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Background The intestinal microbiota plays a crucial role in the maintenance of gut homeostasis. Changes in crosstalk between the intestinal epithelial cells, immune cells and the microbiota are critically involved in the development of inflammatory bowel disease. In the experimental mouse model, the development of colitis induced by dextran sulfate sodium (DSS) promotes overgrowth of the opportunistic yeast pathogen Candida glabrata. Conversely, fungal colonization aggravates inflammatory parameters. In the present study, we explored the effect of C. glabrata colonization on the diversity of the gut microbiota in a DSS-induced colitis model, and determined the impact of soluble [beta]-glucans on C. glabrata-host interactions. Results Mice were administered a single inoculum of C. glabrata and were exposed to DSS treatment for 2 weeks in order to induce acute colitis. For [beta]-glucan treatment, mice were administered with soluble [beta]-glucans purified from C. glabrata (3 mg per mouse), orally and daily, for 5 days, starting on day 1. The number of C. glabrata colonies and changes in microbiota diversity were assessed in freshly collected stool samples from each tagged mouse, using traditional culture methods based on agar plates. An increase in Escherichia coli and Enterococcus faecalis populations and a reduction in Lactobacillus johnsonii and Bacteroides thetaiotaomicron were observed during colitis development. This decrease in L. johnsonii was significantly accentuated by C. glabrata overgrowth. Oral administration of [beta]-glucans to mice decreased the overgrowth of aerobic bacteria and IL-1[beta] expression while L. johnsonii and B. thetaiotaomicron populations increased significantly. [beta]-glucan treatment increased IL-10 production via PPAR[gamma] sensing, promoting the attenuation of colitis and C. glabrata elimination. Conclusions This study shows that the colonic inflammation alters the microbial balance, while [beta]-glucan treatment increases the anaerobic bacteria and promotes colitis attenuation and C. glabrata elimination. Keywords: [beta]-Glucans, Candida glabrata, Microbiota, Colitis, Anaerobic bacteria, Escherichia coli, Enterococcus faecalis, Author(s): Rogatien Charlet[sup.1,2,3] , Clovis Bortolus[sup.1,2,3] , Melissandre Barbet[sup.1,2,3] , Boualem Sendid[sup.1,2,3] and Samir Jawhara[sup.1,2,3] Background The commensal intestinal microbiota helps to maintain stability and prevent overgrowth or infection with [...]

The purpose of this study was to investigate whether luminal leptin alters ion transport properties of the intestinal epithelium under acute inflammatory conditions. Monolayers of human intestinal T84 epithelial cells and a rat model of chemotherapy-induced enterocolitis were used. Cells were treated with leptin and mounted in Ussing chambers to measure basal and secretagogue-induced changes in transepithelial short-circuit current (ISC). Furthermore, the role of MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating responses to leptin was investigated. Acute colitis in Sprague-Dawley rats was induced by intraperitoneal injection of 40 mg/kg methotrexate. Leptin (100 ng/ml) induced a time-dependent increase in basal [I.sub.SC] in [T.sub.84] intestinal epithelial cells (P < 0.01). Moreover, pretreatment of [T.sub.84] cells with leptin for up to 1 h significantly potentiated carbachol- and forskolin-induced increases in [I.sub.SC]. Pretreatment with an inhibitor of MAPK abolished the effect of leptin on basal, carbachol- and forskolin-induced chloride secretion (P < 0.05). However, the PI3K inhibitor, wortmannin, only blunted the effect of leptin on forskolin-induced increases in [I.sub.SC]. Furthermore, leptin treatment evoked both ERK1/2 and Akt1 phosphorylation in T84 cells. In the rat model, luminal leptin induced significant increases in [I.sub.SC] across segments of proximal and, to a lesser extent, distal colon (P < 0.05). We conclude that luminal leptin is likely an intestinal chloride secretagogue, particularly when present at elevated concentrations and/or in the setting of inflammation. Our findings may provide a mechanistic explanation, at least in part, for the clinical condition of secretory diarrhea both in hyperleptinemic obese patients and in patients with chemotherapy-induced intestinal inflammation. intestinal ion transport doi: 10.1152/ajpgi.00320.2009.

