Tsuguhiko Seo

High dose probiotic and prebiotic cotherapy for remission induction of active Crohn's disease

Background:  Clinical trials of probiotic treatment for Crohn’s disease (CD) have yielded conflicting results. This study assessed the clinical usefulness of combined probiotic and prebiotic therapy in the treatment of active CD.

A randomized controlled trial on the efficacy of synbiotic versus probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis.

OBJECTIVE Studies suggest that synbiotic therapy could prove more effective in the treatment of ulcerative colitis (UC) than therapies limited to probiotics or prebiotics. This study compared the effect of each of these therapies in the treatment of UC. METHODS One hundred twenty outpatients with UC were randomly sorted into three groups of 40 patients each for probiotic, prebiotic, or synbiotic therapy. The probiotic group ingested one daily capsule consisting of Bifidobacterium longum 2 x 10(9) colony-forming units and the prebiotic group ingested daily 8.0-g doses of psyllium. The synbiotic group underwent both treatments. All patients completed Inflammatory Bowel Disease Questionnaires (IBDQs) at the onset of the trial, at the 2-wk midpoint, and at the 4-wk end of the trial. Blood variables were also evaluated in a subset of 32 patients randomly selected from all groups and values were compared with IBDQ scores. RESULTS Thirty-one patients in the probiotic group, 31 in the prebiotic group, and 32 in the synbiotic group qualified for analyses. The remaining 26 patients had incomplete questionnaires. Total IBDQ scores improved within groups by the end of the trial (probiotics 162 to 169, NS; prebiotics 174 to 182, NS; synbiotics 168 to 176, P = 0.03). Individual scores improved as follows: probiotics, emotional function (P = 0.03); prebiotics, bowel function (P = 0.04); and synbiotics, systemic and social functions (P = 0.008 and P = 0.02). C-reactive protein decreased significantly only with synbiotic therapy (from 0.59 to 0.14 mg/dL, P = 0.04). There were no adverse events. CONCLUSION Patients with UC on synbiotic therapy experienced greater quality-of-life changes than patients on probiotic or prebiotic treatment. These data suggest that synbiotic therapy may have a synergistic effect in the treatment of UC.

Prevention of nonsteroidal anti-inflammatory drug–induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy

BACKGROUND There is no known preventive agent against nonsteroidal anti-inflammatory drug (NSAID) induced small-intestinal injury. OBJECTIVE To evaluate by capsule endoscopy whether coadministration of prostaglandin (PG) can prevent small-intestinal damage induced by short-term NSAID treatment. DESIGN Single-blind, randomized, controlled trial. SETTING All procedures were performed at Nippon Medical School. SUBJECTS Thirty-four healthy male volunteers. METHODS All subjects were randomly assigned to 2 groups: an NSAID-control group, who underwent NSAID (diclofenac sodium, 25 mg 3 times daily) and omeprazole (20 mg once daily) treatment, and an NSAID-PG group, who received PG (misoprostol, 200 microg 3 times daily) in addition to the same NSAID-omeprazole treatment. Eligible subjects, 15 per group, underwent capsule endoscopy before and 14 days after treatment. MAIN OUTCOME MEASUREMENTS The number of mucosal breaks at capsule endoscopy. RESULTS NSAID treatment significantly increased the mean (SD) number of mucosal breaks per subject, from a basal level of 0.1 +/- 0.3 up to 2.9 +/- 6.3 lesions in the NSAID-control group (P = .012). In contrast, there was no significant change in the mean number of mucosal breaks before and after PG cotreatment (P = 0.42). Thus, the mean number of posttreatment mucosal breaks per subject was significantly higher in the NSAID-control group than in the NSAID-PG group (P = .028). There was a significant increase in the percentage of subjects in the NSAID-control group, with at least 1 mucosal break after treatment (from 6.7% to 53.3%), whereas there was no change in the incidence of mucosal breaks in the NSAID-PG group, which remained at 13.3%. (P = .002). LIMITATIONS Single-center, open-label study. CONCLUSIONS PG cotherapy reduced the incidence of small-intestinal lesions induced by a 2-week administration of diclofenac sodium.

Diagnostic yield of double-balloon endoscopy in patients with obscure GI bleeding.

