Naoki Yorifuji

The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice

Luminal nutrients stimulate enteroendocrine L cells to release gut hormones, including intestinotrophic glucagon‐like peptide‐2 (GLP‐2). Because L cells express the bile acid receptor TGR5 and dipeptidyl peptidase‐IV (DPPIV) rapidly degrades GLPs, we hypothesized that luminal TGR5 activation may attenuate intestinal injury via GLP‐2 release, which is enhanced by DPPIV inhibition.

Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration

The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Treatment with an exogenous GLP-2 analogue increases intestinal villous mass and prevents intestinal injury. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP4), DPP4 inhibition may be an effective treatment for intestinal ulcers. We measured mRNA expression and DPP enzymatic activity in intestinal segments. Mucosal DPP activity and GLP concentrations were measured after administration of the DPP4 inhibitor sitagliptin (STG). Small intestinal ulcers were induced by indomethacin (IM) injection. STG was given before IM treatment, or orally administered after IM treatment with or without an elemental diet (ED). DPP4 mRNA expression and enzymatic activity were high in the jejunum and ileum. STG dose-dependently suppressed ileal mucosal enzyme activity. Treatment with STG prior to IM reduced small intestinal ulcer scores. Combined treatment with STG and ED accelerated intestinal ulcer healing, accompanied by increased mucosal GLP-2 concentrations. The reduction of ulcers by ED and STG was reversed by co-administration of the GLP-2 receptor antagonist. DPP4 inhibition combined with luminal nutrients, which up-regulate mucosal concentrations of GLP-2, may be an effective therapy for the treatment of small intestinal ulcers.

The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice

Patients with type 2 diabetes mellitus are known to have an increased risk of colorectal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used as a new therapeutic tool for type 2 diabetes. Since the substrates for DPP-4 include intestinotrophic hormones and chemokines such as GLP-2 and stromal cell-derived factor-1 (SDF-1), which are associated with tumor progression, DPP-4 inhibitors may increase the risk of colorectal tumors. However, the influence of DPP-4 inhibitors on colorectal neoplasia in patients with type 2 diabetes remains unknown. In the present study, we show that long-term administration of a DPP-4 inhibitor, sitagliptin (STG), suppressed colon carcinogenesis in leptin-deficient (ob/ob) C57BL/6J mice. Colonic mucosal concentrations of glucagon‑like peptide-1 (GLP-1) and GLP-2 were significantly elevated in the ob/ob mice. However, mucosal GLP concentrations and the plasma level of SDF-1 were not affected by the administration of STG. Real‑time PCR analysis revealed that colonic mucosal IL-6 mRNA expression, which was significantly upregulated in the ob/ob mice, was significantly suppressed by the long-term administration of STG. These results suggest that a DPP-4 inhibitor may suppress colon carcinogenesis in mice with type 2 diabetes in a GLP-independent manner. Since DPP-4 has multiple biological functions, further studies analyzing other factors related to colon carcinogenesis are needed.

Recurrent Abdominal Pain Accompanied by Small Intestinal Lesions

Question: A 57-year-old woman was admitted to our hospital with upper abdominal pain, accompanied by a fever of 38.6 C and panperitonitis. She had experienced the same symptoms of fever and panperitonitis for the previous 2 years. The symptoms would disappear after 2–3 days, but this cycle repeated every few months, and she had frequently been admitted to other hospitals for short durations. The patient had previously undergone surgery for appendicitis, but had no history of oral medication. Laboratory tests on admission revealed a white blood cell count of 17,660/mm, neutrophil count of 14,834/mm, and C-reactive protein level of 6.83 mg/dL, indicating a strong inflammatory response. Swelling of the mesenteric lymph nodes and an elevated density of mesenteric fatty tissue were noted on abdominal computed tomography (Figure A). Upper gastrointestinal endoscopy and colonoscopy did not reveal any abnormalities. Capsule endoscopy (CE) revealed hyperemia and erosions with white exudate in the jejunal mucosa (Figure B). Double balloon endoscopy (DBE) revealed hyperemia, edema, fragility, and erosion in the jejunum mucosa (Figure C). What is the diagnosis? Look on page 25 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

Multiple Mesenteric Panniculitis as a Complication of Sjögren's Syndrome Leading to Ileus.

Mesenteric panniculitis (MP) is a benign fibroinflammatory process characterized by the presence of fat necrosis, chronic inflammation and fibrosis in the mesentery. Although various causal factors, such as malignancy, chronic inflammatory conditions and autoimmune processes, have been identified, the precise etiology remains unknown. We herein report a rare case of MP accompanying Sjögrens syndrome in which a mass lesion and intestinal stenosis were observed simultaneously. This condition led to ileus, which was effectively treated using prednisolone.

Effect of Adalimumab on an Enterocutaneous Fistula in Patients with Crohn's Disease: A Case Series

Crohns disease (CD) is characterized by transmural inflammation of the gastrointestinal tract, which predisposes patients to the formation of a fistula. The efficacy of adalimumab (ADA) for an enterocutaneous fistula remains unclear. In this report, we present a case series of 3 patients with enterocutaneous fistulizing CD treated with ADA. ADA treatment achieved sustained complete fistula closure in one patient. The other two cases, which failed to achieve fistula closure, had intestinal stenosis and were not receiving concomitant azathioprine. Combination therapy with ADA and azathioprine may be a useful option and an alternative to surgery for enterocutaneous fistulizing CD.