Serotonin (5-HT)-containing enterochromaffin (EC) cells of the intestine transduce chemical and mechanical stimuli from the intestinal lumen by releasing 5-HT on to afferent nerve terminals. Dysfunctional mucosal 5-HT signaling has been implicated in heightened visceral sensitivity and altered motility in patients with inflammatory bowel disease and in animal models. Our aim was to characterize the release and uptake of 5-HT in the mouse dextran sulfate sodium (DSS; 5% wt/vol) model of colitis. We made electrochemical recordings and used an ELISA assay to determine mucosal 5-HT release and uptake in untreated mice and mice with DSS-induced colitis. Peak and steady-state 5-HT concentrations were measured before and during blockade of the serotonin reuptake transporter (SERT) with 1 [micro]M fluoxetine. Electrochemical recordings showed that colons from DSS-treated mice had roughly twice the steady-state levels of extracellular 5-HT and compression-evoked 5-HT release compared with untreated mice. Fluoxetine doubled the compression-evoked and steady-state 5-HT levels in control and DSS mice. These data were supported by ELISA assays, which showed enhanced 5-HT release during colitis, by immunohistochemical analyses, which showed increases in EC cell numbers, and by real-time PCR, which identified a decrease in SERT mRNA expression in the mucosa during colitis. These data are the first to demonstrate 5-HT release close to its release site and near its site of action during DSS-colitis. We conclude that DSS-colitis increases 5-HT availability primarily by an increase in the numbers of EC cells and/or of content of 5-HT in these EC cells. inflammation; enterochromaffin cell; electrochemistry doi:10.1152/ajpgi.00318.2009.

Attaching and effacing bacterial pathogens attach to the apical surface of epithelial cells and disrupt epithelial barrier function, increasing permeability and allowing luminal contents access to the underlying milieu. Previous in vitro studies demonstrated that the neuropeptide vasoactive intestinal peptide (VIP) regulates epithelial paracellular permeability, and the high concentrations and close proximity of VIP-containing nerve fibers to intestinal epithelial cells would support such a function in vivo. The aim of this study was to examine whether VIP treatment modulated Citrobacter rodentium-induced disruption of intestinal barrier integrity and to identify potential mechanisms of action. Administration of VIP had no effect on bacterial attachment although histopathological scoring demonstrated a VIP-induced amelioration of colitis-induced epithelial damage compared with controls. VIP treatment prevented the infection-induced increase in mannitol flux a measure of paracellular permeability, resulting in levels similar to control mice, and immunohistochemical studies demonstrated that VIP prevented the translocation of tight junction proteins: zonula occludens-1, occludin, and claudin-3. Enteropathogenic Escherichia coli (EPEC) infection of Caco-2 monolayers confirmed a protective role for VIP on epithelial barrier function. VIP prevented EPEC-induced increase in long myosin light chain kinase (MLCK) expression and myosin light chain phosphorylation (p-MLC). Furthermore, MLCK inhibition significantly attenuated bacterial-induced epithelial damage both in vivo and in vitro. In conclusion, our results indicate that VIP protects the colonic epithelial barrier by minimizing bacterial-induced redistribution of tight junction proteins in part through actions on MLCK and MLC phosphorylation. tight junctions; Caco-2 cells; transepithelial resistance doi: 10.1152/ajpgi.90551.2008

Several lines of studies have suggested that activins are critical mediators of inflammation and tissue repair. As activins and their receptors are expressed in the gastrointestinal tract, we tested the hypothesis that activin signaling is involved in the development of colitis by using two murine models of colitis induced by dextran sodium sulfate (DSS) or in mdr1a-/- mice. By immunohistochemistry, expression of activins was found increased in both models and correlated with the severity of inflammation. Activin expression was observed in macrophages as well as in some nonmacrophage cells. Furthermore, while activin receptors are normally expressed in colonic epithelial cells, their expression was further increased in both epithelial cells and inflammatory cells in inflamed colonic mucosa. Moreover, in vitro studies showed that activin A inhibited proliferation and induced apoptosis of intestinal epithelial cells, and this growth inhibition was largely reversed by administration of the activin inhibitor, follistatin. Because we also observed an increased number of apoptotic epithelial cells in both colitis models, the upregulation of activins occurring in colitis could be involved both in the inflammatory process and in growth inhibition of the intestinal epithelium. Importantly, in vivo administration of follistatin attenuated inflammatory cell infiltration during colitis. Rectal bleeding was reduced, and the integrity of epithelium was preserved in the DSS/follistatin-treated group compared with the group treated with DSS alone. Bromodeoxyuridine incorporation studies showed an increase in proliferative epithelial cells in the DSS/ follistatin-treated group, suggesting that follistatin accelerates epithelial cell proliferation/repair during colitis. Overall, our results reveal that activin signaling may play an important role in the pathogenesis and resolution of colitis. These findings suggest new therapeutic options in inflammatory bowel diseases. follistatin; inflammation; proliferation doi: 10.1152/ajpgi.90631.2008

