling and TNF-α. The results reported here strongly suggest that a local injection of dsRNA targeting CLR could be an effective local therapeutic approach at the inflammation site in the treatment of a growing, clinically relevant hospital-acquired disease, C. difficile infection.
- Published
- 2013
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44. Collagenous colitis and ileitis under treatment with duloxetine.
- Author
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Sisman G, Sadri S, Batur S, and Dobrucali A
- Subjects
- Aged, Antidepressive Agents administration & dosage, Antidepressive Agents adverse effects, Biopsy, Chronic Disease, Colon pathology, Diarrhea etiology, Diarrhea physiopathology, Duloxetine Hydrochloride, Female, Humans, Ileum pathology, Recurrence, Treatment Outcome, Colitis, Collagenous chemically induced, Colitis, Collagenous complications, Colitis, Collagenous pathology, Colitis, Collagenous therapy, Colonoscopy methods, Depressive Disorder, Major drug therapy, Ileitis chemically induced, Ileitis complications, Ileitis pathology, Ileitis therapy, Thiophenes administration & dosage, Thiophenes adverse effects, Withholding Treatment
- Published
- 2012
45. Capecitabine-induced terminal ileitis.
- Author
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Al-Gahmi AM, Kerr IG, Zekri JM, and Zagnoon AA
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma secondary, Aged, Antimetabolites, Antineoplastic therapeutic use, Capecitabine, Colonoscopy, Crohn Disease diagnosis, Deoxycytidine adverse effects, Deoxycytidine therapeutic use, Diagnosis, Differential, Fluorouracil adverse effects, Fluorouracil therapeutic use, Humans, Ileitis diagnosis, Male, Prodrugs, Rectal Neoplasms drug therapy, Rectal Neoplasms secondary, Crohn Disease chemically induced, Deoxycytidine analogs & derivatives, Fluorouracil analogs & derivatives, Ileitis chemically induced
- Published
- 2012
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46. Whole-genome microarray analysis and functional characterization reveal distinct gene expression profiles and patterns in two mouse models of ileal inflammation.
- Author
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Avula LR, Knapen D, Buckinx R, Vergauwen L, Adriaensen D, Van Nassauw L, and Timmermans JP
- Subjects
- ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Animals, Cell Adhesion drug effects, Cell Adhesion genetics, Cell Adhesion immunology, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Female, Gene Expression, Gene Expression Profiling, Genome, Inflammation chemically induced, Inflammation parasitology, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Receptors, IgE metabolism, Schistosoma mansoni, Schistosomiasis mansoni genetics, Schistosomiasis mansoni immunology, Toll-Like Receptors genetics, Toll-Like Receptors metabolism, Trinitrobenzenesulfonic Acid, Ileitis chemically induced, Ileitis genetics, Ileitis immunology, Ileitis parasitology, Ilium drug effects, Ilium immunology, Ilium parasitology, Inflammation genetics, Transcriptome genetics
- Abstract
Background: Although a number of intestinal inflammatory conditions pertain to the ileum, whole-genome gene expression analyses in animal models of ileal inflammation are lacking to date. Therefore, we aimed to identify and characterize alterations in gene expression in the acutely inflamed ileum of two murine models of intestinal inflammation, namely intestinal schistosomiasis and TNBS-induced ileitis, compared to healthy controls. To this end, we used whole-genome microarrays, followed by bioinformatics analyses to detect over-represented Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology categories., Results: Following screening of almost all known mouse genes and transcripts represented on the array, intestinal schistosomiasis and TNBS-induced ileitis yielded 207 and 1417 differentially expressed genes, respectively, with only 30 overlapping concordantly changed genes. Functional category groups consisting of complement and coagulation cascades, extracellular matrix (ECM)-receptor interaction, Fc epsilon receptor I signaling pathways and protein activation cascade, cell adhesion categories were over-represented in the differential gene list of intestinal schistosomiasis. Antigen processing and presentation, cell adhesion molecules, ABC transporters, Toll-like receptor signaling pathways and response to chemical stimulus categories were over-represented in the differential gene list of TNBS-induced ileitis. Although cytokine-cytokine receptor interaction, intestinal immune network for IgA production, focal adhesion pathways and immune, inflammatory and defense response categories were over-represented in the differential gene lists of both inflammation models, the vast majority of the associated genes and changes were unique to each model., Conclusions: This study characterized two models of ileal inflammation at a whole-genome level and outlined distinct gene expression profiles and patterns in the two models. The results indicate that intestinal schistosomiasis involves Th2 responses, complement activation, protein activation and enhanced ECM turnover, while TNBS-induced ileitis involves Th17 responses, defective antigen processing and presentation and altered Toll-like receptor-mediated responses. Signs of an impaired epithelial barrier are apparent in both inflammation models. Furthermore, the comprehensive differential gene list and functional groups provided by this study constitute an interesting starting point to explore new targets and extended functional networks dealing with small bowel inflammation.
- Published
- 2012
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47. Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice.
- Author
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Brandl K, Tomisato W, Li X, Neppl C, Pirie E, Falk W, Xia Y, Moresco EM, Baccala R, Theofilopoulos AN, Schnabl B, and Beutler B
- Subjects
- Animals, Colitis chemically induced, Colitis genetics, Colitis pathology, Dextran Sulfate toxicity, Female, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Goblet Cells ultrastructure, Golgi Apparatus genetics, Golgi Apparatus metabolism, Golgi Apparatus ultrastructure, Humans, Ileitis chemically induced, Ileitis genetics, Ileitis metabolism, Ileitis pathology, Male, Membrane Proteins genetics, Mice, Mice, Transgenic, Paneth Cells ultrastructure, Colitis metabolism, Goblet Cells metabolism, Membrane Proteins metabolism, Mutation, Paneth Cells metabolism
- Abstract
Using an environmentally sensitized genetic screen we identified mutations that cause inflammatory colitis in mice. The X-linked Klein-Zschocher (KLZ) mutation created a null allele of Yipf6, a member of a gene family believed to regulate vesicular transport in yeast, but without known functions in mammals. Yipf6 is a five transmembrane-spanning protein associated with Golgi compartments. Klein-Zschocher mutants were extremely sensitive to colitis induced by dextran sodium sulfate (DSS) and developed spontaneous ileitis and colitis after 16 mo of age in specific pathogen-free housing conditions. Electron microscopy, gene expression, and immunocytochemistry analyses provided evidence that impaired intestinal homeostasis stemmed from defective formation and secretion of large secretory granules from Paneth and goblet cells. These studies support a tissue- and organ-specific function for Yipf6 in the maintenance of intestinal homeostasis and implicate the orthologous human gene as a disease susceptibility locus.
- Published
- 2012
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- View/download PDF
48. β-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice.
- Author
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Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS, Alexander K, Velasco J, Strutton G, Tran A, Benham H, Rehaume L, Wilson RJ, Kikly K, Davies J, Pettit AR, Brown MA, McGuckin MA, and Thomas R
- Subjects
- Animals, Arthritis, Experimental immunology, Autoantibodies immunology, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Autoimmunity immunology, Ileitis immunology, Ileitis pathology, Interleukin-17 immunology, Joints immunology, Joints pathology, Mice, Spondylarthritis immunology, Spondylarthritis pathology, T-Lymphocytes immunology, T-Lymphocytes pathology, Arthritis, Experimental pathology, Arthritis, Rheumatoid pathology, Ileitis chemically induced, Spondylarthritis chemically induced, beta-Glucans
- Abstract
Objective: The spondylarthritides (SpA), including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, and arthritis associated with inflammatory bowel disease, cause chronic inflammation of the large peripheral and axial joints, eyes, skin, ileum, and colon. Genetic studies reveal common candidate genes for AS, PsA, and Crohn's disease, including IL23R, IL12B, STAT3, and CARD9, all of which are associated with interleukin-23 (IL-23) signaling downstream of the dectin 1 β-glucan receptor. In autoimmune-prone SKG mice with mutated ZAP-70, which attenuates T cell receptor signaling and increases the autoreactivity of T cells in the peripheral repertoire, IL-17-dependent inflammatory arthritis developed after dectin 1-mediated fungal infection. This study was undertaken to determine whether SKG mice injected with 1,3-β-glucan (curdlan) develop evidence of SpA, and the relationship of innate and adaptive autoimmunity to this process., Methods: SKG mice and control BALB/c mice were injected once with curdlan or mannan. Arthritis was scored weekly, and organs were assessed for pathologic features. Anti-IL-23 monoclonal antibodies were injected into curdlan-treated SKG mice. CD4+ T cells were transferred from curdlan-treated mice to SCID mice, and sera were analyzed for autoantibodies., Results: After systemic injection of curdlan, SKG mice developed enthesitis, wrist, ankle, and sacroiliac joint arthritis, dactylitis, plantar fasciitis, vertebral inflammation, ileitis resembling Crohn's disease, and unilateral uveitis. Mannan triggered spondylitis and arthritis. Arthritis and spondylitis were T cell- and IL-23-dependent and were transferable to SCID recipients with CD4+ T cells. SpA was associated with collagen- and proteoglycan-specific autoantibodies., Conclusion: Our findings indicate that the SKG ZAP-70W163C mutation predisposes BALB/c mice to SpA, resulting from innate and adaptive autoimmunity, after systemic β-glucan or mannan exposure., (Copyright © 2012 by the American College of Rheumatology.)
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- 2012
- Full Text
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49. Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.