Laparoscopic and endoscopic cooperative surgery for intra-mucosal gastric carcinoma adjacent to the ulcer scars

BackgroundLaparoscopic and endoscopic cooperative surgery (LECS) was performed for the local resection of gastrointestinal stromal tumors (GIST). LECS enables less resection of the lesion area and preserves function. Furthermore, LECS can be safely performed and independent of tumor location. However, LECS is not usually used for cases involving gastric carcinoma because it may seed tumor cells into the peritoneal cavity when the gastric wall is perforated. Here, we report seven cases of LECS for intra-mucosal gastric carcinoma, which were difficult to carry out by endoscopic submucosal dissection (ESD) because of ulcer scars.MethodsWe performed LECS (classical LECS and inverted LECS) in seven cases of intra-mucosal gastric carcinoma. All cases had ulcer scars beside the tumor. LECS was chosen because ESD was thought to be difficult because of the ulcer scars. We only selected cases in which the patients did not prefer gastrectomy and endoscopic examination was indicative of intra-mucosal gastric carcinoma.ResultsIn all cases, LECS was performed without severe complications including postoperative stenosis. Histopathology findings proved that the tumors were intra-mucosal carcinoma and had been resected completely. Furthermore, there were ulcer scars (Ul IIIs-IVs) beside the tumor. Currently, dissemination and recurrence have not been apparent.ConclusionsLECS for intra-mucosal gastric carcinoma is an efficient procedure, but strict observation is necessary because of the possibility of peritoneal dissemination. Results suggest that LECS is likely to be effective for cases involving intra-mucosal gastric carcinoma that are difficult to treat by ESD due to ulcer scars.

Tu1222 Non-Steroidal Anti-Inflammatory Drugs-Induced Small Intestinal Damage Is Associated With Autophagy and Apoptosis

were decreased 1.5-fold (± 0.2, p<0.02) and 7.1-fold (± 1.4, p<0.01) in the setting of acute Hh inhibition. Finally, mice exposed to LDE treatment for 6 days were predisposed to significant, damaging colitis secondary to 3% DSS challenge as evidenced by increased weight loss (35% vs 15%), increased histological damage and inflammatory infiltrate when compared to solvent treated controls exposed to DSS. Our initial evaluation of the effect of Hh targeted therapies on the gastrointestinal tract indicates that inhibiting epithelial derived Hh signaling leads to a pro-inflammatory immune environment thereby predisposing the GI tract to inflammatory mediated damage when challenged. While targeting the Hh pathway for treatment of malignancies is attractive and powerful, understanding the resultant effect on mucosal immune homeostasis is a critical component to developing safe and tolerable therapies. 1 Sekulic et al NEJM 2012; 366:2171-79. 2 Chang et al. J. Am Acad Dermatol. 2013 Nov 1, S0190-9622 (13). 3 Keating GM Drugs 2012 72(11)1535-41.

Mo1913 Influence of a Dipeptidyl Peptidase-4 Inhibitor on Intestinal Neoplasia Formation in APC MIN/+ Mice Fed a High Fat Diet

Background: The association between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. It is also well known that a high fat diet (HFD) promotes insulin resistance which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP4) inhibitors are used clinically in diabetes therapy to prolong the effects of glucagon-like peptide-1 (GLP-1). However, because another derivative from proglucagon, the intestinotrophic hormone GLP-2, is also a substrate for DPP-4, DPP-4 inhibitionmay enhance intestinal carcinogenesis by increasing endogenous active GLP-2. We therefore conducted this study to investigate the influence of a DPP-4 inhibitor on intestinal tumorigenesis in Apc Min/+ mice fed a HFD. Material and Methods: Segmental differences in DPP-4, 8, and 9 mRNA expression and DPP enzyme activity were determined in the mice. The DPP-4 inhibitor, sitagliptin (0.3, 1 or 3 mg/kg), was given orally. Mucosal DPP activity and GLP concentrations were measured 24 hr after administration. Six-week-old male Apc Min/+ mice were randomized to either a HFD (60 kcal fat) group or control diet (10 kcal fat) group for 9 weeks. Each group was divided into two groups, which were either treated or not treated with sitagliptin (3 mg/kg/day, i.g.). The mice were sacrificed 9 weeks after the initiation of treatment. The small intestine was coiled up into a Swiss roll, which was used to determine the number, size, and localization of tumors. Results: DPP-4 mRNA was expressed at high levels in the jejunum and ileum, with high DPP-4 activity also being detected. Oral sitagliptin caused a dose-dependent suppression in mucosal DPP-4 activity. Although the mucosal concentration of total GLP-2 was not affected, the concentration of GLP-1(7-36) was significantly elevated in the mucosa of the ileum. From seven to eight weeks after the initiation of sitagliptin treatment, bloody and inconsistent stools were observed mainly in the control diet and sitagliptin-treated mice. These mice also showed significantly lower body weight gains. In the control diet group, daily treatment with sitagliptin caused a significant increase in the number of intestinal tumors compared with mice not treated with sitagliptin. Daily treatment with sitagliptin suppressed the number of intestinal tumors in the HFD group, although this change was not statistically significant. Conclusion: This study demonstrated that chronic treatment with sitagliptin increased endogenous mucosal GLPs in the intestine and promoted intestinal tumorigenesis in lean mice, whereas sitagliptin treatment tended to suppress tumorigenesis in mice fed a HFD. Because a HFD promotes insulin resistance and intestinal neoplasia, DPP-4 inhibition may also be useful as an agent for preventing cancer in obese or diabetic patients.

Tu1231 Inhibition of RAC-1 Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.