Background: A shift in composition of intestinal microbiota is regarded to be important for the symptoms and complications of short bowel syndrome (SBS). However, attempts to normalize the colonic microbiota in SBS have not been formally... more
Background: A shift in composition of intestinal microbiota is regarded to be important for the symptoms and complications of short bowel syndrome (SBS). However, attempts to normalize the colonic microbiota in SBS have not been formally studied. We investigated whether two weeks' treatment with Saccharomyces boulardii influences colonic microbiota and has an impact on the lactate levels in SBS patients. Methods: Symptoms and colonic microbiota were investigated in 14 SBS adult patients on long-term parenteral nutrition who were treated with Saccharomyces boulardii (Sb). A 250 mg capsule Sb was given twice daily for two weeks. Microbiota were investigated using structure functional fluorescence in situ hybridization (FISH) analysis of Carnoy fixated stool cylinders. Altogether 82 FISH probes representing different groups of microbiota were used. Stool samples were collected at days 0, 7, 14, as related to the start of Sb therapy. 10 healthy untreated persons were used as controls. Results: The patients had an apparently SBS-specific increase in the prevalence of Lactobacilli. Bacteroides (Bac303), Roseburia (EREC) groups increased, and Bifidobacteriaceae (Bac 164) and Enterobacteriaceae (Ebac) groups decreased significantly with Sb therapy in SBS. These changes all represented an alteration towards the distribution seen in the normal controls. The changes in all other microbial groups were not consistent, and the median values did not change significantly. The SBS-specific increase in Lactobacilli demonstrated a tendency to decrease, which was however statistically non-significant. However, probiotic treatment decreased levels of lactic acid from 30, 72 mg/dL to 18, 64 mg/dL, so to the reference value. Conclusions: The composition of colonic microbiota in patients with SBS on long term parenteral nutrition differs significantly from that in healthy persons. Saccharomyces boulardii treatment made the microbiota more similar to healthy controls. Especially strong effects are observed with regard to Bacteroides, Roseburia, Bifidobacteriaceae and Enterobacteriaceae groups. None of these bacterial groups showed complete normalization when compared to healthy controls however. The concentration of plasma lactate fell to reference values after Sb treatment. It is possible that the two-week treatment was insufficient to unravel specific shifts in other bacterial groups or to normalize the main fermentative groups. Longer-term therapeutic studies are necessary for what appears a promising strategy.
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... Sammy Bedoui a , E-mail The Corresponding Author and Thomas Gebhardt a , E-mail The Corresponding Author. ... Furthermore, Murphy and colleagues recently reported that mice lacking the transcription factor batf3 are not only defective... more
... Sammy Bedoui a , E-mail The Corresponding Author and Thomas Gebhardt a , E-mail The Corresponding Author. ... Furthermore, Murphy and colleagues recently reported that mice lacking the transcription factor batf3 are not only defective in cross-presenting model antigen, but ...
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Loss of parietal cells initiates the development of spasmolytic polypeptide-expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) which enhances the ability to defend against reactive oxygen species (ROS) in... more
Loss of parietal cells initiates the development of spasmolytic polypeptide-expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) which enhances the ability to defend against reactive oxygen species (ROS) in epithelial cells is expressed de novo in SPEM of K19-Wnt1/C2mE mice, a transgenic model of gastric tumorigenesis, and is required for the efficient development of SPEM and gastric tumor in these animals. The role of ROS and its downstream signaling in CD44-dependent gastric tumorigenesis has remained unknown, however. With the use of the K19-Wnt1/C2mE mouse we now show that parietal cells in the inflamed stomach are highly sensitive to oxidative stress and manifest activation of p38MAPK signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38MAPK signaling, inhibited parietal cell loss and the subsequent gastric tumorigenesis. Our results indicate that signa...
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The clinical significance of cytomegalovirus (CMV) reactivation complicating ulcerative colitis (UC) patients has been uncertain. It has therefore remained undetermined whether or not CMV reactivation should be treated in UC patients... more
The clinical significance of cytomegalovirus (CMV) reactivation complicating ulcerative colitis (UC) patients has been uncertain. It has therefore remained undetermined whether or not CMV reactivation should be treated in UC patients under immunosuppression. The aim of the study was to clarify the natural history of CMV reactivation in UC patients. Sixty-nine UC patients with moderate to severe activity were enrolled in the study. All of the patients were treated with prednisolone, and/or immunosuppressants such as cyclosporine A. We sequentially monitored CMV reactivation every 2 wk up until 8 wk using the CMV antigenemia (Ag) assay and plasma quantitative real-time polymerase chain reaction (PCR) assay for CMV. Immunoglobulin (Ig) G for CMV was positive in 48 patients (69.6%) and negative in 21 patients (30.4%). CMV was reactivated in 25 patients out of the 48 seropositive patients (52.1%) during the study period. The CMV Ag and PCR values were low and none of the patients showed ...