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring [CD45Rb.sup.hi] T cells into [RAG1.sup.-/-] mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in [RAG1.sup.-/-] mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-[alpha], and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, [PGE.sub.2], and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing. innate immunity; inflammatory bowel disease; antigen presenting cells

Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGFI-stimulated growth is augmented by the [[alpha].sub.v][[beta].sub.3] integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although [[alpha].sub.v][[beta].sub.3] integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 [+ or -] 10% and 90 [+ or -] 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 [+ or -] 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3[beta] phosphorylation in muscle cells of TNBS-treated rats were also increased by 140-180%. TNBS treatment increased basal muscle cell proliferation by 130 [+ or -] 15% and decreased apoptosis by 20 [+ or -] 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an [[alpha].sub.v][[beta].sub.3] integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of [[alpha].sub.v][[beta].sub.3] integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease. Crohn's disease; insulin-like growth factor

Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and impairment of norepinephrine release from sympathetic varicosities. The sympathetic innervation of the GI tract modulates motility, blood flow, and secretion, and therefore defective norepinephrine release may contribute to symptom generation in IBD. Accordingly, our aim here was to utilize the mouse model of dextran sulfate sodium (DSS; 5% wt/vol) of IBD to determine how norepinephrine release is reduced during GI inflammation. We hypothesized that the inflammation-induced reduction in norepinephrine release was due to inhibition of voltage-gated [Ca.sup.2+] current ([I.sub.Ca]) in prevertebral sympathetic neurons. We compared [[sup.3]H]norepinephrine release in the colon and jejunum and [I.sub.Ca] amplitude in superior mesenteric ganglion (SMG) neurons from control mice and mice with DSS-induced colitis. Changes to voltage-gated [Ca.sup.2+] channels were investigated by fura 2-AM [Ca.sup.2+] imaging, perforated patch-clamp electrophysiology, and real-time PCR. Depolarization-induced norepinephrine release from the inflamed colon and uninflamed jejunum was significantly impaired in mice treated with DSS, as was depolarization-induced [Ca.sup.2+] influx in SMG neurons. Colitis reduced [I.sub.Ca] in SMG neurons by inhibiting [omega]-conotoxin GVIA (300 nM)-sensitive N-type [Ca.sup.2+] channels. The [omega]-conotoxin GVIA-sensitive component of norepinephrine release was significantly smaller in the colon during colitis. The inhibition of [I.sub.Ca] was accompanied by a decrease in mRNA encoding the [Ca.sup.2+] channel alpha subunit (CaV 2.2) and a rightward shift in the voltage dependence of activation of [I.sub.Ca]. These findings suggest that DSS-induced colitis attenuates norepinephrine release in the colon and jejunum due to inhibition of N-type voltage-gated [Ca.sup.2+] channels. This may contribute to functional alterations in both inflamed and uninflamed regions of the GI tract during inflammation. sympathetic postganglionic neuron; inflammation; calcium current

Here, we describe an N-ethyl-N-nitrosourea (ENU)-induced mis-sense error in the membrane-bound transcription factor peptidase site 1 (S1P)-encoding gene (Mbtps1) that causes enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis. S1P cleaves and activates cAMP response element binding protein/ATF transcription factors, the sterol regulatory element-binding proteins (SREBPs), and other proteins of both endogenous and viral origin. Because S1P has a nonredundant function in the ATF6-dependent unfolded protein response (UPR), woodrat mice show diminished levels of major endoplasmic reticulum chaperones GRP78 (BiP) and GRP94 in the colon upon DSS administration. Experiments with bone marrow chimeric mice reveal a requirement for S1P in nonhematopoietic cells, without which a diminished UPR and colitis develop. ER stress | UPR | site 1 protease | inflammatory bowel disease

Recent findings indicate that dextran sodium sulfate (DSS)-induced colitis is associated with a prothrombogenic phenotype, with P-selectin playing a major role in platelet recruitment. It has been suggested that probiotics may ameliorate colonic inflammation. We therefore investigated how treatment with Lactobacillus reuteri influenced P-selectin expression, leukocyte and platelet endothelial cell interactions, and colitis severity in DSS-treated rats. Rats were divided into the following four groups: nontreated, DSS treated (5% in drinking water for 9 days), L. reuteri, and L. reuteri and DSS treated. The rats were anesthetized with Inactin (120 mg/kg ip), and the dual radiolabeled monoclonal antibody technique was used to quantify P-selectin expression. Leukocyte-endothelial and platelet-endothelial cell interactions were studied in colonic venules with intravital microscopy. Colitis severity was assessed using a disease activity index. Disease activity index increased, as did the expression of P-selectin in the entire colon after DSS treatment, but both were reduced to control levels with L. reuteri pretreatment. The increased platelet- and leukocyte-endothelial cell interactions after DSS treatment were abolished by pretreatment with L. reuteri. L. reuteri protects against DSS-induced colitis in rats. The protection is associated with reduced P-selectin expression and a decrease in leukocyte- and platelet-endothelial cell interactions. dextran sulfate sodium; disease activity index

One of the main secondary toxic side effects of antimitotic agents used to treat cancer patients is intestinal mucositis. This one is characterized by compromised digestive and absorptive functions, barrier integrity, and immune competence. At the same time, food intake is decreased, which may induce intestinal damages per se. The aim of the study was to characterize which alterations are specific to methotrexate, independently of the anorexic effect of the drug. Male Sprague-Dawley rats received subcutaneously saline solution as control group or 2.5 mg/kg of methotrexate during 3 days (D0-D2). Methotrexate-treated rats were compared with ad libitum and pair-fed controls. Histological examinations and specific markers of the immune and nonimmune gut barrier function were assessed at D4 or D7. Compared with ad libitum and pair-fed controls, methotrexate induced at D4 villus atrophy associated with epithelial necrosis. Mucosal protein synthesis rate and mucin contents of methotrexate treated rats were reduced. At the same time, cathepsin D proteolytic activity was increased compared with ad libitum and pair-fed controls, whereas calpain activity was increased when compared with the only pair-fed controls. These intestinal lesions were associated with various metabolic disturbances such as increased TNF-[alpha] level and inflammation score in the jejunum but also disturbances of amino acid concentrations in the duodenum and plasma. At D7, these alterations were partially or completely normalized. In addition to the consequences of a low food intake, methotrexate further impairs different biological processes leading to a dramatic loss of gut homeostasis. Targeted nutritional management of chemotherapy receiving patients should be set up to prevent or limit such alterations. chemotherapy; intestine; nutrition; mucin; protein turnover

Continuous disruption of circadian rhythms, as seen in human shift workers, has been associated with the development of a number of adverse mental and physiological conditions. However, scientific evidence linking circadian disruption to overall health, particularly in animal models, is not well documented. In this study, we have demonstrated that exposing C57BL/6J mice to 12-h phase shifts every 5 days for 3 mo had no effect on body weight or intestinal physiology. However, when animals were further challenged with dextran sodium sulfate to induce colitis, chronic shifting of the light-dark cycle led to a dramatic increase in the progression of the colitis as indicated by reduced body weight, abnormal intestinal histopathology, and an exacerbated inflammatory response. These data indicate that circadian disruption is an important predisposing factor that may provoke the onset or worsening of various disease states such as inflammatory disorders. This study provides further evidence for continued investigations using animal models of circadian disruption to examine the consequences of circadian disruption on health when organisms are faced with a 'challenging' environment. circadian rhythms; shift work; circadian disorganization

