Colitis Research Papers - Academia.edu (original) (raw)

The aim of the present study was to examine the effects of phenylpropanoid glycoside, Teupolioside, biotechnologically produced by IRBN22 Ajuga reptans cell line, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Teupolioside was administered daily orally (0.2 or 2 mg kg-1). On Day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. Four days after DNBS administration, colon TNF- and IL-1β productions were increased, associated with colon damage. Neutrophil infiltration, by myeloperoxidase activity, in the mucosa was associated with up-regulation of ICAM-1 and P-selectin and high levels of malondialdehyde.

- by and +1
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- Immunohistochemistry, Cell line, Inflammatory Bowel Disease, Lipid peroxidation

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c 2/2 ) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c 2/2 mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.

- by Michael Valentino
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- Membrane Proteins, DNA damage, Multidisciplinary, Intestinal Mucosa

Background and Aims: Impairment of small intestinal absorption has been described in patients with ulcerative colitis and in animal models of experimental colitis. The pathophysiology of this dysfunction has not been elucidated. The aim of this study was to investigate the effect of chemical colitis on jejunal fluid absorption and determine the role of the enteric nervous system and some putative neurotransmitters. Methods: A rat model of iodoacetamide-induced colitis was used. Jejunal net fluid absorption was evaluated by the in-vivo single pass perfusion technique. The effects of i) tetrodotoxin (TTX), ii) benzylalkonium chloride (BAC), iii) capsaicin, iv) VIP antagonism (VIPa), v) nitric oxide synthase (NOS) inhibition and vi) 5-HT 3 and 5-HT 4 receptor antagonism on the changes in fluid movement were investigated. Results: A significant decrease in jejunal net fluid absorption was found at 2 and 4 days after colitis induction [mean 26(SD 14) and 28(19), respectively; p<0.0002 as compared to sham rats 61(6.5) µl min -1 g -1 dry intestinal weight]. No evident histologic changes were seen in jejunal sections. TTX and BAC reversed this decrease in fluid absorption [54(13) and 44(14); p=0.0005 and p=0.019, respectively as compared to colitis]. Ablation of capsaicin sensitive primary afferent fibers had a partial effect [45(5); p=0.001 and p=0.003 compared to colitis and sham, respectively). Constitutive and neuronal NOS inhibition and VIPa returned jejunal net fluid absorption to normal values [66(19), 61 and 56 , respectively]. 5-HT 3 and 5H-T 4 receptor antagonism had no effect. Conclusion:

- by Camille Nassar and +1
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- Physiology, Enzyme Inhibitors, Serotonin, Nitric oxide

Background & Aims: There is mounting evidence that matrix metalloproteinases are the predominant proteinases expressed in the gut mucosa during active inflammatory bowel disease. We investigated the role of metalloproteinase 9 (MMP-9), a secreted gelatinase that is consistently up-regulated in both animal models and human inflammatory bowel disease and is associated with disease severity, in the pathogenesis of colitis by using mice containing a targeted deletion of the MMP-9 gene. Methods: Dextran sodium sulfate–induced colitis and Salmonella typhimurium–induced enterocolitis were used as animal models to study colitis. Results: MMP-9 activity and protein expression were absent from normal colonic mucosa but were up-regulated during experimental colitis. MMP-9−/− mice exposed to dextran sodium sulfate or salmonella had a significantly reduced extent and severity of colitis. Immunohistochemical studies showed that MMP-9 was localized to epithelial cells and granulocytes during active colitis. The immune response to systemic administration of Salmonella typhimurium was not affected in MMP-9−/− mice. Neutrophil transmigration studies and bone marrow chimeras showed that neutrophil MMP-9 is neither required for its migration nor sufficient to induce tissue damage during colitis and that epithelial MMP-9 is important for tissue damage. MMP-9 inhibited cell attachment and wound healing in the model intestinal epithelial cell line, Caco2-BBE. Conclusions: Taken together, our data suggest that MMP-9 expressed by epithelial cells may play an important role in the development of colitis by modulating cell–matrix interaction and wound healing. Thus, strategies to inhibit MMP-9 may be of potential therapeutic benefit.

