Estradiol Has Differential Effects on Acute Colonic Inflammation in the Presence and Absence of Estrogen Receptor β Expression

Background

Inflammatory bowel disease (IBD) increases the risk of developing colon cancer. This risk is higher in men compared to women, implicating a role for female hormones in the protection against this disease. Studies from our laboratory demonstrated that estradiol (E₂) protects against inflammation-associated colon tumor formation when administered following chemical carcinogen and induction of chronic colitis.

Aim

This study seeks to better understand the effect of E₂ on acute colitis in the presence and absence of estrogen receptor β (ERβ).

Methods

Inflammation was induced by 2,4,6-trinitrobenzenesulfonic acid in wild-type (WT) and ERβ knockout (ERβKO) mice implanted with a control or E₂-containing pellet and killed 5 days later. Inflammation and injury were scored by a pathologist. Apoptosis and proliferation were assessed by immunohistochemistry. Cytokines were measured by multiplex analysis.

Results

E₂ treatment reduced inflammation in the middle colon in WT mice and the distal colon in ERβKO mice compared to control mice. WT mice had reduced IL-6, IL-12, IL-17, GM-CSF, IFN-γ, MCP-1, MIP-1α, and TNF-α, and ERβKO had reduced IL-6 and IFN-γ expression in response to E₂. Injury scores were lower in E₂-treated ERβKO mice compared to control ERβKO mice. ERβKO mice had increased proliferation in the basal third of crypts in the distal colon and decreased apoptosis in the proximal colon.

Conclusions

These data suggest that E₂ has differential protective effects against acute colitis in the presence or absence of ERβ and provide insight into how E₂ may protect against IBD.

     

Aryl Hydrocarbon Receptor Activation Down-Regulates IL-7 and Reduces Inflammation in a Mouse Model of DSS-Induced Colitis

Background and Aims

The pathogenesis of inflammatory bowel disease (IBD) is associated with dysregulation of intestinal immune system. Aryl hydrocarbon receptor (AHR) is believed to control the chronic inflammation in the gut. Besides, interleukin-7 (IL-7) is proved to be an important cytokine that activates mucosal inflammation in IBD. Moreover, intraepithelial lymphocytes (IELs) are one of the key immunological compartments involved in regulating intestinal inflammation. In this study, we investigated the function of 6-formylindolo (3,2-b) carbazole (Ficz), a ligand of AHR, on IL-7, colitis, and IEL phenotypes.

Methods

Colitis was induced by administration of dextran sulfate sodium (DSS) to wild-type C57BL/6J mice for 7 days. Mice were weighted, colon tissues were collected and measured, and histology analyses were performed. IELs were isolated from colon, and the phenotype and activation of IELs were examined using flow cytometry detection. The expression of AHR and IL-7 was measured by immunofluorescence, Western blot, and RT-PCR.

Results

Ficz down-regulated epithelial-derived IL-7 expression in mice with DSS-induced colitis and ameliorated DSS-induced colitis. Ficz also decreased CD8αβ⁺ and CD8⁺ IEL subpopulations, enhanced TCRγδ⁺ IEL subpopulation, and reduced the percentage of activated CD4⁺ and CD8⁺ subpopulations.

Conclusions

Ficz could down-regulate epithelial-derived IL-7 expression in mice with DSS-induced colitis and inhibit inflammation in the gastrointestinal tract of mice. AHR-related compounds might be the new and promising therapeutic medicaments for the treatment of patients with IBD.

     

Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease

Background

Approximately 15–20% of ulcerative colitis patients and 20–40% of those with Crohn’s disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action.

Aims

This report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action.

Methods

We report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy.

Results

Vedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn’s disease.

Conclusions

These cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.

     

Severe Intestinal Inflammation in the Small Intestine of Mice Induced by Controllable Deletion of Claudin-7

Background

As a potential tumor suppressor gene, Claudin-7 (Cldn7), which is a component of tight junctions, may play an important role in colorectal cancer occurrence and development.

Aims

To generate a knockout mouse model of inducible conditional Cldn7 in the intestine and analyze the phenotype of the mice after induction with tamoxifen.

Methods

We constructed Cldn7-flox transgenic mice and crossed them with Villin-CreERT2 mice. The Cldn7 inducible conditional knockout mice appeared normal and were well developed at birth. We induced Cldn7 gene deletion by injecting different dosages of tamoxifen into the mice and then conducted a further phenotypic analysis.

Results

After induction for 5 days in succession at a dose of 200 µl tamoxifen in sunflower oil at 10 mg/ml per mouse every time, the mice appeared dehydrated, had a lower temperature, and displayed inactivity or death. The results of hematoxylin–eosin staining showed that the intestines of the Cldn7 inducible conditional knockout mice had severe intestinal defects that included epithelial cell sloughing, necrosis, inflammation and hyperplasia. Owing to the death of ICKO mice, we adjusted the dose of tamoxifen to a dose of 100 µl in sunflower oil at 10 mg/ml per mouse (aged more than 8 weeks old) every 4 days. And we could induce atypical hyperplasia and adenoma in the intestine. Immunofluorescent staining indicated that the intestinal epithelial structure was destroyed. Electron microscopy experimental analysis indicated that the intercellular gap along the basolateral membrane of Cldn7 inducible conditional knockout mice in the intestine was increased and that contact between the cells and matrix was loosened.

Conclusions

We generated a model of intestinal Cldn7 inducible conditional knockout mice. Intestinal Cldn7 deletion induced by tamoxifen initiated inflammation and hyperplasia in mice.

     

Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases

Purpose

Interleukin-6 (IL-6) production and signalling are increased in the inflamed mucosa in inflammatory bowel diseases (IBD). As published serum levels of IL-6 and its soluble receptors sIL-6R and sgp130 in IBD are from small cohorts and partly contradictory, we systematically evaluated IL-6, sIL-6R and sgp130 levels as markers of disease activity in Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

Consecutive adult outpatients with confirmed CD or UC were included, and their disease activity and medication were monitored. Serum from 212 CD patients (815 measurements) and 166 UC patients (514 measurements) was analysed, and 100 age-matched healthy blood donors were used as controls.

Results

IL-6 serum levels were significantly elevated in active versus inactive CD and UC, also compared with healthy controls. However, only a fraction of IBD patients showed increased serum IL-6. IL-6 levels ranged up to 32.7 ng/mL in active CD (>?5000-fold higher than in controls), but also up to 6.9 ng/mL in inactive CD. Increases in active UC (up to 195 pg/mL) and inactive UC (up to 27 pg/mL) were less pronounced. Associations between IL-6 serum levels and C-reactive protein concentrations as well as leukocyte and thrombocyte counts were observed. Median sIL-6R and sgp130 levels were only increased by up to 15%, which was considered of no diagnostic significance.

Conclusions

Only a minority of IBD patients shows elevated IL-6 serum levels. However, in these patients, IL-6 is strongly associated with disease activity. Its soluble receptors sIL-6R and sgp130 do not appear useful as biomarkers in IBD.

     

Depletion of Foxp3+ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury

Background

Accumulating evidence suggests that Foxp3+ regulatory T (Treg) cells act as inhibitory mediators of inflammation; however, the in vivo mechanism underlying this protection remains elusive in liver diseases.

Aims

To clarify the in vivo role of Foxp3+ Treg cells in liver fibrosis, we used the DEREG mouse, which expresses the diphtheria toxin receptor under control of the Foxp3 promoter, allowing for specific deletion of Foxp3+ Treg cells.

Methods

Bile duct ligation-induced liver injury and fibrosis were assessed by histopathology, fibrogenic gene expression, and measurement of cytokine and chemokine levels.

Results

Depletion of Foxp3+ Treg cells enhanced Th17 cell response as demonstrated by the increase of IL-17+ cells and related gene expressions including Il17f, Il17ra, and Rorgt in the fibrotic livers of DEREG mice. Of note, infiltration of CD8+ T cells and Cd8 gene expression was significantly increased in the livers of DEREG mice. Consistent with increased IL-17+ and CD8+ T cell responses, DEREG mice generated higher levels of inflammatory cytokines (TNF-α, IL-6, and IL-12p70) and chemokines (MCP-1, MIP-1α, and RANTES). These results were concordant with severity of liver fibrosis and hepatic enzyme levels (ALT and ALP).

Conclusions

The present findings demonstrate that Foxp3+ Treg cells inhibit the profibrogenic inflammatory milieu through suppression of pro-fibrogenic CD8+ and IL-17+ T cells.

     

Transgenic Expression of Vitamin D Receptor in Gut Epithelial Cells Ameliorates Spontaneous Colitis Caused by Interleukin-10 Deficiency

Background

Vitamin D deficiency is common in patients with inflammatory bowel diseases. The vitamin D receptor (VDR) is a nuclear hormone receptor mediating the activity of vitamin D hormone. Our previous studies showed that intestinal epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this activity is independent of non-epithelial immune VDR actions. Interleukin (IL)-10-deficient mouse is a chronic colitis model that develops colitis due to aberrant immune responses. Here we used IL-10 null (IL-10KO) model to assess the anti-colitic activity of epithelial VDR in the setting of an aberrant immune system.

Methods

We crossed IL-10KO mice with villin promoter-driven human (h) VDR transgenic (Tg) mice to generate IL-10KO mice that carry the hVDR transgene in intestinal epithelial cells (IL-10KO/Tg). IL-10KO and IL-10KO/Tg littermates were studied in parallel and followed for up to 25 weeks.

Results

By 25 weeks of age, accumulatively 79 % IL-10KO mice developed prolapse, whereas only 40 % IL-10KO/Tg mice did so (P < 0.001). Compared with IL-10KO mice, IL-10KO/Tg littermates showed markedly reduced mucosal inflammation in both small and large intestines, manifested by attenuation in immune cell infiltration and histological damage and a marked decrease in pro-inflammatory cytokine production. IL-10KO/Tg mice also showed reduced intestinal epithelial cell apoptosis as a result of diminished PUMA induction and caspase 3 activation.

Conclusion

These observations demonstrate that targeting hVDR expression to intestinal epithelial cells is sufficient to attenuate spontaneous colitis caused by an ill-regulated immune system, confirming a critical role of the epithelial VDR signaling in blocking colitis development.

     

Altered Gut Microbiota Composition and Immune Response in Experimental Steatohepatitis Mouse Models

Background

Although several types of diet have been used in experimental steatohepatitis models, comparison of gut microbiota and immunological alterations in the gut among diets has not yet been performed.

Aim

We attempted to clarify the difference in the gut environment between mice administrated several experimental diets.

Methods

Male wild-type mice were fed a high-fat (HF) diet, a choline-deficient amino acid-defined (CDAA) diet, and a methionine-choline-deficient (MCD) diet for 8 weeks. We compared the severity of steatohepatitis, the composition of gut microbiota, and the intestinal expression of interleukin (IL)-17, an immune modulator.

Results

Steatohepatitis was most severe in the mice fed the CDAA diet, followed by the MCD diet, and the HF diet. Analysis of gut microbiota showed that the composition of the Firmicutes phylum differed markedly at order level between the mice fed the CDAA and HF diet. The CDAA diet increased the abundance of Clostridiales, while the HF diet increased that of lactate-producing bacteria. In addition, the CDAA diet decreased the abundance of lactate-producing bacteria and antiinflammatory bacterium Parabacteroides goldsteinii in the phylum Bacteroidetes. In CDAA-fed mice, IL-17 levels were increased in ileum as well as portal vein. In addition, the CDAA diet also elevated hepatic expression of chemokines, downstream targets of IL-17.

Conclusions

The composition of gut microbiota and IL-17 expression varied considerably between mice administrated different experimental diets to induce steatohepatitis.

     

College inflammatory bowel disease (C-IBD) day: a targeted approach to shared decision-making in college age students with IBD—a 2-year pilot project

Background

Adherence to treatment is a key therapeutic goal in chronic disorders including diabetes, inflammatory bowel disease (IBD), and hypertension. Non-adherence has been associated with increased health care costs. Previous studies have evaluated adherence to treatment in inflammatory bowel disease, as well as predictors of non-adherence. Higher belief of necessity for medications and membership of IBD patient organizations have been associated with higher medication adherence.

Aim

This study aimed to identify patient reported factors that influence understanding of IBD in college age patients with IBD.

Methods

We conducted questionnaire based survey among a group of college age patients with IBD who attended a structured program. The program consisted of a clinical appointment with an IBD physician, lecture by an IBD physician, followed by interactive segment between patients. Educational material was available for patients to review. In addition, opportunity was given to patients to share their story and ask questions in a safe environment.

Results

A total of 26 patients participated in the two C-IBD sessions over a 2-year period. Twenty-three were enrolled in college, 1 was a recent graduate, and 2 were of college age but not enrolled. All patients thought the program was beneficial, 96% rated the overall experience as “awesome” or “very good.” Seventy-six percent of patients reported sharing their story as the most beneficial. Only 19% found the physician lecture beneficial.

Conclusion

A targeted approach to a vulnerable population with IBD is an additional useful tool in improving understanding of IBD. This may lead to improved compliance with management plans.

     

Bactericidal/permeability increasing protein gene polymorphism and inflammatory bowel diseases: meta-analysis of five case–control studies

Objective

Bactericidal/permeability increasing protein (BPI) gene polymorphisms have been extensively investigated in terms of their associations with inflammatory bowel disease (IBD), with contradictory results. The aim of this meta-analysis was to evaluate associations between BPI gene polymorphisms and the risk of IBD, Crohn’s disease (CD), and ulcerative colitis (UC).

Methods

Eligible studies from PubMed, Embase, and Cochrane library databases were identified.

Results

Ten studies (five CD and five UC) published in five papers were included in this meta-analysis. G645A polymorphism was associated with a decreased risk of UC in allele model, dominant model, and homozygous model.

Conclusions

Our data suggested that BPI G645A polymorphism was associated with a decreased risk of UC; the BPI G645A polymorphism was not associated with the risk of CD.

     

Die Rolle der Selbsthilfegruppen in der Onkologie

Background

Little is known about self-help associations and their possibilities. Obstacles often prevent early contacts between affected people.

Objectives

The psychosocial support given by self-help associations in different phases is evaluated.

Materials and methods

Based on the experience of the Deutsche ILCO and from cooperation with other organizations and institutions, various dimensions of self-help groups are investigated.

Results

On the professional side, there is a lack of knowledge and of attitude. Suitable structures are rare.

Conclusions

The removal of barriers and development of effective structures are overdue.

     

The effect of interleukin-22 treatment on autoimmune diabetes in the NOD mouse

Aims/hypothesis

The aim of this study was to determine whether therapy with the cytokine IL-22 could be used to prevent the development of, or treat, autoimmune diabetes in the NOD mouse.

Methods

Six-week-old NOD mice were administered bi-weekly either recombinant mouse IL-22 (200 ng/g) or PBS (vehicle control) intraperitoneally until overt diabetes was diagnosed as two consecutive measurements of non-fasting blood glucose ≥ 11 mmol/l. At this time, NOD mice in the control arm were treated with LinBit insulin pellets and randomised to bi-weekly therapeutic injections of either PBS or IL-22 (200 ng/g) and followed until overt diabetes was diagnosed, as defined above.

Results

IL-22 therapy did not delay the onset of diabetes in comparison with the vehicle-treated mice. We did not observe an improvement in islet area, glycaemic control, beta cell residual function, endoplasmic reticulum stress, insulitis or macrophage and neutrophil infiltration as determined by non-fasting blood glucose, C-peptide and histological scoring. Therapeutic administration of IL-22 did not reduce circulating lipopolysaccharide, a marker of impaired gut mucosal integrity.

Conclusions/interpretation

Our study suggests that, at this dosing regimen introduced either prior to overt diabetes or at diagnosis of diabetes, recombinant mouse IL-22 therapy cannot prevent autoimmune diabetes, or prolong the honeymoon period in the NOD mouse.

     

Remote Patient Monitoring in IBD: Current State and Future Directions

Purpose of Review

Mobile apps are now increasingly used in conjunction with telemedicine and wearable devices to support remote patient monitoring (RPM). The goal of this paper is to review the available evidence and assess the scope of RPM integration into standard practices for care and management of chronic disease in general and, more specifically, inflammatory bowel disease (IBD).

Recent Findings

RPM has been associated with improvements in health outcomes and indicators across a broad range of chronic diseases. However, there is limited data on the effectiveness of RPM in IBD care. From the emerging literature and body of research, we found promising results about the feasibility of integrating RPM in IBD care and RPM’s capacity to support IBD improvement in key process and outcome metrics.

Summary

Concerns regarding privacy and provider acceptability have limited the mass integration of RPM to date. However, with the healthcare industry’s move toward value-based population care and the advent of novel payment models for RPM reimbursement, the adoption of RPM into standard IBD care practices will likely increase as the technology continues to improve and become a mainstream tool for healthcare delivery in the near future.

     

CMV Infection in Pediatric IBD

Purpose of Review

Patients with inflammatory bowel disease (IBD) are predisposed to infections. Cytomegalovirus (CMV) colitis in adult IBD patients, particularly ulcerative colitis (UC), is related to severe or steroid-refractory disease. The aim of this review is to summarize the data on the prevalence and role of CMV colitis in children with IBD.

Recent Findings

Data on CMV colitis in children continue to be very limited due to its rarity. As in adults, children with coexisting UC and CMV tend to have more severe colitis, are resistant to corticosteroids, and are at high risk for colectomies on short- and long-term follow-up.

Summary

In children, as in adults, the significance of CMV colitis, in terms of whether CMV is a pathogen that aggravates acute severe colitis or simply reflects disease severity, is still unknown.

     

Remote Effects of Transplanted Perivascular Adipose Tissue on Endothelial Function and Atherosclerosis

Purpose

Perivascular adipose tissue (PVAT) surrounds the arterial adventitia and plays an important role in vascular homeostasis. PVAT expands in obesity, and inflamed PVAT can locally promote endothelial dysfunction and atherosclerosis. Here, using adipose tissue transplantation, we tested the hypothesis that expansion of PVAT can also remotely exacerbate vascular disease.

Methods

Fifty milligrams of abdominal aortic PVAT was isolated from high-fat diet (HFD)-fed wild-type mice and transplanted onto the abdominal aorta of lean LDL receptor knockout mice. Subcutaneous and visceral adipose tissues were used as controls. After HFD feeding for 10 weeks, body weight, glucose/insulin sensitivity, and lipid levels were measured. Adipocytokine gene expression was assessed in the transplanted adipose tissues, and the thoracic aorta was harvested to quantify atherosclerotic lesions by Oil-Red O staining and to assess vasorelaxation by wire myography.

Results

PVAT transplantation did not influence body weight, fat composition, lipid levels, or glucose/insulin sensitivity. However, as compared with controls, transplantation of PVAT onto the abdominal aorta increased thoracic aortic atherosclerosis. Furthermore, PVAT transplantation onto the abdominal aorta inhibited endothelium-dependent relaxation in the thoracic aorta. MCP-1 and TNF-α expression was elevated, while adiponectin expression was reduced, in the transplanted PVAT tissue, suggesting augmented inflammation as a potential mechanism for the remote vascular effects of transplanted PVAT.

Conclusions

These data suggest that PVAT expansion and inflammation in obesity can remotely induce endothelial dysfunction and augment atherosclerosis. Identifying the underlying mechanisms may lead to novel approaches for risk assessment and treatment of obesity-related vascular disease.

     

Paricalcitol reduces oxidative stress and inflammation in hemodialysis patients

Background

Treatment with selective vitamin D receptor activators such as paricalcitol have been shown to exert an anti-inflammatory effect in patients on hemodialysis, in addition to their action on mineral metabolism and independently of parathyroid hormone (PTH) levels. The objective of this study was to evaluate the additional antioxidant capacity of paricalcitol in a clinical setting.

Methods

The study included 19 patients with renal disease on hemodialysis, of whom peripheral blood was obtained for analysis at baseline and three months after starting intravenous paricalcitol treatment. The following oxidizing and inflammatory markers were quantified: malondialdehyde (MDA), nitrites and carbonyl groups, indoleamine 2,3-dioxygenase (IDO), tumor necrosis factor alfa (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18) and C-reactive protein (CRP). Of the antioxidants and anti-inflammatory markers, superoxide dismutase (SOD), catalase, reduced glutathione (GSH), thioredoxin, and interleukin-10 (IL-10) levels were obtained.

Results

Baseline levels of oxidation markers MDA, nitric oxide and protein carbonyl groups significantly decreased after three months on paricalcitol treatment, while levels of GSH, thioredoxin, catalase and SOD activity significantly increased. After paricalcitol treatment, levels of the inflammatory markers CRP, TNF-α, IL-6 and IL-18 were significantly reduced in serum and the level of anti-inflammatory cytokine IL-10 was increased.

Conclusions

In renal patients undergoing hemodialysis, paricalcitol treatment significantly reduces oxidative stress and inflammation, two well known factors leading to cardiovascular damage.

     

The Role of Interleukin-10 in the Pathophysiology of Preeclampsia

Purpose of Review

The pathophysiology of preeclampsia is complex and not entirely understood. A key feature in preeclampsia development is an immunological imbalance that shifts the maternal immune response from one of tolerance towards one promoting chronic inflammation and endothelial dysfunction. As a key regulator of immunity, IL-10 not only has immunomodulatory activity, but also directly benefits vasculature and promotes successful cellular interactions at the maternal-fetal interface. Here we focus on the mechanisms by which the dysregulation of IL-10 may contribute to the pathophysiology of preeclampsia.

Recent Findings

Dysregulation of IL-10 has been demonstrated in various animal models of preeclampsia. Decreased IL-10 production in both placenta and peripheral blood mononuclear cells has been reported in human studies, but with inconsistent results.

Summary

The significance of IL-10 in preeclampsia has shifted from a key biomarker to one with therapeutic potential. As such, a better understanding of the role of this cytokine in the pathophysiology of preeclampsia is of paramount importance.

     

Preoperative optimization of patients with inflammatory bowel disease undergoing gastrointestinal surgery: a systematic review

Purpose

Surgical management of inflammatory bowel disease (IBD) is a challenging task. The aim of preoperative optimization (PO) is to decrease the risk of complications and reduce the length of postoperative stay. The aim of this study was to review and grade the available evidence, attain clear recommendations, and point out potential future research.

Methods

Studies were identified from electronic databases (PubMed, Embase, and Cochrane Library) and scanning reference lists in relevant papers. English-written studies examining PO in adult patients with IBD were included. Eight PO factors were investigated.

Results

Management of IBD is a multidisciplinary task. Steroid withdrawal is recommended while steroid stress dose is not recommended. Thiopurines appear to be safe, but it may be prudent to plan the procedure remotely from the last dose of an anti-TNF agent. Nutritional risk screening is recommended to unveil and correct any malnutrition. Thrombosis prophylaxis prior to surgery is well supported by evidence while extended 4-week prophylaxis needs further research. Percutaneous ultrasound or CT-guided drainage for intra-abdominal abscesses is recommended, but it is unclear for how long supplementary antibiotics (ABs) should be used. Oral AB 24 h prior to open surgery might improve outcome if given as complementary to IV perioperative AB. Mechanical bowel preparation is not supported by evidence. Comorbidities must be treated accordingly prior to surgical intervention. Smoking cessation can be beneficial for wound healing.

Conclusion

Multimodel PO intervention in IBD patients is recommended.

     

Cytomegalovirus,inflammatory bowel disease,and anti-TNFα

Background and purpose

Anti-TNFα agents emerged in inflammatory bowel disease (IBD) as an effective option in situations that, otherwise, would be refractory to medical therapy. Cytomegalovirus infection may present with a high spectrum of manifestations and lead to high morbidity and mortality. However, its clinical significance in IBD course remains unknown and data on its association with anti-TNFα are limited.

Aims

This study aims to evaluate cytomegalovirus (CMV) infection/disease in patients with IBD treated with anti-TNFα; if possible, possible risk factors associated with CMV infection/disease in IBD patients under anti-TNFα as well as the influence of CMV infection/disease in IBD course would be determined.

Methods

During three consecutive years, all IBD patients starting infliximab in our department were included. Cytomegalovirus status before anti-TNFα was evaluated. Data regarding IBD, therapeutic and IBD course after infliximab, were recorded. CMV analysis was performed with polymerase chain reaction (PCR)-cytomegalovirus in peripheral blood and colonoscopy with biopsies (histopathology/immunohistochemistry).

Results

We included 29 patients: female—83%; Crohn’s disease–51.8%, ulcerative colitis—44.8%, non-classified colitis—3.4%; 23 cytomegalovirus seropositive. Median follow-up: 19 months (3–36). During follow-up, 14 patients were under combination therapy with azathioprine and 5 did at least 1 cycle of corticosteroids. Twenty-one patients responded to infliximab. We registered 8 exacerbations of IBD. Four patients discontinued infliximab: none had CMV infection. We documented 1 case of intestinal cytomegalovirus infection—detected in biopsies performed per protocol in an asymptomatic UC patient, who responded to valganciclovir without infliximab discontinuation.

Conclusions

Infliximab, with/without immunosuppression, does not confer an increased risk of (re)activation of cytomegalovirus. Cytomegalovirus was not responsible neither for significant morbidity nor mortality in IBD.

     

Preconditioning with Intravenous Colitic Cell-Free DNA Prevents DSS-Colitis by Altering TLR9-Associated Gene Expression Profile

Background

Presence of cell-free-circulating DNA (fcDNA) sequences in sera of patients with inflammatory bowel diseases (IBD) is a well-established phenomenon. Potential roles of fcDNA in diagnosis, prognosis and therapy monitoring of chronic inflammatory colonic disorders have already been examined, albeit its actual biological function still remains unclear.

Aims and Methods

In the present experiment, we studied the immunobiological effects of isolated fcDNA of normal and inflammatory origin administered intravenously to mice prior to induction of dextran sulfate sodium (DSS)-colitis. In addition to evaluate the current disease and histological activity, changes of the gene expression profile in isolated lamina propria cells upon TLR9 ligation were assayed.

Results

A single intravenous dose of fcDNA pretreatment with colitic fcDNA exhibited beneficial response concerning the clinical and histological severity of DSS-colitis as compared to effects of normal fcDNA. Pretreatment with colitic fcDNA substantially altered the expression of several TLR9-related and inflammatory cytokine genes in a clinically favorable manner.

Conclusions

During the process of acute colitis, the subsequent inflammatory environment presumably results in changes of fcDNA with the potential to facilitate the downregulation of inflammation and improvement of regeneration. Thus, preconditioning of mice with colitis-derived fcDNA via TLR9 signaling could exert a tissue-protective effect and influence beneficially the course of DSS-colitis. Elucidating mechanisms of immune response alterations by nucleic acids may provide further insight into the etiology of IBD and develop the basis of novel immunotherapies.