[Na.sup.+]/[H.sup.+] exchanger 3 (NHE3) provides a major route for intestinal [Na.sup.+] absorption. NHE3 has been considered a target of proinflammatory cytokines and enteropathogenic bacteria, and impaired NHE3 expression and/or activity may be responsible for inflammation-associated diarrhea. However, the possibility of loss of NHE3 function reciprocally affecting gut immune homeostasis has not been investigated. In this report, we describe that NHE3-deficient mice spontaneously develop colitis restricted to distal colonic mucosa. [NHE3.sup.-/-] mice housed in a conventional facility exhibited phenotypic features such as mild diarrhea, occasional rectal prolapse, and reduced body weight. Genomewide microarray analysis identified not only a large group of transport genes that potentially represent an adaptive response, but also a considerable number of genes consistent with an inflammatory response. Histological examination demonstrated changes in the distal colon consistent with active inflammation, including crypt hyperplasia with an increased number of 5-bromo-2'deoxyuridine-positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of [pSer.sup.276]-Re1A-positive cells, and a significant decrease in periodic acid-Schiff-positive goblet cells. Real-time PCR demonstrated elevated expression of inducible nitric oxide synthase (38-fold), TNF-[alpha] (6-fold), macrophage inflammatory protein-2 (48fold), and IL-18 (3-fold) in the distal colon of [NHE3.sup.-/-] mice. [NHE3.sup.-/-] mice showed enhanced bacterial adhesion and translocation in the distal colon. Colitis was ameliorated by oral administration of broad-spectrum antibiotics. In conclusion, NHE3 deficiency leads to an exacerbated innate immune response, an observation suggesting a potentially novel role of NHE3 as a modifier gene, which when downregulated during infectious or chronic colitis may modulate the extent and severity of colonic inflammation. colon; knockout; microarray; S1c9a3

The mechanisms underlying the susceptibility of individuals with caspase recruitment domain 15 (CARD15) mutations and corresponding abnormalities of nucleotide-binding oligomerization domain 2 (NOD2) protein to Crohn disease are still poorly understood. One possibility is based on previous studies showing that muramyl dipeptide (MDP) activation of NOD2 negatively regulates TLR2 responses and that absence of such regulation leads to heightened Th1 responses. We now report that administration of MDP protects mice from the development of experimental colitis by downregulating multiple TLR responses, not just TLR2. The basis of these in vivo findings was suggested by in vitro studies of DCs, in which we showed that prestimulation of cells with MDP reduces cytokine responses to multiple TLR ligands and this reduction is dependent on enhanced IFN regulatory factor 4 (IRF4) activity. Further studies of mouse models of colitis showed that this inhibitory role of IRF4 does in fact apply to MDP-mediated protection from colitis, since neither IRF4-deficient mice nor mice treated with siRNA specific for IRF4 were protected. These findings indicate that MDP activation of NOD2 regulates innate responses to intestinal microflora by downregulating multiple TLR responses and suggest that the absence of such regulation leads to increased susceptibility to Crohn disease., Introduction Nucleotide-binding oligomerization domain 2 (NOD2) is a cytosolic protein that has an essential role in innate immunity as a sensor of a peptide derived from bacterial peptidoglycan (PGN), muramyl [...]

The role of NO in inflammatory bowel disease is controversial. Studies indicate that endothelial nitric oxide synthase (eNOS) might be involved in protecting the mucosa against colonic inflammation. The aim of this study was to investigate the involvement of nitric oxide (NO) in regulating colonic mucosal blood flow in two different colitis models in rats. In anesthetized control and colitic rats, the distal colon was exteriorized and the mucosa visualized. Blood flow (laser-Doppler flowmetry) and arterial blood pressure were continuously monitored throughout the experiments, and vascular resistance was calculated. Trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) was used to induce colitis. All groups were given the NOS inhibitor [N.sup.[omega]]-nitro-L-arginine (L-NNA) or the inducible NOS (iNOS) inhibitor L-[N.sup.6]-(1-iminoethyl)-lysine (L-NIL). iNOS, eNOS, and neuronal NOS (nNOS) mRNA in colonic samples were investigated with real-time RT-PCR. Before NOS inhibition, colonic mucosal blood flow, expressed as perfusion units, was higher in both colitis models compared with the controls. The blood flow was reduced in the TNBS- and DSS-treated rats during L-NNA administration but was not altered in the control group. Vascular resistance increased more in the TNBS- and DSS-treated rats than in the control rats, indicating a higher level of vasodilating NO in the colitis models. L-NIL did not alter blood pressure or blood flow in any of the groups, iNOS and eNOS mRNA increased in both colitis models, whereas nNOS remained at the control level. TNBS- and DSS-induced colitis results in increased colonic mucosal blood flow, most probably due to increased eNOS activity. Trinitrobenzene sulfonic acid; dextran sulfate sodium; inducible nitric oxide synthase; neuronal nitric oxide synthase