- by mauricio rojas
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- Immune response, Gastroenterology, Wound Healing, Extracellular Matrix

To determine the gastrointestinal toxic effects of idarubicin and cytosine arabinoside combination therapy in patients with newly diagnosed acute myelogenous leukemia (AML). We performed a single-institution retrospective analysis of the incidence of neutropenic colitis in patients with newly diagnosed AML receiving idarubicin and cytosine arabinoside combination therapy. Using pharmacy records, we identified 78 patients who received idarubicin during the study period of January 1997 to September 1998 and who agreed to a review of their medical records. Patients with preexisting bowel conditions were excluded from this analysis. We used a strict definition of neutropenic colitis that included clinical findings (severe abdominal pain, diarrhea, hematochezia, and/or peritoneal signs) plus radiographic evidence of bowel inflammation in the absence of an identified bacterial pathogen. Of the 78 patients receiving idarubicin and cytosine arabinoside for treatment of AML, 65 were included...

- by Louis Letendre
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- Treatment Outcome, Acute Myeloid Leukemia, Ct, Mayo Clinic

Abbreviations used in this paper: ACCA, antichitobioside carbohydrate IgA antibodies; ALCA, antilaminaribioside carbohydrate IgG antibodies; ASCA, anti-Saccharomyces cerevisiae antibodies; AUC, area under the curve; CD, Crohn's disease; gASCA, anticovalently attached mannan antibodies; HC, healthy controls; OGD, other-than-IBD gastrointestinal diseases; RFU, relative fluorescence units; UC, ulcerative colitis.

- by Avi Shtevi
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- Gastroenterology, Adolescent, Saccharomyces cerevisiae, Antibodies
- by Michaela Diamanti
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- Inflammation, Endoplasmic Reticulum Stress, Protein Stability, Mice

PURPOSE: To gain recent epidemiologic information about inflammatory bowel disease in The Netherlands, a prospective study over four years (1991–1995) was performed. METHODS: The incidence of inflammatory bowel disease and its subgroups was examined using standardized reports of newly diagnosed patients. A separate study compared the Inflammatory Bowel Disease Registration and computerized diagnostic files of a subgroup of general practitioners with the aim of estimating completeness of case ascertainment. RESULTS: The following mean incidence rates (per 100,000 inhabitants and year) were found: 6.9 (95 percent confidence interval, 5.9–7.9) for Crohn's disease, 10 (95 percent confidence interval, 8.7–11.2) for ulcerative colitis (23 percent of these with ulcerative proctitis), and 1.1 (95 percent confidence interval, 0.7–1.5) for indeterminate colitis. In the age category 20 to 29 years, the incidence rate of Crohn's disease with small-bowel involvement was higher in females than in males. In extended ulcerative colitis, a male preponderance was observed in the older age groups. Estimated case ascertainment was 78 percent. CONCLUSIONS: Compared with recent studies in neighboring countries, the observed age and gender standardized incidence rates are high in the south of The Netherlands. Completeness of case ascertainment might have contributed to this observation; however, case ascertainment was low in ulcerative proctitis. In the study area, differences in age and gender standardized incidence rates and in disease localizations could be compatible with an influence of environmental risk factors.

- by Reinhold Stockbrugger and +1
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- Adolescent, Inflammatory Bowel Disease, Prospective studies, Child

Endogenous trefoil (TFF) peptides have reparative and anti-inflammatory actions in colitis because luminal application in vivo potently reduces inflammatory indices and accelerates healing. Since chronic production of NO via inducible nitric oxide synthase activity (iNOS) leads to tissue damage and inflammation, we tested whether TFF2 could inhibit NO production in a monocyte cell line in response to bacterial endotoxin, and in vivo by measuring inflammatory indices and nitrated protein expression in rat colon after colitis induction. We showed that TFF2 can inhibit iNOS and NO in monocytes and inflammatory compartment size in vivo, and conclude that trefoils can regulate monocyte NO-mediated inflammation in colitis.

