Tatsuro Katsuno

The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells

Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib−/−) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.

Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinsons disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinsons disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinsons disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinsons disease.

Caprylic acid and medium-chain triglycerides inhibit IL-8 gene transcription in Caco-2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A

Medium‐chain triglyceride (MCT) is often administered to patients with Crohns disease (CD) or short‐bowel syndrome. However, little is known about the effects of medium‐chain fatty acids (MCFAs) and MCT on intestinal inflammation. In this study we examined whether caprylic acid, one of the MCFAs, and MCT suppress IL‐8 secretion by differentiated Caco‐2 cells. We found for the first time that caprylic acid and MCT suppress IL‐8 secretion by Caco‐2 cells at the transcriptional level when precultured together for 24 h. We also tried to clarify the mechanism of IL‐8 gene inhibition by examining the activation of NF‐κB and other transcription factors by electrophoretic mobility shift assay (EMSA), and found that caprylic acid did not modulate their activation. The result of dual‐luciferase assay using Caco‐2 cells transfected with IL‐8 promoter/luciferase reporter plasmid revealed that caprylic acid inhibited the activation of IL‐8 promoter. Similar results were observed when cells were precultured with the well‐known potent histone deacetylase inhibitor trichostatin A (TSA). We examined the state of H4 acetylation in IL‐8 promoter using the technique known as chromatin immunoprecipitation (Chr‐IP). TSA rapidly induced H4 acetylation in IL‐8 promoter chromatin, whereas caprylic acid did not. These results suggest that the inhibition of IL‐8 gene transcription induced by caprylic acid and TSA does not necessarily require the marked suppression of transcription factors, and the mechanism of inhibition of IL‐8 gene transcription may be different between caprylic acid and TSA.

The Epithelia-Specific Membrane Trafficking Factor AP-1B Controls Gut Immune Homeostasis in Mice

BACKGROUND & AIMS Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis. METHODS The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice. RESULTS Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohns disease. CONCLUSIONS AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.

Clostridium butyricum TO-A Culture Supernatant Downregulates TLR4 in Human Colonic Epithelial Cells

The present study was performed to examine whether probiotics affect Toll-like receptor 4 (TLR4) expression in human colonic epithelial cells. Culture supernatants or heat-killed bacteria of Bacillus mesentericus TO-A, Clostridium butyricum TO-A, and Streptococcus faecalis T-110 were applied to human colonic epithelial cells. Treatment with C. butyricum TO-A culture supernatant significantly reduced TLR4 mRNA level (×0.16), even in the presence of interferon-γ (IFN-γ; ×0.21) as compared with untreated controls. High-performance liquid chromatography analysis showed that C. butyricum TO-A supernatant contains formate, acetate, and butyrate. Interestingly, TLR4 mRNA was significantly suppressed (×0.15–×0.22) only when cells were treated with solutions containing butyrate. Electrophoretic mobility shift assay suggested that the binding affinity of PU.1 to the promoter region of the TLR4 gene was markedly inhibited when the cells were treated with butyrate. This study suggested that butyrate produced by C. butyricum TO-A downregulates TLR4 mRNA level in human colonic epithelial cells.

Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal carcinoma.

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged.

Emergence of Fibrocytes Showing Morphological Changes in the Inflamed Colonic Mucosa

Fibrocytes contribute to wound healing and are uniquely defined by coexpression of hematopoietic and mesenchymal cell markers. In this study, trafficking of fibrocytes was determined in a murine model of colitis induced by administering 3% dextran sodium sulfate (DSS) for seven days. Colonic tissues were immunostained for CD45, collagen type I (Col I), and α-SMA. On day 0, there were no CD45+Col I+ cells in colonic tissues. However, on day 7 when inflammatory cells showed remarkable accumulation, oval-shaped CD45+Col I+ fibrocytes were obvious in the submucosal layer. On day 14 when colonic tissues were in the healing phase, numerous spindle-shaped CD45+Col I+ fibrocytes were observed. Emergence of CD45+Col I+ fibrocytes preceded the appearance of α-SMA+ myofibroblasts. Oval-shaped fibrocytes recruited as early as the inflammatory phase of colitis are likely to differentiate into spindle-shaped fibrocytes in the healing phase, suggesting that fibrocytes may promote wound healing in inflamed colonic tissues.

Vonoprazan is superior to proton pump inhibitors in healing artificial ulcers of the stomach post-endoscopic submucosal dissection: A propensity score-matching analysis.

Proton pump inhibitors (PPI) are effective at healing artificial ulcers after endoscopic submucosal dissection (ESD) for gastric neoplasms; however, the efficacy of vonoprazan is not completely understood. The aim of the present study was to determine the healing effect of vonoprazan on artificial ulcers post‐gastric ESD relative to PPI.

Efficacy of computed image modification of capsule endoscopy in patients with obscure gastrointestinal bleeding.

AIM To investigate whether flexible spectral color enhancement (FICE) improves diagnostic yields of capsule endoscopy (CE) for obscure gastro-intestinal bleeding (OGIB). METHODS The study subjects consisted of 81 patients. Using FICE, there were three different sets with different wavelengths. Using randomly selected sets of FICE, images of CE were evaluated again by two individuals who were not shown the conventional CE reports and findings. The difference between FICE and conventional imaging was examined. RESULTS The overall diagnostic yields in FICE sets 1, 2, 3 and conventional imaging (48.1%) were 51.9%, 40.7%, 51.9% and 48.1%, respectively, which showed no statistical difference compared to conventional imaging. The total numbers of detected lesions per examination in FICE imaging and conventional imaging were 2.5 ± 2.1 and 1.8 ± 1.7, respectively, which showed a significant difference (P = 0.01). CONCLUSION The diagnostic yield for OGIB is not improved by FICE. However, FICE can detect significantly more small bowel lesions compared to conventional imaging.

Predictive factors of response to intravenous ciclosporin in severe ulcerative colitis: the development of a novel prediction formula

When treating patients with severe ulcerative colitis (UC), accurate prediction of drug efficacy contributes to early clinical decision‐making.