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Treatment of mice with a pomegranate peel extract (PPX) decreased the pathogenicity of Citrobacter rodentium (Cr) infections. Here, we investigate the effects of PPX on the microbiome of uninfected or Cr‐infected C3H/HeNCr mice by 16S rRNA gene sequencing. Mice were treated with water or PPX for 14 days, feces were collected, and then, the mice were infected with Cr and feces collected again at day 6 postinfection. DNA was isolated from the fecal samples and subjected to 16S rRNA gene sequencing to determine the microbial composition. Differences in the composition of the microbiome were observed for untreated and PPX‐treated mice with PPX mice having decreased diversity. PPX treatment decreased the Firmicutes/Bacteroidetes ratio by increasing Bacteroidetes and decreasing Firmicutes levels. The decrease in Firmicutes was driven by a large reduction in Lactobacillus. PPX treatment increased the abundance of Proteobacteria and Verrucomicrobiae and decreased Actinobacteria. The relative abundance of Cr reached 22% in water‐treated but only 5% in PPX‐treated infected mice. These results suggest that consumption of pomegranate polyphenols altered the microbiome, making it more resistant to displacement by infection with Cr, indicating that pomegranate polyphenols may mitigate the pathogenic effects of food‐borne bacterial pathogens.

BackgroundAntibiotic-associated colitis caused by Clostridium difficile (C. difficile) is the most common cause of hospital-acquired diarrhea. The pathogenesis of C. difficile colitis is mediated b...

Ischaemic colitis is the most common form of gastrointestinal ischaemia, but may be confused with acute mesenteric ischaemia, inflammatory bowel disease or infectious colitis. This review article outlines the current classification, epidemiology and risk factors, as well as approaches about diagnosis and management to guide clinical practice. It also identifies areas for further research.

Inflammatory bowel diseases (IBDs) are recurrent intestinal pathologies characterized by a compromised epithelial barrier and an exaggerated immune activation. Mediators of immune cell infiltration may represent new therapeutic opportunities. Metallothioneins (MTs) are stress-responsive proteins with immune-modulating functions. Metallothioneins have been linked to IBDs, but their role in intestinal inflammation is inconclusive. We investigated MT expression in colonic biopsies from IBDs and acute infectious colitis patients and healthy controls and evaluated MT's role in experimental colitis using MT knockout mice and anti-MT antibodies. Antibody potential to target extracellular MT and its mechanism was tested in vitro. Biopsies of patients with active colitis showed infiltration of MT-positive cells in a pattern that correlated with the grade of inflammation. MT knockout mice displayed less severe acute dextran sulphate sodium (DSS)-induced colitis compared to congenic wild-type mice based on survival, weight loss, colon length, histological inflammation and leukocyte infiltration. Chronic DSS-colitis confirmed that Mt1 and Mt2 gene disruption enhances clinical outcome. Blockade of extracellular MT with antibodies reduced F4/80-positive macrophage infiltration in DSS- and trinitrobenzene sulphonic acid-colitis, with a tendency towards a better outcome. Whole-body single-photon emission computer tomography of mice injected with radioactive anti-MT antibodies showed antibody accumulation in the colon during colitis and clearance during recovery. Necrotic and not apoptotic cell death resulted in western blot MT detection in HT29 cell supernatant. In a Boyden chamber migration assay, leukocyte attraction towards the necrotic cell supernatant could be abolished with anti-MT antibody, indicating the chemotactic potential of endogenous released MT. Our results show that human colitis is associated with infiltration of MT-positive inflammatory cells. Since antibody blockade of extracellular MT can reduce colitis in mice, MT may act as a danger signal and may represent a novel target for reducing leukocyte infiltration and inflammation in IBD patients.

The probiotic Bifidobacterium longum NCC3001 normalizes anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis. Using a model of chemical colitis we test whether the anxiolytic effect of B. longum involves vagal integrity, and changes in neural cell function. Methods Mice received dextran sodium sulfate (DSS, 3%) in drinking water during three 1-week cycles. Bifidobacterium longum or placebo were gavaged daily during the last cycle. Some mice underwent subdiaphragmatic vagotomy. Behavior was assessed by step-down test, inflammation by myeloperoxidase (MPO) activity and histology. BDNF mRNA was measured in neuroblastoma SH-SY5Y cells after incubation with sera from B. longum- or placebo-treated mice. The effect of B. longum on myenteric neuron excitability was measured using intracellular microelectrodes.Chronic colitis was associated with anxiety-like behavior, which was absent in previously vagotomized mice. B. longum normalized behavior but had no effect on MPO activity or histological scores. Its anxiolytic effect was absent in mice with established anxiety that were vagotomized before the third DSS cycle. B. longum metabolites did not affect BDNF mRNA expression in SH-SY5Y cells but decreased excitability of enteric neurons.In this colitis model, anxiety-like behavior is vagally mediated. The anxiolytic effect of B. longum requires vagal integrity but does not involve gut immuno-modulation or production of BDNF by neuronal cells. As B. longum decreases excitability of enteric neurons, it may signal to the central nervous system by activating vagal pathways at the level of the enteric nervous system.

Inflammatory bowel disease (IBD) is increasing in many parts of the Asia-Pacific region. There is a need to improve the awareness of IBD and develop diagnostic and management recommendations relevant to the region. This evidence-based consensus focuses on the definition, epidemiology and management of ulcerative colitis (UC) in Asia. A multi-disciplinary group developed the consensus statements, reviewed the relevant literature, and voted on them anonymously using the Delphi method. The finalized statements were reviewed to determine the level of consensus, evidence quality and strength of recommendation. Infectious colitis must be excluded prior to diagnosing UC. Typical histology and macroscopic extent of the disease seen in the West is found in the Asia-Pacific region. Ulcerative colitis is increasing in many parts of Asia with gender distribution and age of diagnosis similar to the West. Extra-intestinal manifestations including primary sclerosing cholangitis are rarer than in the West. Clinical stratification of disease severity guides management. In Japan, leukocytapheresis is a treatment option. Access to biologic agents remains limited due to high cost and concern over opportunistic infections. The high endemic rates of hepatitis B virus infection require stringent screening before initiating immune-suppressive agents. Vaccination and prophylactic therapies should be initiated on a case-by-case basis and in accordance with local practice. Colorectal cancer complicates chronic colitis. A recent increase in UC is reported in the Asia-Pacific region. These consensus statements aim to improve the recognition of UC and assist clinicians in its management with particular relevance to the region.

To investigate the possible contribution of peripheral sensory mechanisms to abdominal pain following infectious colitis, we examined whether the Citrobacter rodentium mouse model of human E. coli infection caused hyperexcitability of nociceptive colonic dorsal root ganglion (DRG) neurons and whether these changes persisted following recovery from infection. Mice were gavaged with C. rodentium or distilled water. Perforated patch clamp recordings were obtained from acutely dissociated Fast Blue labelled colonic DRG neurons and afferent nerve recordings were obtained from colonic afferents during ramp colonic distensions. Recordings were obtained on day 10 (acute infection) and day 30 (infection resolved). Following gavage, colonic weights, myeloperoxidase (MPO) activity, stool cultures, and histological scoring established that infection caused colitis at day 10 which resolved by day 30 in most tissues. Electrophysiological recordings at day 10 demonstrated hyperexcitability of colonic DRG neurons (40% mean decrease in rheobase, P= 0.02; 50% mean increase in action potential discharge at twice rheobase, P= 0.02). At day 30, the increase in action potential discharge persisted (∼150% increase versus control; P= 0.04). In voltage clamp studies, transient outward (IA) and delayed rectifier (IK) currents were suppressed at day 10 and IA currents remained suppressed at day 30. Colonic afferent nerve recordings during colonic distension demonstrated enhanced firing at day 30 in infected animals. These studies demonstrate that acute infectious colitis evokes hyperexcitability of colonic DRG neurons which persists following resolution of the infection and that suppression of IA currents may play a role. Together, these findings suggest that peripheral pain mechanisms could contribute to post-infectious symptoms in conditions such as post-infectious irritable bowel syndrome.

Background: It is necessary to exclude infectious colitis by fecal culture for diagnosis of ischemic colitis. But even if pathogenic bacteria are excluded, it is expected that the population of normal bacterial flora of the lesion is probably changing. We have performed bacterial culture using colonoscopic sampling in order to detect more important bacteria, when we diagnose ischemic colitis on colonoscopy. Methods: The subject group comprised 81 patients diagnosed with ischemic colitis between January 1998 and July 2004. During initial colonoscopy, we sprayed 20 mL saline on the most severe site of the inflammatory lesion and collected the fluid by suction for culture (colonoscopic spraying wash culture). When only one species of bacteria was isolated, we registered the bacteria as the predominant organism. When two or more species of bacteria were isolated, we registered the bacteria that were isolated most superior in number. Results: Escherichia coli (48 patients), Klebsiella (22 patients), Enterococcus (22 patients), Enterobacter (12 patients) and others were registered. Generally, younger patients (under 50 years) had prominently E. coli, and elderly patients (above 70 years) had Klebsiella. Patients with baseline disease such as hypertension, diabetes mellitus, and hyperlipidemia generally had Enterococcus. Patients without baseline disease generally had E. coli. Sex and the length of period after onset were not significantly different. Colonoscopic features of the cases isolated only one species of bacteria by colonoscopic spraying wash culture that were different to each other. Conclusion: It is expected that age and baseline diseases contribute to the onset of ischemic colitis and to the disruption of normal flora. Meanwhile, it is supposed that the disruption of normal flora is related to the induction of various configurations of ischemic colitis.