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Natural History, Adolescent, Biopsy, Humans, Female, and 15 moreMale, Cytomegalovirus, Cyclosporine, Clinical Sciences, Aged, Middle Aged, Adult, Cytomegalovirus Infections, Colon, Immunoglobulin, immunoglobulin G, Immunosuppressive Agents, antiviral agent, Antiviral Therapy, and hematoxylin and eosin
Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors... more
Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined Apc(Δ716) Tgfbr2(ΔIEC) compound mutant mice that carry mutations in Apc and Tgfbr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple Tgfbr2(ΔIEC) mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these Tgfbr2(ΔIEC) mice developed invasive colon cancer associated with chronic inflammation. We also found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causing MMP2 activation. These results suggest that ...
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Intestinal crypt fission is a homeostatic phenomenon, observable in healthy adult mucosa, but which also plays a pathological role as the main mode of growth of some intestinal polyps. Building on our previous individual based model for... more
Intestinal crypt fission is a homeostatic phenomenon, observable in healthy adult mucosa, but which also plays a pathological role as the main mode of growth of some intestinal polyps. Building on our previous individual based model for the small intestinal crypt and on in vitro cultured intestinal organoids, we here model crypt fission as a budding process based on fluid mechanics at the individual cell level and extrapolated predictions for growth of the intestinal epithelium. Budding was always observed in regions of organoids with abundant Paneth cells. Our data support a model in which buds are biomechanically initiated by single stem cells surrounded by Paneth cells which exhibit greater resistance to viscoelastic deformation, a hypothesis supported by atomic force measurements of single cells. Time intervals between consecutive budding events, as simulated by the model and observed in vitro, were 2.84 and 2.62 days, respectively. Predicted cell dynamics was unaffected within ...
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ABSTRACT The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and... more
ABSTRACT The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-gamma (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16(+) monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocyte antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-gamma and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.
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Interleukin (IL)-12 and IL-18 are major interferon (IFN)-gamma-inducing factors that collaborate with each other. The present study was conducted to determine the distinct roles of IL-12 and IL-18 in the development of dextran sulphate... more
Interleukin (IL)-12 and IL-18 are major interferon (IFN)-gamma-inducing factors that collaborate with each other. The present study was conducted to determine the distinct roles of IL-12 and IL-18 in the development of dextran sulphate sodium (DSS) colitis in mice. Colitis was induced in IL-12p35(-/-), IL-18(-/-), IL-18 receptor(-/-) and control mice with DSS. Clinical and histopathological analysis was conducted using survival rate, weight loss score, diarrhoea score, bloody stool score and histological score. In addition, cytokine production by lamina propria mononuclear cells (LPMCs) was examined using the specific enzyme-linked immunoassay. IL-12p35(-/-) mice developed only a mild disease associated with no lethality and few histopathological abnormalities. In contrast, IL-18(-/-) and IL-18R(-/-) mice developed more severe colitis associated with high lethality and more histopathological abnormalities compared with control mice. LPMCs from DSS-fed IL-18(-/-) mice produced significantly higher amounts of IFN-gamma, while LPMCs from DSS-fed IL-12(-/-) mice produced lower amounts of IFN-gamma and tumour necrosis factor (TNF)-alpha compared with control mice. These results suggest that IL-18 might function with manners different from IL-12 at some pathological conditions in the development of colitis.