Activation of TLRs by bacterial products results in rapid activation of genes encoding products designed to protect the host from perturbing microbes. In the intestine, which is colonized by a large and diverse population of commensal bacteria, TLR signaling may not function in a simple on/off mode. Here, we show that the flagellin receptor TLR5 has an essential and nonredundant role in protecting the gut from enteric microbes. Mice lacking TLR5 (TLR5KO mice) developed spontaneous colitis, as assessed by well-defined clinical, serologic, and histopathologic indicators of this disorder. Compared with WT littermates, TLR5KO mice that had not yet developed robust colitis exhibited decreased intestinal expression of TLR5-regulated host defense genes despite having an increased bacterial burden in the colon. In contrast, such TLR5KO mice displayed markedly increased colonic expression of hematopoietic-derived proinflammatory cytokines, suggesting that elevated levels of bacterial products may result in activation of other TLRs that drive colitis in TLR5KO mice. In accordance, deletion of TLR4 rescued the colitis of TLR5KO mice in that mice lacking both TLR4 and TLR5 also had elevated bacterial loads in the colon but lacked immunological, histopathological, and clinical evidence of colitis. That an engineered innate immune deficiency ultimately results in spontaneous intestinal inflammation supports the notion that an innate immune deficiency might underlie some instances of inflammatory bowel disease., Introduction Detection of bacterial products by germline-encoded receptors of the innate immune system, particularly TLRs, results in rapid activation of gene expression designed to protect the host from the perturbing [...]

The induction and perpetuation of chronic colitis are thought to involve a complex set of adhesive interactions between T cells and endothelial cells located on the vasculature within secondary lymphoid tissue and the intestine. The objective of this study was to assess the roles of T cell-associated CD18, CD62L (L-selectin), ICAM-1, and P-selectin glycoprotein ligand-1 (PSGL-1) in the induction of chronic colitis in mice. CD[4.sup.+]CD2[5.sup.-] T cells derived from either wild-type (WT), CD18-deficient [CD18 knockout (KO)], CD62L KO, ICAM-1 KO, or PSGL-1 KO mice were adoptively transferred into recombinase activating gene-1 (RAG-1)-deficient mice (RAG KO mice) to assess the potential of these T cells to induce chronic colitis. At 8-10 wk following T cell transfer, we observed moderate to severe colitis as assessed by increases in colon weight-to-length ratios and by blinded histopathological analysis. In contrast, we found that transfer of CD 18 KO T cells into RAG KO recipients resulted in the significant attenuation of colonic inflammation in these mice. Furthermore, we observed fewer infiltrating CD[4.sup.+] T cells in the colonic lamina propria in the CD18 KO [right arrow] RAG KO group compared with the WT [right arrow] RAG KO group. Finally, message levels of colonic TNF-[alpha], IL-1[beta], and IFN-[gamma] were significantly reduced in CD18 KO [right arrow] RAG KO mice compared with colitic control animals. We conclude that T cell-associated CD18, but not CD62L, ICAM-1, or PSGL-1, is required for the development of chronic colitis. T cell trafficking; inflammation; inflammatory bowel disease; cytokines; intracellular adhesion molecule-1; P-selectin glycoprotein ligand-1 doi:10.1152/ajpgi.00573.2006

Cytomegalovirus infection occurs in immunocompromised patients. We present a 45-year-old male with no prior medical history who presented to the hospital with weight loss and nonbloody diarrhea. During hospitalization, he developed severe hematochezia and hypotension. Colonoscopy revealed dusky, friable mucosa. The patient arrested and was resuscitated. Specimen from emergent colectomy showed ischemic changes secondary to cytomegalovirus infection of endothelium and small-vessel thrombosis. An HIV test was subsequently positive with CD4 count of 2 per microliter. The patient was treated with antiretroviral therapy and ganciclovir. He survived postoperative infections and was eventually discharged. In summary, this case of near-fatal cytomegalovirus colitis represents an unusual presentation of undiagnosed HIV infection. Cytomegalovirus infection should be included in the differential diagnosis of immunocompromised patients with gastrointestinal symptoms. Hematochezia may be from intestinal ulceration or severe ischemic damage. Antiretroviral therapy and ganciclovir or foscarnet should be initiated promptly. Surgery is indicated in life-threatening hemorrhage or obvious bowel necrosis.

Background: [α.sub.1]-Acid glycoprotein ([α.sub.1]-AGP) is an acute phase protein in most mammalian species whose concentration rises 2-5-fold during an acute phase reaction. Its serum concentration has often been used as [...]

Stress can reactivate colitis in mice and CD4+ T cells appear to be involved. Stress reduces levels of mucin and increases mucosal permeability, which would allow sensitizing agents to enter the mucosa more easily.