- by Louise Judd
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- Physiology, Macrophages, Cell line, Nitric oxide
- by Joseph Silva
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- Clostridium difficile, Diarrhea, Infection Control, Bacterial Toxins

Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects including anti-inflammatory, cardio-and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative Colitis (UC) is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a Dextran Sulfate Sodium (DSS) mouse model of colitis, which resembles human UC pathology. Resveratrol mixed in food ameliorates DSSinduced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, down regulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propiria, and modulates CD3 + T cells that express tumor necrosis factor-alpha and interferon gamma. Markers of inflammation and inflammatory stress (p53 and p53-Phospho-Serine 15), are also down regulated by resveratrol. Since chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with Azoxymethane (AOM) + DSS to 20% in AOM + DSS + Resveratrol (300 p.p.m.) treated mice. Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS treated mice had 2.4 ± 0.7 tumors per animal compared with AOM + DSS + 300 p.p.m. resveratrol, which had 0.2 ± 0.13 tumors per animal. The current study indicates that resveratrol is a useful, non-toxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis.

- by Prakash Nagarkatti and +1
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- Cancer, Flow Cytometry, Inflammation, Immunohistochemistry

Objective and design: To investigate the severity and duration of colitis induced by two different doses of 2,4,6-trinitrobenzenesulfonic acid (TNBS) and the changes in mast cell number in acute infl ammation and in the recovery process of colitis. Methods: Colitis was induced in rats by an enema of TNBS (10 or 30 mg) in 25 % ethanol. Macroscopic and histologic changes of the colon, colon weight and mast cell counts were examined at various times (7, 30 and 60 days) after colitis induction. Results: TNBS induced a colonic damage which was doserelated for both severity and time necessary to complete recovery. On day 7 after colitis induction 10 mg TNBS induced macroscopic and microscopic alterations of colonic architecture that completely resolved at day 60. By contrast, 30 mg TNBS induced massive necrosis, thickening of the colon, severe histologic changes that were only partially reversed after two months. Mast cell number in the submucosa and muscularis propria decreased signifi cantly in the acute phase of infl ammation (7 days) and slowly increased thereafter, reaching a maximum level (up to about 5-fold) at day 60 after both doses of TNBS. Conclusions: Present data confi rm the ability of TNBS to induce in rats damage to the colon that was dose-dependent for severity and duration. Moreover, these data unravel a different role of mast cells in TNBS-induced colitis: an early degranulation in the acute phase of infl ammation and a subsequent accumulation of mast cells in the late phase of the disease, associated with tissue repair.

- by Gabriella Coruzzi
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- Inflammation, Mast Cells, Tissue repair, Clinical Sciences

The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiotahost relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine 1 . Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergentlike molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro 2 , might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century 3 . Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced lowgrade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed hostmicrobiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

- by Omry Koren
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- Obesity, Inflammation, Diet, Multidisciplinary

Intussusceptive angiogenesis is a process that forms new blood vessels by the intraluminal division of a single blood vessel into two lumens. Referred to as nonsprouting or intussusceptive angiogenesis, this angiogenic process has been described in morphogenesis and chronic inflammation. Mechanical forces are relevant to the structural changes associated with intussusceptive angiogenesis because of the growing evidence that physiologic forces influence gene transcription. To provide a detailed analysis of the spatial distribution of physiologic shear stresses, we developed a 3D finite element model of the intraluminal intussusceptive pillar. Based on geometries observed in adult intussusceptive angiogenesis, physiologic shear stress distribution was studied at pillar sizes ranging from 1μm to 10μm. The wall shear stress calculations demonstrated a marked spatial dependence with discrete regions of high shear stress on the intraluminal pillar and lateral vessel wall. Further, the intussusceptive pillar created a "dead zone" of low wall shear stress between the pillar and vessel bifurcation apex. We conclude that the intraluminal flow fields demonstrate sufficient spatial resolution and dynamic range to participate in the regulation of intussusceptive angiogenesis by intraluminal flow fields.