BACKGROUND Double-balloon endoscopy (DBE) is a new method that allows visualization, tissue sampling, and therapeutic intervention of a variety of pathologies throughout the small-intestinal tract. OBJECTIVE In the present study, we evaluated the diagnostic yield of DBE and its impact on the final diagnosis, treatment, and clinical outcome of patients with obscure GI bleeding (OGIB). DESIGN AND SETTING A hospital-based cross-sectional, follow-up study. PATIENTS We studied 108 consecutive patients (66 men and 42 women) referred to our hospital from July 2003 to February 2007 for the evaluation of OGIB: 13 patients with overt-ongoing bleeding, 76 with overt-previous bleeding, and 19 with occult OGIB. MAIN OUTCOME MEASUREMENTS Diagnostic yield, a final diagnosis, treatment, and clinical outcome were all analyzed in each group. RESULTS DBE diagnostic rates for patients with overt-ongoing, overt-previous, and occult bleeding were 100.0%, 48.4% and 42.1%, respectively. The difference in diagnostic yields between the overt-ongoing group and the 2 other groups was statistically significant (P < .005). The most common sources of bleeding were ulcers and tumor lesions. Small-intestinal lesions were identified in 52 of 108 patients; of which 36 patients (69.2%) were biopsied and 49 patients (94.2%) received treatment. Eight patients (7.4%) had recurrent bleeding during the mean follow-up period of 28.5 months. Sensitivity, specificity, and positive and negative predictive values of DBE in the diagnoses of small-intestinal lesions in patients with OGIB were 92.7%, 96.4%, 98.1%, and 87.1%, respectively. No serious complications were encountered. CONCLUSIONS DBE was proven to be a very useful diagnostic tool and had a therapeutic impact in the majority of patients with OGIB. The best candidates for the procedure were patients with overt-ongoing bleeding.

Distribution of small intestinal mucosal injuries as a result of NSAID administration.

Eur J Clin Invest 2010; 40 (6): 504–510

Helicobacter pylori infection increases the risk of colorectal adenoma and adenocarcinoma, especially in women

BackgroundRecent reports suggest that Helicobacter pylori infection can potentially increase the risk of colorectal cancer. The purpose of this study was to assess the association between H. pylori infection and the risk of colorectal adenoma and adenocarcinoma, and to evaluate any differences on the basis of sex.MethodsThe subjects were 669 (40- to 80-year-old) patients who underwent both barium enema examination and total colonoscopy, and who were evaluated for H. pylori infection by 13C-urea breath test, urease test, or histological diagnosis of biopsied gastric specimens. There were 142 H. pylori-negative and 527-positive patients. The odds ratios (ORs) for H. pylori-positive patients with colorectal adenoma and adenocarcinoma, and for tumor patients with either adenoma or adenocarcinoma were calculated.ResultsAmong the H. pylori-negative patients, there were 52 patients without tumor, 63 with adenoma, 27 with adenocarcinoma, and 90 with tumor. Among the H. pylori-positive patients, there were 136, 264, 127, and 391 patients respectively. Pooling all subjects, those infected with H. pylori had a significantly increased OR for adenoma, adenocarcinoma, or tumor, compared to H. pylori-free patients (OR, 1.60, 1.80, and 1.66, respectively). For female H. pylori-positive subjects, the risk of having adenocarcinoma or tumor was significantly higher than that for their H. pylori-free counterparts, while for male H. pylori-positive and -negative subjects, there was no such significant difference.ConclusionsThe results therefore suggest that, in patients aged 40–80 years, H. pylori infection increased the risk of colorectal adenoma and adenocarcinoma, with significantly higher risks for female patients.

Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma.

Background and aims: Cyclooxygenase 2 (COX-2) expression in subepithelial macrophages of colorectal adenoma has been suggested as the first in a series of steps leading to colorectal tumorigenesis. We tested the hypothesis that chemokines released from human colorectal adenoma epithelium might be involved in COX-2 expression in macrophages of the lamina propria. Methods: Endoscopic samples of sporadic colorectal adenomas were tested by enzyme linked immunosorbent assay for chemokines involved in macrophage chemotaxis. Localisation of adenoma macrophage chemoattractant protein 1 (MCP-1) and COX-2 were determined by immunohistochemistry. The effects of MCP-1, in the presence or absence of celecoxib, on COX-2 expression, and prostaglandin (PG) E2 and vascular endothelial growth factor (VEGF) release, were examined in human macrophages isolated from peripheral blood. Results: MCP-1 levels were markedly higher in adenoma with mild-moderate dysplasia (129.7 (19.9) pg/mg protein) and severe dysplasia (227.9 (35.4) pg/mg protein) than in normal colonic mucosa (55.8 (4.2) pg/mg protein). Other chemokine levels, macrophage inflammatory proteins (MIP)-1α and MIP-1β, and the chemokine regulated on activation of normal T cell expressed and secreted (RANTES) did not vary significantly between adenoma and normal mucosa. MCP-1 levels in both adenoma and normal colonic mucosa increased significantly three hours after tissue cultivation in vitro. MCP-1 immunoreactivity was restricted to the adenoma epithelium, with no reactivity seen in adjacent normal epithelial cells. MCP-1 stimulated COX-2 expression and PGE2 and VEGF release in human macrophages. Celecoxib, a selective COX-2 inhibitor, inhibited MCP-1-induced PGE2 and VEGF release in macrophages. Addition of exogenous PGE2 reversed this inhibitory effect on VEGF release, suggesting that MCP-1 in adenoma epithelial cells might be involved in COX-2 expression and subsequent macrophage activation. Conclusions: MCP-1 in colorectal adenoma epithelial cells might be involved in macrophage migration and COX-2 expression, leading to the subsequent development of colonic adenoma.