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Gastroenterology, Treatment Outcome, Medicine, Adsorption, Prospective studies, and 15 moreHumans, Ulcerative colitis, INTENSIVE CARE, Female, Male, Follow-up studies, Colonoscopy, Clinical Sciences, Adult, Monocytes, Time Factors, Disease Activity, Pilot Projects, Adverse effect, and leukocyte Count
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Gastroenterology, Biology, Inflammation, Macrophages, Medicine, and 14 moreAntibodies, Humans, Intestinal Mucosa, Mice, Animals, Clinical Sciences, Colitis, Murine Model, Neurosciences, Crohn Disease, Neutralizing antibodies, Interleukin, Intestinal Inflammation, and Paediatrics and reproductive medicine
MACROPHAGE·DERIVED IL-18 MEDIATED COLITIS IN THE MURINE MODEL OF CROHN'S DISEASE. Takanori Kanai, Mamoru Watanabe, Akira Okazawa, Toshiro Sato, Hiromasa Ishii, Kiyoshi Takeda, Shizuo Akira, Masao Ikeda, Masashi Kurimoto, Toshifumi... more
MACROPHAGE·DERIVED IL-18 MEDIATED COLITIS IN THE MURINE MODEL OF CROHN'S DISEASE. Takanori Kanai, Mamoru Watanabe, Akira Okazawa, Toshiro Sato, Hiromasa Ishii, Kiyoshi Takeda, Shizuo Akira, Masao Ikeda, Masashi Kurimoto, Toshifumi Hibi, Keio Cancer Ctr, Tokyo, Japan; Sch of Med, Keio Univ, Tokyo, Japan; Institute of Microbiology, Osaka Univ, Osaka, Japan; Hayashibara Biochemical Lab Inc, Okayama, Japan.
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Immune response, Gastroenterology, Biology, Medicine, Dendritic Cells, and 13 moreHumans, Dendritic cell, Clinical Sciences, Lymph Node, Protein Binding, Neurosciences, Crohn Disease, Case Control Studies, Interleukin, Interferon gamma, Lymph nodes, Mesentery, and Paediatrics and reproductive medicine
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Immune response, Gastroenterology, Kinetics, Flow Cytometry, Cytokines, and 15 moreImmunohistochemistry, Medicine, Cell Division, Inflammatory Bowel Disease, Humans, Intestinal Mucosa, Clinical Sciences, Intestines, Monoclonal Antibody, Neurosciences, Inflammatory Bowel Diseases, Case Control Studies, Interleukin, Intestinal Inflammation, and Drug synergism
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Gastroenterology, Biology, Medicine, Humans, Ulcerative colitis, and 15 morePolymerase Chain Reaction, Clinical Sciences, Peripheral blood lymphocyte, B Lymphocytes, Base Sequence, Colon, Gene Family, Neurosciences, Enzyme Linked Immunosorbent Assay, Autoantibodies, Gene Expression Regulation, Case Control Studies, Molecular Sequence Data, Nucleotide sequence, and Paediatrics and reproductive medicine
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Gastroenterology, Biology, Adult Stem Cells, Medicine, Gene expression, and 15 moreT cell receptor, Hematopoietic Stem Cells, Cell Differentiation, Humans, Intestinal Mucosa, Clinical Sciences, Immunophenotyping, Lymph Node, DNA binding proteins, Neurosciences, Immunoglobulins, Crohn Disease, Hematopoietic Stem Cell, Interferon gamma, and Paediatrics and reproductive medicine
Vitamin K is essential for the posttranslational modifications of blood coagulation factors and proteins present in the bone matrix. Vitamin K is distributed not only in the liver and bones but is also abundant in the brain, kidney, and... more
Vitamin K is essential for the posttranslational modifications of blood coagulation factors and proteins present in the bone matrix. Vitamin K is distributed not only in the liver and bones but is also abundant in the brain, kidney, and gonadal tissues. However, the function of extra-hepatic/bone vitamin K has not been fully elucidated. Previously, we observed that dietary supplementation with vitamin K suppresses inflammation, and vitamin K deficiency decreases testicular testosterone production in rats. Here, we examined whether the dietary vitamin K state affects testicular steroidogenesis in lipopolysaccharide (LPS)-treated rats because vitamin K has anti-inflammatory activity. Male Wistar rats were fed either vitamin K-free or control diets for 35 d, and then intraperitoneally administered LPS (0.5 mg kg(-1) body weight) to induce inflammation for 6 h. Vitamin K deficiency symptoms were not observed in the vitamin K-free diet group; however, the vitamin K levels in the testis were significantly lower in the vitamin K-free diet group than in the control diet group. After LPS treatment, plasma testosterone levels were significantly reduced in the vitamin K-free diet group compared with the control diet group. Testicular mRNA and protein levels of Cyp11a, a rate-limiting enzyme in steroidogenesis, corresponded to plasma testosterone levels. However, plasma luteinizing hormone levels were unaffected by diet and LPS. Phosphorylated nuclear factor κB p65 in the testis was significantly increased in the LPS-treated, vitamin K-free diet group compared with control. These results indicate that dietary vitamin K affects testicular vitamin K levels and ameliorates the LPS-induced reduction in testicular testosterone synthesis. Testicular vitamin K might facilitate the inhibition of inflammation signal transduction and maintain steady levels of testosterone.