- by Lino Miele
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- Fluid Mechanics, Computational Biology, Microvascular Physiology, Geometric model

Colitis cystica profunda (CCP) is an uncommon benign condition characterized by mucin-filled cysts located in the submucosa, frequently associated with the solitary ulcer and rectal prolapse syndromes. The diagnosis of this entity is important as it can mimic rectal cancer and therefore may result in unnecessary surgical resection. Endoscopic examination and barium enema findings are suggestive but not specific, neither are superficial biopsy findings. Transrectal ultrasound is helpful in the diagnosis by imaging the layers of the rectal wall. The authors report a 16-year-old male with a rectal lesion mimicking malignant mass on endoscopic examination. The lesion was defined as CCP, based on MR imaging findings which disclosed multiple noninfiltrating submucosal cysts, confirmed by histopathological examination. To our knowledge, this is the first case of CCP in the radiology literature describing MRI findings.

- by Nagihan Inan and +2
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- Magnetic Resonance Imaging, Ultrasound, Adolescent, Abdominal Imaging
- by Anna Madill
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- Psychology, Clinical Psychology, Social Psychology, Developmental Psychology
- by Aderbal Sabra and +1
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- Child, Developmental disabilities, Hyperplasia, Pervasive Developmental Disorder

The generation of transgenic mice that lack or overexpress genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is widely used in mice. Here we describe a novel model, chemical stimulation of the colon, which we have developed in mice. Mice of either sex were injected i.v. with 30 mg/kg Evan's Blue for subsequent determination of plasma extravasation. For behavioural testing, they were placed on a raised grid and 50 ml of saline, mustard oil (0.25±2.5%) or capsaicin (0.03±0.3%) was administered by inserting a ®ne cannula into the colon via the anus. Visceral pain-related behaviours (licking abdomen, stretching, contractions of abdomen etc) were counted for 20 min. Before intracolonic administration, and 20 min after, the frequency of withdrawal responses to the application of von Frey probes to the abdomen was tested. The colon was removed post-mortem and the Evan's Blue content measured. Mustard oil and capsaicin administration evoked dose-dependent visceral pain behaviours, referred hyperalgesia (signi®cant increase in responses to von Frey hairs) and colon plasma extravasation. The peak behavioural responses were evoked by 0.1% capsaicin and by 1% mustard oil respectively. The nociceptive behavioural responses were dose-dependently reversed by morphine (ED50 1.9^1 mg/ kg s.c.). We conclude that this model represents a useful tool both for phenotyping mutant mice and for classical pharmacology since information on visceral pain, referred hyperalgesia and colon in¯ammation can all obtained from the same animal. q (J.M.A. Laird).

- by Jennifer Laird
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- Animal Behavior, Pain, Transgenic Mice, Mice

Colon cancer is the third most common malignant neoplasm in the world and it remains an important cause of death, especially in western countries. The toxic environmental pollutant, 1, 2-dimethylhydrazine (DMH), is also a colon-specific carcinogen. Tannic acid (TA) is reported to be effective against various types of chemically induced toxicity and also carcinogenesis. In the present study, we evaluated the chemopreventive efficacy of TA against DMH induced colon toxicity in a rat model. Efficacy of TA against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, lipid peroxidation, histopathological changes and expression of early molecular markers of inflammation and tumor promotion. DMH treatment induced oxidative stress enzymes (p<0.001) and an early inflammatory and tumor promotion response in the colons of Wistar rats. TA treatment prevented deteriorative effects induced by DMH through a protective mechanism that involved redu...

- by Rehan Khan
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- Oxidative Stress, Antioxidants, Glutathione, Catalase

Glyphosate, the active ingredient in Roundup ® , is the most popular herbicide used worldwide. The industry asserts it is minimally toxic to humans, but here we argue otherwise. Residues are found in the main foods of the Western diet, comprised primarily of sugar, corn, soy and wheat. Glyphosate's inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport. Consequences are most of the diseases and conditions associated with a Western diet, which include gastrointestinal disorders, obesity, diabetes, heart disease, depression, autism, infertility, cancer and Alzheimer's disease. We explain the documented effects of glyphosate and its ability to induce disease, and we show that glyphosate is the "textbook example" of exogenous semiotic entropy: the disruption of homeostasis by environmental toxins.

- by Stephanie Seneff and +1
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- Bioengineering, Pharmacology, Biochemistry, Genetics
- by Jennifer Bonheur
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- Inflammatory Bowel Disease, Ulcerative colitis, Clinical Sciences, Colitis
- by Ethiran Kathiravan
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- Biology, Calcium, Medicine, Intestinal Mucosa

Intestinal dendritic cells (DCs) have been shown to display specialized functions, including the ability to promote gut tropism to lymphocytes, to polarize noninflammatory responses, and to drive the differentiation of adaptive Foxp3 + regulatory T (T reg ) cells. However, very little is known about what drives the mucosal phenotype of DCs. Here, we present evidence that the local microenvironment, and in particular intestinal epithelial cells (ECs), drive the differentiation of T reg -cell-promoting DCs, which counteracts Th1 and Th17 development. EC-derived transforming growth factor-(TGF-) and retinoic acid (RA), but not thymic stromal lymphopoietin (TSLP), were found to be required for DC conversion. After EC contact, DCs upregulated CD103 and acquired a tolerogenic phenotype. EC-conditioned DCs were capable of inducing de novo T reg cells with gut-homing properties that when adoptively transferred, protected mice from experimental colitis. Thus, we have uncovered an essential mechanism in which EC control of DC function is required for tolerance induction.

- by Marcello Chieppa
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- Cytokines, Dendritic Cells, Biological Sciences, Cell Differentiation

- by Stephanie Seneff
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- Bioengineering, Biochemistry, Genetics, Computer Science
- by Julia Mills
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- Gastroenterology, Regulation, Transcription Factors, Apoptosis
- by Diana Hassel
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- Horses, Colitis, Anti-Bacterial Agents, Ehrlichiosis
- by Eli Ehrenpreis
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- Medicinal Plants, Ulcerative colitis, Monoclonal Antibodies, Caustics

We recently characterized Winnie mice carrying a missense mutation in Muc2 , leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie , there was a fourfold increase in activated dendritic cells (DCs; CD11c + major histocompatibility complex (MHC) class II hi ) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal T H 17 signature genes Il17a , IL17f , Tgfb , and Ccr6 , particularly in the distal colon.

- by Rajaraman Eri
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- Immune response, Cytokines, Inflammation, Endoplasmic Reticulum Stress

Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and keratinocytes, and is involved in immune homeostasis or inflammation. The mechanism through which TSLP regulates intestinal inflammation is unclear. Here, we report that mouse dendritic cells (DCs) express TSLP both in vitro and in vivo in response to Toll-like receptor ligation in a MyD88-dependent fashion. TSLP is produced by the CD103(+) subset of tolerogenic gut DCs and is downregulated during experimental colitis. TSLP produced by DCs acts directly on T cells by reducing their capacity to produce interleukin (IL)-17 and fostering the development of Foxp3(+) T cells. Consistently, TSLP protects against colitis development through a direct action on T cells, as adoptive transfer of naïve T cells from TSLPR(-/-) to SCID mice results in a more severe colitis, with increased frequency of IL-17-producing T cells and inflammatory cytokines. Hence, we describe a new anti-inflammatory role of TSLP in the gut.

- by Giacomo Rossi
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- Cytokines, Dendritic Cells, Signal Transduction, Toll like receptor signaling

Eosinophilic colitis is induced by antigens present in cow's milk proteins in formula or human milk. In the last few years, an increasing number of cases have been diagnosed in exclusively breast-fed infants. We performed a retrospective study of 13 infants diagnosed with allergic colitis in our unit between January 1997 and January 2004. All the infants had been exclusively breast-fed. In all patients, initial symptoms were digestive (12 with mucus and bloody stools). Onset of symptoms occurred at 0-3 months in 77 %. Laboratory data of the allergic compound were negative. The main locations were the descending and sigmoid colon (75 %). Biopsy demonstrated acute inflammation, with neutrophil infiltration and an increase in eosinophils. In all patients, initial treatment consisted of exclusion of cow's milk proteins from the mother's diet. Ten of the 13 patients showed no improvement, requiring exclusive administration of protein-free hydrolyzate. In 3 infants, breastfeed...

- by María Alonso
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- Infant, Newborn Infant, Colitis, Breast feeding

The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) is widely used in retroviral gene transfer vectors. However, this element contains an open-reading frame (ORF) encoding a truncated peptide of the woodchuck hepatitis virus X protein (WHX). Because we are developing a lentiviral vector for the gene therapy of Wiskott-Aldrich syndrome (WAS), we evaluated whether the WPRE was needed in the gene transfer cassette and tested the possibility of replacing it with a mutated derivative. The transcriptional activity of the WPRE was undetectable in the context of the lentiviral vector but the element was capable of translating a polypeptide. This capability was abrogated by mutating the WHX ORF translation start. The WPRE was required to express high levels of the transgene and for that, the native form or mutated derivatives functioned equivalently. The vector using a WAS gene promoter and the mut6 WPRE induced long-term expression of the WAS transgene in vivo, correcting cytoskeletal defects, thymocyte and B-cell numbers and improved the colitis of WAS-null mice. By providing additional evidence of efficacy of this WAS lentiviral vector with improved safety features, our results validate a mutated WPRE, which should be useful in future gene therapy applications.

- by Samia Martin
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- Gene Therapy, Protein synthesis, Biological Sciences, Cell line

Here, the study was conducted to evaluate the effect of pomegranate (Punica granatum) peel extract on infected rats with Blastocystis spp. Anti-protozoan activities were determined by monitoring Blastocystis spp. shedding in stools and histopathological changes of intestine of infected rats. Additionally, we evaluated the antioxidant properties of pomegranate peel extract on different groups through measuring the concentration of Malondialdehyde (MDA). In this work, Punica granatum peel extract-treatment lowered the shedding of cysts very close to nitazoxanide (NTZ) treatment. These data were statistically significant P value ≤ 0.0001. Pomegranate peel extract was found to have the highest anti-lipid peroxidation effect, assessed by measuring MDA level. The inhibitory effect of pomegranate peel extract on lipid peroxidation was significant when compared to NTZ-treated group (P value ≤ 0.0003). As well, histolopathological examination of the intestine showing that Blastocystis spp. were often observed in the infected group without treatment either within the luminal material or at the tip of the epithelium compared to the infected treated groups. Pomegranate peel extract can be used as alternative therapy for blastocystosis and for developing novel anti Blastocystis drugs. Additionally, these results show clinical evidence that pomegranate peel extract has components act as powerful antioxidants.

- by Nisreen Toni
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- Colitis

Background: The pathophysiology of inflammatory bowel disease (IBD) includes leukocyte infiltration, blood and lymphatic remodeling, weight loss and protein enteropathy. The roles of angiopoietin-2 (Ang-2) in initiating gut inflammation,... more

- by Michael Bernas
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- Lymphangiogenesis, Inflammatory Bowel Disease, Mice, Weight Loss

Background: T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model.

- by Bart Lambrecht
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- Dendritic Cells, Tacrolimus, Inflammatory Bowel Disease, Mice

Bile acid malabsorption (BAM) has been described in patients with collagenous colitis. There are no similar studies in lymphocytic colitis. The possibility that BAM might not necessarily be part of the microscopic colitis process and that both entities could simply be concomitant has not been evaluated. Our aim was to assess the frequency and severity of BAM in patients with microscopic colitis as well as in patients with previously unexplained functional chronic diarrhea. Likewise, we wanted to investigate the effect of cholestyramine on the induction and maintenance of remission of these conditions. A [75Se]HCAT abdominal retention test was performed in 26 patients with collagenous colitis, 25 with lymphocytic colitis, and 32 with previously unexplained functional chronic diarrhea. Patients with microscopic colitis who had BAM as well as a subgroup of eight collagenous colitis patients without BAM received treatment with cholestyramine. All patients with previously unexplained chronic diarrhea who had BAM were treated with cholestyramine. Twenty-two (43.1%) patients with microscopic colitis and 24 (75%) patients with previously unexplained functional chronic diarrhea presented with BAM. The frequency of BAM was higher in lymphocytic colitis than in collagenous colitis (60% vs 27%; P = 0.025). Cholestyramine induced clinical remission in 19 of 22 patients with microscopic colitis and BAM, none of eight patients with collagenous colitis without BAM, and all patients with previously unexplained chronic diarrhea and BAM. In conclusion, BAM seems to be common in patients with microscopic colitis—mainly in lymphocytic colitis—and in those with previously unexplained functional chronic diarrhea, suggesting that idiopathic BAM and microscopic colitis are often concomitant conditions. In this setting, cholestyramine seems to be highly effective in stopping diarrhea.

- by Bam Bam
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- Diarrhea, Prospective studies, Digestive and Liver Diseases, Chronic Disease

Lansoprazole is a potent proton pump inhibitor that has been well tolerated with minimal serious adverse events. One of the most commonly reported side effects is diarrhea in 3-8% of study patients. During 1997, approximately 850 veterans at our institution had their proton pump inhibitor converted from omeprazole to lansoprazole because of a formulary change. A number of patients subsequently developed chronic watery diarrhea. While evaluating six of these patients, we discovered microscopic colitis that resolved with discontinuation of lansoprazole. The diarrhea was described as three to 10 loose, nonbloody bowel movements per day with some abdominal cramping. Colonoscopy in five patients and flexible sigmoidoscopy in one patient revealed normal colonic mucosa, but random biopsies all supported microscopic colitis (five cases of lymphocytic colitis and one case of collagenous colitis). Complete symptom resolution occurred in all patients within 4 to 10 days of discontinuing lansoprazole. In all patients, follow-up biopsies demonstrated normalization of the colonic histology. This is the first published case series of patients with microscopic colitis that correlated clinically and histologically with the initiation and discontinuation of lansoprazole. (Am J Gastroenterol 2002;97:2908 -2913

- by Yogesh Maheshwari
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- Enzyme Inhibitors, Diarrhea, Complication, Colonoscopy

Please cite this article in press as: Ohland, C.L., et al., Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology (2013), http://dx.Summary Modulation of the gut microbiota with diet and probiotic bacteria can restore intestinal homeostasis in inflammatory conditions and alter behavior via the gut-brain axis. The purpose of this study was to determine whether the modulatory effects of probiotics differ depending on diet and mouse genotype. At weaning, wild type (WT) and IL-10 deficient (IL-10 À/À ) 129/SvEv mice were placed on a standard mouse chow or a Western-style diet (fat 33%, refined carbohydrate 49%) AE Lactobacillus helveticus ROO52 (10 9 cfu/d) for 21 days. Animal weight and food eaten were monitored weekly. Intestinal immune function was analysed for cytokine expression using the Meso Scale Discovery platform. Spatial memory and anxiety-like behavior was assessed in a Barnes maze. Terminal restriction fragment length polymorphism (TRFLP) was used to analyze the fecal microbiota. Both WT and IL-10 À/À mice on a Western diet had increased weight gain along with changes in gut microbiota and cytokine expression and altered anxiety-like behavior. The ability of L. helveticus to modulate these factors was genotype-and diet-dependent. Anxietylike behavior and memory were negatively affected by Western-style diet depending on inflammatory state, but this change was prevented with L. helveticus administration. However, probiotics alone decreased anxiety-like behavior in WT mice on a chow diet. Mice on the Western diet had decreased inflammation and fecal corticosterone, but these markers did not correlate with changes in behavior. Analysis of bacterial phyla from WTand IL-10 À/À mice showed discrete clustering of the groups to be associated with both diet and probiotic supplementation, with the diet-induced shift normalized to some degree by L. helveticus. These findings suggest that the type of diet consumed by the host and the presence or absence of active inflammation may significantly alter the ability of probiotics to modulate host physiological function. # Please cite this article in press as: Ohland, C.L., et al., Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology (2013), http://dx.

- by Aducio Thiesen
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- Probiotics, Cytokines, Inflammation, Anxiety
- by Carlo Calabrese
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- Intestinal Mucosa, Ulcerative colitis, Clinical Sciences, Colitis
- by Avinash Supe and +1
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- Immunology, Electron Microscopy, Inflammation, Immunohistochemistry

Two siblings suVering from mental retardation, progressive bronchiectasis, extensive warts, and persistent hepatitis B are described. The propositus also had an unusual physiognomy and non-specific colitis. Both patients had a marked... more

- by Yaakov Naparstek and +1
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- Dermatology, Adolescent, Mental Retardation, Hepatitis B

The authors present a neonatal case of allergic colitis, which manifested the difficulty of spontaneous defecation and irregular narrowing of distal rectum in contrast enema. Rectal suction biopsy showed positive acetylcholinesterase activity. These clinical, radiological and histological findings were indistinguishable from Hirschsprung's disease. Gastrointestinal symptoms were improved by the cessation of cow's milk formula. The present findings may impact on the less recognizable gastrointestinal manifestation of allergic colitis.