- Author
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D'Mello S, Trauernicht A, Ryan A, Bonkowski E, Willson T, Trapnell BC, Frank SJ, Kugasathan S, and Denson LA
- Subjects
- Adolescent, Animals, Autoantibodies blood, Body Height, Body Weight, Carrier Proteins blood, Child, Child, Preschool, Female, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Humans, Ileitis chemically induced, Infant, Liver chemistry, Male, Mice, Mice, Knockout, Nod2 Signaling Adaptor Protein genetics, Receptors, Somatotropin analysis, Retrospective Studies, STAT5 Transcription Factor physiology, Crohn Disease physiopathology, Failure to Thrive physiopathology, Growth Hormone physiology, Ileitis physiopathology
- Abstract
Background: Growth failure remains a common complication of pediatric Crohn's disease (CD) and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥ 1.6 μg/mL) granulocyte macrophage colony stimulating factor autoantibodies (GM-CSF Ab) are more likely to experience complicated ileal disease requiring surgery. We hypothesized that concurrent GM-CSF Ab and CARD15 risk allele carriage (C15(+) GMAb(+) ) would be associated with growth failure in CD and growth hormone (GH) resistance in murine ileitis., Methods: We enrolled 229 pediatric CD patients at two sites and determined CARD15 genotype, serum GM-CSF Ab, and GH binding protein (GHBP), and height (HTz) and weight (WTz) z-scores at diagnosis. Ileitis was induced in card15-deficient mice by GM-CSF neutralization and nonsteroidal antiinflammatory drug (NSAID) exposure. Hepatic GH receptor (GHR) abundance and GH-dependent Stat5 activation were determined by western blot and Igf-I mRNA expression by real-time polymerase chain reaction (PCR)., Results: Mean (95% confidence interval [CI]) HTz at diagnosis was reduced to -0.48 (-4.2, 2.3) in C15(+) GMAb(+) patients, compared to -0.07 (-4.9, 3.4) in disease controls (P ≤ 0.05). Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15(+) GMAb(+) patients. Hepatic GHR abundance, GH induction of Stat5 tyrosine phosphorylation, and Igf-I mRNA expression were reduced in male card15-deficient mice with ileitis due to GM-CSF neutralization and NSAID exposure., Conclusions: Innate dysfunction due to concurrent genetic variation in CARD15 and neutralizing GM-CSF Ab is associated with linear growth failure in pediatric CD, and hepatic GH resistance in murine ileitis., (Copyright © 2011 Crohn's & Crohn's & Colitis Foundation of America, Inc.)
- Published
- 2012
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50. Inhibitory effects of bromelain, a cysteine protease derived from pineapple stem (Ananas comosus), on intestinal motility in mice.
- Author
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Borrelli F, Capasso R, Severino B, Fiorino F, Aviello G, De Rosa G, Mazzella M, Romano B, Capasso F, Fasolino I, and Izzo AA
- Subjects
- Acetylcholine pharmacology, Animals, Barium Compounds pharmacology, Bromelains metabolism, Caco-2 Cells, Chlorides pharmacology, Cholinergic Agonists pharmacology, Croton Oil pharmacology, Diabetes Mellitus, Experimental physiopathology, Electric Stimulation, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Ileitis chemically induced, Ileitis physiopathology, Male, Mice, Muscle Contraction drug effects, Peptides metabolism, Receptor, PAR-1 antagonists & inhibitors, Receptor, PAR-2 antagonists & inhibitors, Ananas enzymology, Bromelains pharmacology, Gastrointestinal Motility drug effects, Gastrointestinal Transit drug effects
- Abstract
Background: Bromelain (BR) is a cysteine protease with inhibitory effects on intestinal secretion and inflammation. However, its effects on intestinal motility are largely unexplored. Thus, we investigated the effect of this plant-derived compound on intestinal contractility and transit in mice., Methods: Contractility in vitro was evaluated by stimulating the mouse isolated ileum, in an organ bath, with acetylcholine, barium chloride, or electrical field stimulation. Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine. Transit was also evaluated in pathophysiologic states induced by the pro-inflammatory compound croton oil or by the diabetogenic agent streptozotocin., Key Results: Bromelain inhibited the contractions induced by different spasmogenic compounds in the mouse ileum with similar potency. The antispasmodic effect was reduced or counteracted by the proteolytic enzyme inhibitor, gabexate (15 × 10(-6) mol L(-1) ), protease-activated receptor-2 (PAR-2) antagonist, N(1) -3-methylbutyryl-N(4) -6-aminohexanoyl-piperazine (10(-4) mol L(-1) ), phospholipase C (PLC) inhibitor, neomycin (3 × 10(-3) mol L(-1) ), and phosphodiesterase 4 (PDE4) inhibitor, rolipram (10(-6) mol L(-1) ). In vivo, BR preferentially inhibited motility in pathophysiologic states in a PAR-2-antagonist-sensitive manner., Conclusions & Inferences: Our data suggest that BR inhibits intestinal motility - preferentially in pathophysiologic conditions - with a mechanism possibly involving membrane PAR-2 and PLC and PDE4 as intracellular signals. Bromelain could be a lead compound for the development of new drugs, able to normalize the intestinal motility in inflammation and diabetes., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
- Full Text
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