We studied the impact of administering XPro1595, a novel antagonist of soluble tumor necrosis factor-α(TNFα), on the regulation of hepatic cytochrome P450 enzymes in the Citrobacter rodentium model of infectious colitis. XPro1595 was administered subcutaneously every 3 days throughout the infection, or as a single injection near the peak of infection. When given throughout the infection, XPro1595 selectively blocked the downregulation of Cyp3a11 and 3a25 mRNAs, as well as the induction of Cyp2a4/5, without affecting the downregulation of Cyp4a10, Cyp4a14, Cyp2b10, or flavin-mooxygenase-3. Induction of Cyp3a11, Cyp3a25, Cyp2c29, and Cyp3a13 mRNAs were observed only in XPro1595-treated mice. Administration of a single dose of XPro1595 was relatively ineffective. These results (1) confirm the role of soluble TNFα in hepatic Cyp3a regulation during infectious colitis deduced from studies in TNFα receptor-1 knockout mice; (2) indicate the potential for soluble TNFα -specific antagonists to cause disease-dependent drug–drug interactions; and (3) suggest a novel mechanism by which an anti-inflammatory therapeutic protein can produce an opposite effect to that of the disease by selectively neutralizing one of multiple signals regulating drug-metabolizing enzyme expression. More research is needed to determine whether or not this is applicable to other diseases or disease models.

We studied the initial rectal biopsy from 46 patients in whom subsequent follow-up established the diagnosis of either self-limited colitis or inflammatory bowel disease. An additional 12 non-inflamed rectal biopsies were also studied. There was between 2 and 8 years of follow-up in each of these cases. Staining for fibrin (MSB, fibrinogen), platelets (factor XIIIA, Y2/51), and capillary basement membrane (reticulin, collagen 4) was performed to identify thrombotic material within capillaries. Mucosal capillary thrombi were best identified by staining for factor XIIIA; thrombi were observed in 8/13 cases of ulcerative colitis, 4/10 cases of Crohn's disease, 1/3 cases of unspecified inflammatory bowel disease and 5/20 cases of self-limited colitis. The presence of capillary thrombi was not related to the severity of inflammation, but none of the control biopsies showed capillary thrombi. Their presence seems of little diagnostic value in distinguishing inflammatory bowel disease from self-limited colitis. The pathogenetic significance of these mucosal capillary thrombi is uncertain.

Cyclooxygenase-2 has shown increased expression on crypt epithelium, inflammatory cells of the lamina propria and myenteric neural cells of active inflammatory bowel disease. In tuberculosis colitis, colonoscopic findings are multiple discrete ulcers on terminal ileum, ic valve and cecum with normal surrounding mucosa which are similar with Crohn's colitis. Pathologically the two disease show similar chronic inflammation and granuloma because typical acid fast bacilli and caseation necrosis are not usually detected by biopsy. We evaluated Cox-2 expression on mucosal biopsy and surgical specimen of tuberculous colitis comparing with Crohn's colitis and nonspecific infectious colitis using immunohistochemistry. This study included 10 patients with tuberculous colitis which are confirmed by antituberculosis treatment, and 10 patients with active Crohn's colitis and 10 patients with acute infectious colitis. We find high Cox-2 expression on both crypt epithelium and laminar propria lymphocyte (LPL) in all of tuberculous colitis (10 of 10). There are low and weak expression on epithelium (two of 10) and LPL (nine of 10) of Crohn's colitis and epithelium (one of 10) and LPL (seven of 10) of infectious colitis. Cox-2 expression on crypt epithelium in patients with tuberculous colitis is significantly higher than Crohn's colits and infectious colitis (P

The expression of plasminogen activators was analysed in mucosal homogenates from inflammatory bowel disease patients to determine whether the urokinase-type (u-PA) is implicated in the pathogenesis of mucosal tissue injury. Homogenates of mucosal biopsy tissue from ulcerative colitis, Crohn's disease, infectious colitis and normal control patients were subjected to polyacrylamide gel electrophoresis. The types of plasminogen activator present were detected by zones of lysis in a fibrin-agarose gel overlay. All the tissues studied displayed tissue plasminogen activator activity (t-PA). In ulcerative colitis, 18 of the 19 diseased colon biopsies, but none of six biopsies from uninvolved areas of the same colon, showed u-PA activity. Similar results were found in 12 Crohn's disease patients. Biopsies from the infectious colitis group and from radiation colitis patients also showed both u-PA and t-PA activity. The age, sex, duration of disease, and presence and type of treatment did not affect u-PA expression in the inflamed mucosa. The results suggest that u-PA may be implicated in the mediation of tissue injury in the inflamed intestinal mucosa.