- by Akio Kubota
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- Acetylcholinesterase, Pediatric Surgery, Infant, Differential Diagnosis

Forty two infants below the age of 2 years presenting with chronic non-infective diarrhoea and shown to have histologically proved colitis were investigated over a five year period. Allergic colitis was the most common cause of colitis, accounting for 62% of the cases. Other colitides diagnosed included: non-specific colitis, autoimmune enterocolitis, and ulcerative colitis accounting for 10% each; severe combined immunodeficiency 7%, and Crohn's disease 3%. A positive family history and a personal history of atopy were obtained in 48% and 29% of the cases respectively. Serum immunoglobulin A, IgG 2 , and IgG 4 were very low in over 50% of the entire cohort of infants with colitis; 66% of those with severe combined immunodeficiency, autoimmune enterocolitis, and ulcerative colitis (n = 11) had low CD3 and CD4 T lymphocytes with an accompanying increase in CD8 in two thirds of those with severe combined immunodeficiency. T lymphocytes were normal in those with allergic colitis. Thus infants with proved non-infective colitis as a group show a high prevalence of IgA, IgG 2 , and IgG 4 deficiency. It is likely that this minor deficiency of mucosa associated immunoglobulin production has a role in the pathogenesis of the colitic process. (Arch Dis Child 1997;76:345-348)

- by Peter Milla and +1
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- Diarrhea, Autoimmune diseases, Ulcerative colitis, Chronic Disease

Background and aims Literature data about the outcome of segmental colitis associated with diverticulosis (SCAD) are scarce. Our aim was to assess the clinical outcome of SCAD according to the type of disease. Patients/methods Twenty-seven SCAD patients underwent a 5-year follow-up (13 males, 14 females; mean age, 63.71 years; range, 50–85 years). Eleven patients were affected by type A, eight by type B, four by type C and four by type D SCAD. During the follow-up, all type B, C, and D patients were under continuous medical treatment. Five type A patients refused any maintaining treatment, but accepted to undergo the clinical, endoscopic, and histological follow-up. Results/findings Five type A patients taking therapy (83.33%), two type A not taking therapy (50%), all type C patients (100%), five type B patients (62.5%) and none of type D (0%) were under continuous remission at the end of the follow-up. All type D patients required further steroid course to obtain remission, and two patients required azathioprine to maintain remission. Interpretations/conclusions SCAD B and D patients fail to maintain long-term remission, often requiring immunosuppressive treatment. SCAD A and C patients show a more benign course; however, long-term treatment guarantees longer remission also in those patients.

- by Marcello Picchio
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- Natural History, Treatment Outcome, Endoscopy, Inflammatory Bowel Disease

Abstract. Background: Heat shock proteins (Hsps) assist other
proteins in their folding and drive the degradation of defective
proteins. During evolution, these proteins have also acquired
other roles. Hsp10 is involved in immunomodulation and tumor
progression. Hsp90 stabilizes a range of “client” proteins
involved in cell signaling. The present study evaluated the
expression levels of Hsp10 and Hsp90 in normal mucosa and
adenocarcinoma samples of human large bowel. Materials and
Methods: Samples of normal mucosa and adenocarcinoma were
collected and Reverse transcriptase-polymerase chain reaction
RT-PCR, western blotting (WB) analyses, as well as
immunohistochemistry were performed to evaluate the expression
levels of Hsp10 and Hsp90. Results: RT-PCR showed a higher
gene expression of Hsp10 and Hsp90 in adenocarcinoma samples
compared to healthy mucosa. WB results confirmed these
findings. Immunohistochemistry revealed higher levels of Hsp10
in adenocarcinoma in both the epithelium and the lamina
propria, while Hsp90 expression was higher in the adenocarcinoma
samples only in the lamina propria. Conclusion:
Hsp10 and Hsp90 may be involved in large bowel carcinogenesis.

- by Giovanni Tomasello and +2
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- Colitis