Microsomal prostaglandin E synthase protein levels correlate with prognosis in colorectal cancer patients

The aim of this study is to investigate the expression of three prostaglandin E synthase (PGES) isomers in colorectal cancer (CRC) tissue and to evaluate their relationship to clinicopathological factors and patient prognosis. Microsomal PGES (mPGES)-1, mPGES-2, cytosolic PGES (cPGES) and cyclooxygenase (COX)-2 protein expression were analyzed by real-time polymerase chain reaction and Western blot. The localization of each PGES and COX-2 protein was examined by immunohistochemistry in 155 surgical resections and correlated to clinicopathological factors and patient prognosis. mPGES-1 mRNA and protein levels were significantly higher in CRC than in paired normal tissues. mPGES-1 immunoreactivity localized in cancer cells in 43% of cases. mPGES-2 immunoreactivity was significantly more pronounced in cancer cells than in adjacent normal epithelium in 36% of cases. cPGES immunoreactivity was homogeneous in cancer cells and thus determined constitutive. mPGES-1 and mPGES-2 correlated with significantly worse prognosis in stage I–III patients. These results indicate that mPGES-1 and mPGES-2 may each play a role in CRC progression.

Heregulin-Induced VEGF Expression via the ErbB3 Signaling Pathway in Colon Cancer

Background/Aims: Heregulin (HRG/NRG) ligation to erbB3/4 promotes their respective heterodimerization with erbB2, and consequent erbB2 tyrosine phosphorylation. Although HRG has been shown to be expressed in a variety of cancer tissues, its expression and role in colon cancer have yet to be clarified. We therefore examined the link between the expression of these erbB receptors, and the relationship between HRG and vascular endothelial growth factor (VEGF) expression in colon cancer. Methods: We analyzed the effects of HRG on VEGF secretion in 6 colorectal cancer cell lines by enzyme-linked immunosorbent assay, and HRG-induced p85 subunit of phosphatidylinositol 3-kinase (p85 PI-3K), Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) activation in Caco-2 colon cancer cell lines by Western blot. We also examined HRG and VEGF mRNA expression in 16 colon cancer biopsy samples by real-time PCR. The localization of HRG and VEGF protein expression in colon cancer tissue was detected by immunohistochemistry. Results: Exogenous HRG stimulated VEGF secretion in all cell lines examined, and VEGF mRNA expression in Caco-2 cells. HRG also activated p85 PI-3K, Akt, ERK1/2, and p38 MAPK. VEGF secretion was inhibited by both specific p38 MAPK inhibitor and proteasome inhibitor that inhibit nuclear factor kappa B (NF-κB) activation. In colon cancer biopsy samples, HRG mRNA expression correlated with VEGF mRNA expression. HRG immunoreactivity was observed both in cancer cells and in mesenchymal cells in colon cancer tissues. Conclusion: These data suggest that HRG might affect colon cancer growth by regulating VEGF secretion via the erbB3 signaling pathway through autocrine and paracrine mechanisms.

Prevention of traditional NSAID-induced small intestinal injury: recent preliminary studies using capsule endoscopy.

Capsule endoscopy and balloon endoscopy, advanced modalities that now allow for full investigation of the entire small intestine, have revealed that non-steroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the small intestine. Traditional NSAIDs can induce small intestinal injuries in over 50% of patients. Several studies have shown that the preventive effect of proton pump inhibitors does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with traditional NSAIDs use. Recently, several randomized controlled trials used capsule endoscopy to evaluate the preventive effect of certain drugs on NSAID-induced small intestinal injuries. These studies show that misoprostol and rebamipide have a preventive effect for NSAID-induced small intestinal mucosal injuries. However, these studies included only a small series of healthy volunteers and tested short-term NSAID treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs.