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PubMed2006

Frequent detection of cytomegalovirus in the intestine of patients with inflammatory bowel disease.

BACKGROUND: Although a growing number of reports have described inflammatory bowel disease (IBD) complicated with cytomegalovirus (CMV) infection, there are limited molecular studies that investigate CMV genome in intestinal sections of patients with IBD. METHODS: A cross-sectional prospective study was conducted between September 2000 and June 2003 in a cohort of 85 patients diagnosed with IBD (58 with ulcerative colitis and 27 with Crohn's disease) in two adult gastrointestinal referral centers in Athens, Greece. Prevalence of CMV infection was estimated by pathologic studies in intestinal sections and by molecular assays in blood and intestinal tissue samples and compared with a control group of 42 individuals with noninflammatory disease. RESULTS: Immunohistochemical staining showed CMV antigen in 10 IBD patients (7 with ulcerative colitis; 9 with severe disease), whereas CMV antigen was not detected in any of the controls. CMV genome in both the intestinal tissue and blood was found by polymerase chain reaction in 23 (27.1%) of the total IBD patients, in 18 (31.0%) of those with ulcerative colitis, and in 5 (18.5%) of those with Crohn's disease. In addition, five (5.9%) IBD patients (2 with ulcerative colitis and 3 with Crohn's disease) had detectable CMV genome in their intestinal samples but not in their blood. In the control group, five (11.9%) individuals had detectable CMV genome in their blood, but only one (2.2%) in his intestine. CONCLUSION: Patients with ulcerative colitis had more often detectable CMV genome in their blood as well as in their intestinal tissue samples as compared with controls (P = 0.022 and P < 0.0001, respectively). However, patients with Crohn's disease had more often detectable CMV genome only in their intestinal tissue samples as compared with controls (P = 0.001). Detection of CMV genome in blood or intestinal tissue was significantly associated with short duration of IBD (P = 0.0088 and 0.04, respectively) but not with age, sex, severity of the disease, activity at colonoscopy, pancolitis, administration of a specific treatment, and surgery. In this cross-sectional prospective study, detection of CMV genome or antigen in the intestine was commonly associated with IBD.

Adolescent↗

PubMed2006

Characteristics of inflammatory bowel disease with onset during the first year of life.

BACKGROUND: Inflammatory bowel disease (IBD) is recognized in young children, however, only rare data on onset and evolution are available in children younger than 1 year. In the present clinical study, we aimed to analyze characteristics and clinical course of children with very early onset IBD. We were particularly interested in the relationship between bacterial infections and the use of antibiotics before the onset of IBD. PATIENTS AND METHODS: The IBD database of Necker-Enfants-Malades-Hospital was screened for patients with IBD with disease onset during the first year of life and a follow-up of at least 2.5 years. Ten patients were identified during the period 1996-2002. RESULTS: All patients presented with rectal bleeding and had colonic involvement. Four patients had definitive diagnosis of Crohn disease; ulcerative or indeterminate colitis was seen in 2 and 4 children, respectively. Five of the patients had a positive history of neonatal or early-onset bacterial infection with use of antibiotics before onset of IBD, 4 patients were still breastfed and 3 just weaned when GI symptoms started. Seven patients had a severe onset of disease requiring bowel rest, parenteral nutrition and steroid medication, followed by azathioprine or cyclosporine medication. Surgery was necessary in 3 of 10 patients. Disease relapses were frequent and observed in 8 of 10 children. DISCUSSION: Very early onset IBD may reflect a subgroup of patients characterized by a particular sensitivity to modifications of the intestinal flora. Neonatal IBD was most often severe in presentation and evolution.

Age of Onset↗

PubMed2026

Ferroptosis as a mediator of gut microbiota-driven inflammatory bowel disease: Evidence from genetic analyses.

Gut microbiota dysbiosis is increasingly recognized as a contributor to inflammatory bowel disease (IBD), yet causal relationships and underlying mechanisms remain unclear. Ferroptosis, an iron-dependent form of regulated cell death, plays a key role in epithelial barrier damage and inflammation. This study aimed to determine whether specific gut microbial taxa are causally associated with IBD and whether ferroptosis-related genes mediate this association using Mendelian randomization (MR). Two-sample MR and mediation MR analyses were performed using genome-wide association study summary data from the FinnGen consortium (IBD), the genome-wide association study catalog (473 gut microbial taxa), and the deCODE database (ferroptosis-related genes). Instrumental variables were selected with thresholds of P < 1 × 10-6 for microbes and P < 5 × 10-8 for traits, and linkage disequilibrium clumping (r2 < 0.001) was applied. Twenty-three microbial taxa showed significant causal associations with IBD (e.g., Chromatiales, OR = 0.51; Acetobacterales, OR = 2.61). Several ferroptosis-related genes were linked to IBD risk (e.g., GPX4, STAT3, IDO1). Mediation MR revealed that genes such as MUC1, IDO1, and ADAM23 partially mediated microbial effects on IBD, with mediation proportions up to 7.6%. This study provides novel genetic evidence supporting a gut microbiota-ferroptosis-IBD axis. Ferroptosis-related pathways may partially mediate microbial effects on IBD pathogenesis and represent promising targets for future therapeutic interventions.

Ferroptosis↗

PubMed1995

Increased frequency of bronchial hyperresponsiveness in patients with inflammatory bowel disease.

Although bronchopulmonary manifestations are rare in inflammatory bowel disease (IBD), subclinical abnormalities have been described in up to 50% of cases. The pathophysiology of these abnormalities remains unknown. However, a latent inflammation of the bronchial mucosa secondary to the inflammation of the intestinal mucosa has been suggested. This subclinical inflammation may lead to increased bronchial responsiveness. We studied the bronchial responsiveness in 38 inflammatory bowel disease (IBD) patients, using the methacholine test. Bronchial hyperresponsiveness was defined by a PC20M < 16 mg/ml. Twenty-four healthy controls were also studied. There was no significant difference in baseline FEV1 between IBD patients and controls. However, there was a significantly greater fall in FEV1 in the IBD patients at the concentrations of methacholine tested. The frequency of bronchial hyperresponsiveness was significantly higher in the IBD population (45%) than in controls (17%; P < 0.03). Atopy, defined by skin test, was more common in IBD patients (42%) than in controls (21%). Even when only nonatopic subjects were considered, the frequency of bronchial hyperresponsiveness was significantly higher in IBD patients (41%) than in controls (5%; P < 0.02). Thus, subclinical bronchial hyperresponsiveness is common in IBD, and may be considered a further extraintestinal manifestation.

Adolescent↗

PubMed2005

Abundance of mRNA of growth hormone receptor and insulin-like growth factors-1 and -2 in duodenal and colonic biopsies of dogs with chronic enteropathies*.

Repair processes of the inflamed intestine are very important for dissolution of chronic enteropathies (CE). Therefore, we examined the mRNA abundance of growth hormone receptor (GHR), insulin-like growth factors (IGF)-1 and -2 in duodenal and colonic biopsies of dogs with CE such as food-responsive diarrhoea (FRD) and inflammatory bowel disease (IBD) before and after treatment as compared with each other and healthy dogs. A clinical score (Canine IBD Activity Index = CIBDAI) was applied to judge the severity of CE. Biopsies of duodenum and colon from client-owned dogs with CE were sampled before (FRD(bef), n = 5; IBD(bef), n = 5) and after treatment (FRD(aft), n = 5; IBD(aft), n = 5). Intestinal control samples were available from a homogenous control population (n = 15; C). Intestinal samples were homogenized, total RNA was extracted, reverse transcribed and analysed by real-time polymerase chain reaction to measure mRNA levels of GHR, IGF-1 and IGF-2. Results were normalized with glyceraldehyde phosphate dehydrogenase as housekeeping gene. The CIBDAI decreased during the treatment period in FRD and IBD (P < 0.01). In duodenum, GHR mRNA levels were higher in all groups than in C (P < 0.001). Duodenal IGF-1 mRNA levels in FRD(aft) and IBD(aft) tended to be higher than in C (P < 0.1). The IGF-2 mRNA abundance in FRD(aft) was higher than in C (P < 0.05) in duodenum. In colon, mRNA levels of IGF-1 in IBD(aft) were higher than in FRD(aft) (P < 0.05) and levels differed between IBD(aft) and C (P < 0.05). In conclusion, mRNA levels of GHR, IGF-1 and IGF-2 in the gastrointestinal tract were increased during CE when compared with gastrointestinally healthy dogs. The data suggest that GHR, IGF-1 and IGF-2 are involved in gastrointestinal repair processes.

Animals↗

PubMed2005

Impaired capsaicin and neurokinin-evoked colonic motility in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with altered sensory and motor function in the human colon. The aim of the present study was to compare neuromuscular function in normal and IBD-affected colon in vitro, with emphasis on inhibitory enteric nerves, sensory neuropeptides and stimulation of axon collaterals. METHODS: Strips of longitudinal and circular muscle were prepared following colectomy from six patients with intestinal carcinoma (mean age 64.2 +/- 4.8 years) and six patients with IBD (Crohn's disease, n = 3; ulcerative colitis, n = 3: mean age 35.8 +/- 5.7 years). Responses were measured to electrical field stimulation, potassium chloride, 1,1-dimethyl-4-phenylpiperazinium iodide, isoprenaline, calcitonin gene-related peptide (CGRP), capsaicin and neurokinin (NK)-1 and -2 receptor subtype-specific agonists, alone or after muscle precontraction. RESULTS: The NK-1 and CGRP receptor-mediated relaxation was reduced in the circular (by 44%, P < 0.05) and longitudinal (by 61%, P < 0.05) muscle from IBD-affected colon, respectively. Maximal NK-2 receptor-mediated contraction was also significantly decreased in both longitudinal (71%, P < 0.001) and circular (51%, P < 0.01) muscle. Capsaicin evoked relaxation in precontracted colonic longitudinal and circular muscle; this was significantly diminished in the IBD-affected colon (by 63%, P < 0.001 and 76%, P < 0.01, respectively). Responses evoked by stimulation of enteric inhibitory nerves were not significantly altered. CONCLUSIONS: Colonic muscle strips from patients with IBD exhibited impaired CGRP and NK-1 receptor-mediated relaxation and NK-2 receptor-mediated contraction. Capsaicin-activated relaxation of colonic smooth muscle is deficient in IBD-affected colon. These results suggest a discrete effect of IBD on sensory-motor coupling and tachykinin-mediated effects on colonic motility.

Adult↗

PubMed2005

Role of esophagogastroduodenoscopy in the initial assessment of children with inflammatory bowel disease.

INTRODUCTION: Diagnosis of inflammatory bowel disease (IBD) and differentiation between Crohn's disease (CD) and ulcerative colitis (UC) can be difficult in children. Several previous studies suggest that esophagogastroduodenoscopy (EGD) and biopsies are important in the initial investigation of children with suspected IBD. The aim of the present paper was to assess the importance of EGD in the initial diagnostic appraisal of children with suspected IBD. METHODS: Children diagnosed with IBD over a 4-year period were identified from a dedicated IBD database. Retrospective chart review documented presenting signs and symptoms, endoscopic features in the upper and lower gastrointestinal tract and histological findings on mucosal biopsies. RESULTS: Eighty-six children were diagnosed with IBD of whom 61 (70.9%) had CD, 13 (21.3%) UC, and the remainder, indeterminate colitis. Esophagogastroduodenoscopy was performed in 76 (88.4%). Nine children were diagnosed with IBD solely on the basis of information obtained following EGD. None of these children had colitis and all had abnormal histological findings on review of mucosal biopsies from the upper gastrointestinal tract. Thirteen (23.6%) of 55 children with CD had granulomas noted within biopsies obtained during EGD and another 20 had significant inflammatory changes on histological examination of upper gastrointestinal tract biopsies. Crohn's disease was diagnosed in 25 of 38 children with pan-colitis. Thirteen children were correctly classified as having CD only following assessment of their upper gastrointestinal tract. This included the presence of upper gut granulomata in eight children. CONCLUSION: The performance of EGD in these children with IBD provided additional diagnostic yield and guided the differentiation of disease type in many patients. Esophagogastroduodenoscopy is an essential component in the initial diagnostic assessment of children with possible CD or UC.

Adolescent↗

PubMed2004

Increased expression of minichromosome maintenance protein 2 in active inflammatory bowel disease.

OBJECTIVE: Minichromosome maintenance protein 2 (Mcm2) is an accurate indicator of cell cycle entry in tissue samples, but its expression in inflammatory bowel disease (IBD) has not previously been investigated. We have used immunohistochemistry to assess the expression of Mcm2, in comparison to the existing proliferation marker Ki-67, in active IBD and IBD without inflammatory activity. MATERIALS AND METHODS: For this experimental study, sections from colonic biopsy and resection specimens of 48 patients with IBD (5 inactive/quiescent Crohn's disease (CD), 13 active CD, 19 inactive/quiescent ulcerative colitis (UC) and 11 active UC) and 15 normal controls were immunostained with antibodies to Mcm2 and Ki-67. The percentage of immunopositive epithelial nuclei was determined by calculating a labelling index (LI) for entire glands and for gland thirds (superficial, middle and basal). RESULTS: The Mcm2 LI was significantly increased in the superficial third of glands in active vs. inactive/quiescent UC (P < 0.0001) and active vs. inactive/quiescent CD (P = 0.001). The Mcm2 LI was significantly greater than the Ki-67 LI in active IBD, both in entire glands (P < 0.0001) and in the superficial third of glands (UC, P = 0.001; CD, P = 0.0002). Mcm2 LIs for entire glands were significantly higher in UC (all cases) compared to CD (all cases) (P = 0.032). CONCLUSIONS: There is increased cell cycle entry, as indicated by expression of Mcm2 and to a lesser extent Ki-67, in the superficial third of colonic glands in active IBD compared to inactive/quiescent IBD. Detection of Mcm2 may contribute to improved histological assessment of small tissue biopsies and may enable the development of a direct stool-based test for detection of active IBD and potentially for assessment of disease activity.

Cell Cycle Proteins↗

PubMed1999

Thromboembolism and resistance to activated protein C in patients with inflammatory bowel disease.

OBJECTIVE: Thromboembolic events are serious complications in patients with inflammatory bowel disease (IBD). Resistance of factor V to degradation by activated protein C (APC) is a major cause for venous thrombosis and is found in approximately 30% of patients with thromboembolism. The aim of the present study was to assess the prevalence of APC resistance and clinical risk factors in patients with IBD. METHODS: One-hundred-two patients with IBD (64 women and 38 men; median age, 35 yr; range, 17-77 yr; 77 with Crohn's disease, 25 with ulcerative colitis) and 102 gender- and age-matched healthy control subjects were investigated prospectively for the presence of APC resistance. None of the healthy controls but 16 patients with IBD had a history of thromboembolism. RESULTS: Patients with IBD and thromboembolism were young, with a median age of 37 yr (range, 17-61 yr). Five (31.3%) of them had APC resistance, which was more common than in patients with IBD without thromboembolism (7%) and in controls (5.9%) (p < 0.01). Three patients had two thromboembolic events, the other 13 each had one. Deep vein thrombosis of the leg and pulmonary emboli were the most common thromboembolic complications (84.2%). Active disease, fistula, or bowel stenosis were found in 10 (52.6%) of 19 thromboembolic events; in three (15.8%) cases thromboembolism happened postoperatively. CONCLUSIONS: APC resistance is not associated with IBD but, when present, increases the risk of thromboembolism. Patients with IBD and thromboembolism are mostly young and clinical risk factors can be found in one-half of cases.

Activated Protein C Resistance↗

PubMed2000

Higher expression of glucocorticoid receptor in peripheral mononuclear cells in inflammatory bowel disease.

OBJECTIVE: Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD. METHODS: Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation. RESULTS: Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p < 0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group. CONCLUSIONS: Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment.

Anti-Inflammatory Agents↗

PubMed2001

Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease.

OBJECTIVES: Correct diagnosis of inflammatory bowel disease (IBD), especially the differentiation between Crohn's disease (CD) and ulcerative colitis (UC), is highly important toward treatment and prognosis. Serological markers are noninvasive diagnostic tools that could be of value in differentiating CD from UC, in cases of indeterminate colitis, and in the identification of subgroups in IBD. The aim of this study was to evaluate the diagnostic accuracy of perinuclear antineutrophil cytoplasmic (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) for IBD. METHODS: ASCA and pANCA were studied in a large cohort of consecutive IBD patients (n = 582: 407 CD, 147 UC, and 28 indeterminate colitis), patients with non-IBD diarrheal illnesses (n = 74), and healthy controls (n = 157). An indirect immunofluorescence technique and a standardized ELISA were performed for detection of pANCA and ASCA, respectively. RESULTS: Prevalence of ASCA and pANCA was high in CD patients (59.7%) and UC (49.7%) patients, respectively. Positivity for both markers was significantly lower in healthy and non-IBD controls. Accuracy data (sensitivity, specificity, PPV, and NPV, respectively) for differentiating IBD from controls are as follows: ASCA+: 60% (243/407), 91% (345/378), 88% (243/276), and 68% (345/509); pANCA+: 50% (73/147), 95% (605/638), 69% (73/106), and 89% (605/679); ASCA+/pANCA-: 56% (229/407), 94% (355/378), 91% (229/252), and 67% (355/533); and pANCA+/ASCA-: 44% (65/147), 97% (620/638), 78% (65/83), and 88% (620/702). CONCLUSIONS: Specificity of serological markers for IBD is high, but low sensitivity makes them less useful as diagnostic tests. The combination of tests is probably more powerful, although, clinical subgroups still need to be defined. The usefulness of these markers in indeterminate colitis needs to be studied prospectively.

Adolescent↗

PubMed2001

Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.

OBJECTIVE: The aim of this study was to determine the outcome of cytomegalovirus (CMV) infections complicating the course of inflammatory bowel disease (IBD). METHODS: The records and clinical courses were reviewed for all IBD patients who were evaluated at the IBD Center of the Cedars-Sinai Medical Center and who developed CMV infection. RESULTS: Ten patients with severe, medically refractory IBD (five ulcerative colitis, three Crohn's colitis, and two indeterminate colitis) developed CMV infection. All but two were hospitalized with exacerbation of their underlying disease and were receiving immunosuppressive treatment with steroids, thiopurines, and/or cyclosporine at the time CMV infection was recognized. Eight patients had documented colonic CMV (one had concurrent upper GI tract involvement), one developed interstitial CMV and Pneumocystis carinii pneumonia, and one developed primary CMV mononucleosis. Prompt treatment with ganciclovir and withdrawal of immunosuppressive treatment resulted in gradual improvement and induction of remission of the underlying IBD in five patients. The patient with concomitant CMV and P. carinii pneumonitis died. In two patients, treatment with ganciclovir did not alter the clinical course of their IBD, and one of them underwent colectomy. In one patient CMV was found on the resected colonic specimen. One patient with primary CMV infection responded also to ganciclovir treatment. CONCLUSIONS: CMV infection may aggravate the course of seemingly refractory IBD in patients who either fail to respond or experience worsening of symptoms despite immunosuppressive therapy. Expedient evaluation, prompt treatment intervention with ganciclovir, and withdrawal of immunosuppressive treatment may avoid complications and mortality. This regimen leads to improvement of the underlying IBD in most patients.

Adolescent↗

PubMed2001

Hyperhomocysteinemia and prevalence of polymorphisms of homocysteine metabolism-related enzymes in patients with inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) have an increased risk of thrombotic complications. Moreover, a hypercoagulable state has been hypothesized as a contributing factor in the pathogenesis of IBD. Recently, a growing amount of interest has focused on mild-to-moderate hyperhomocysteinemia as a risk factor for thromboembolic disease. We aimed to evaluate the prevalence of hyperhomocysteinemia in patients with IBD and to investigate the contribution of genetic defects in the enzymes involved in homocysteine (Hcy) metabolism and vitamin status in determining increased levels of plasma total Hcy (tHcy). METHODS: The concentrations of tHcy, folate, and vitamin B12 as well as the prevalence of methylenetetrahydrofolate reductase (MTHFR) 677C to T mutation and the 68-bp insertion at exon 8 of cystathionine beta-synthase (CBS) were measured in patients with IBD and healthy controls. RESULTS: In all, 17 out of 64 IBD patients (26.5%) and four out of 121 (3.3%) controls had hyperhomocysteinemia with a statistically significant difference (p < 0.0001). No significant difference was found between IBD patients and controls with regard to the prevalence of homozygotes for the C677T variant (TT) of MTHFR or the prevalence of heterozygotes for the CBS-gene mutation (IN). Among the IBD patients the only independent factor significantly associated with hyperhomocysteinemia was folate deficiency (p = 0.0002), regardless of the MTHFR or the CBS genotype. CONCLUSIONS: IBD patients have a higher prevalence of hyperhomocysteinemia than do healthy controls. Folate deficiency is the only independent risk factor in developing hyperhomocysteinemia.

Adult↗

PubMed2002

Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study.

OBJECTIVE: Limited population-based data on inflammatory bowel disease (IBD) and pregnancy outcomes exist. The purpose of this study is to determine the association between maternal IBD status and adverse pregnancy outcomes. METHODS: Using computerized birth records of infants born to mothers with Crohn's disease (CD) or ulcerative colitis (UC) and mothers without diagnoses of IBD (no-IBD) in Washington State, we performed a cross-sectional retrospective study to determine gestational age, birth weight, and congenital malformations. RESULTS: Preterm delivery was seen in 15.2% of CD births, 10.4% of UC births, and 7.2% of no-IBD births. Low birth weight was found in 16.8% of CD births, 7.6% of UC births, and 5.3% of no-IBD births. Smallness for gestational age was present in 15.2% of CD births, 10.5% of UC births, and 6.9% of no-IBD births. Only CD births were at significantly increased risk of preterm delivery (p < 0.0025), low birth weight (p < 0.001), and smallness for gestational age (p < 0.001). Congenital malformations were more commonly recorded in UC births than in controls (7.9% vs 1.7%, p < 0.001), whereas 3.4% of CD births had malformations recorded. Using multivariable logistic regression, CD births were more likely to be preterm (odds ratio [OR] = 2.3, 95% CI = 1.4-3.8) and have low birth weights (OR = 3.6, CI = 2.2-5.9) and smallness for gestational age (OR = 2.3, CI = 1.3-3.9). UC births were more likely to have congenital malformations reported (OR = 3.8, CI = 1.5-9.8). CONCLUSIONS: Maternal IBD is associated with increased odds of preterm delivery, low birth weight, smallness for gestational age (CD), and reporting of congenital malformations (UC).

Adult↗

PubMed2004

Psychological stress and inflammatory bowel disease: a follow-up study in parents who lost a child in Denmark.

OBJECTIVES: Little is known about the association between psychological stress and the risk of inflammatory bowel disease (IBD). This study aimed to examine whether the death of a child is related to the development and exacerbation of IBD in bereaved parents. METHODS: We undertook a follow-up study based on national registers. All 21,062 parents who lost a child (younger than 18 yr) from 1980 to 1996 in Denmark were included in the exposed cohort, and 293,745 parents matched on family structure were selected randomly from the general population to the unexposed cohort. Cox's proportional-hazards regression models were used to evaluate the relative risks (RRs) of first IBD hospitalization in the exposed parents, compared to the unexposed. Poisson regression models were fitted to estimate the frequency of IBD readmission between the exposed and the unexposed IBD parents. We used Wilcoxon tests to compare the mean duration of hospitalizations in the two groups of patients. RESULTS: There were 32 prevalent IBD patients at the study entry in the exposed cohort and 451 prevalent cases in the unexposed cases. We observed 301 incident cases of Crohn's disease (20 in the exposed, 281 in the unexposed) and 766 incident cases of ulcerative colitis (51 in the exposed, 715 in the unexposed). The RRs of first hospitalization for Crohn's disease and ulcerative colitis were 0.97 (95% CI = 0.62-1.53) and 1.01 (95% CI = 0.76-1.34), respectively. For incident or prevalent IBD patients, we did not observe any differences in the frequency or duration of hospitalization in the exposed and unexposed patients. CONCLUSIONS: Our findings do not support an association between psychological stress and the development of IBD in young-to-middle-aged adults.

Adolescent↗

PubMed2006

Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation.

Immunosuppression is currently the treatment of choice for severe inflammatory bowel disease (IBD). Thus, it was anticipated that the course of preexisting IBD should improve after orthotopic liver transplantation (OLT). Despite sufficient allograft immunosuppressive therapy, however, exacerbation of IBD or the development of de novo IBD after OLT were described in some cases, primarily in patients transplanted for end-stage primary sclerosing cholangitis (PSC). In addition, the development of de novo IBD in patients undergoing OLT for indications other than PSC was described. Evaluating our collective of 314 liver transplanted patients we found five patients transplanted for various indications other than PSC (autoimmune hepatitis [AIH], acute-on-chronic hepatitis B, Wilson's disease, and cryptogenic cirrhosis) who developed de novo IBD after OLT despite sufficient immunosuppressive therapy with tacrolimus or cyclosporine. PSC was widely excluded in these patients by clinical and histological examinations and there was no sign of an enteric infection. It was remarkable that all patients were suspected to have an autoimmune background. Four of our patients were women and almost all patients showed histologically typical signs of an ulcerative colitis (UC). To prevent allograft rejection, three of five patients were treated with cyclosporine and the other two with tacrolimus. After diagnosis, treatment with aminosalicylates and corticosteroids led to complete clinical and histological remission. However, relapses occurred frequently after termination of specific therapy. In combination with previous reports, our cases indicate an immune dysregulation leading to the development of de novo IBD after OLT under immunosuppressive therapy. Reviewing the literature, it should be considered that apart from the autoimmune background, immunosuppressive therapy may itself play a major role in the development of de novo IBD. From the clinical point of view, it is of critical importance to detect this phenomenon, since diarrhea is an important cause of morbidity and mortality in transplanted patients and therapy for this disorder completely differs from the treatment for other causes of diarrhea. Aminosalicylates and courses of corticosteroids offer an effective treatment.

Adolescent↗

PubMed1997

Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus.

Inflammatory bowel disease (IBD) is thought to result from either an abnormal immunological response to enteric flora or a normal immunological response to a specific pathogen. No study to date has combined both factors. The present studies were carried out with an immunologically manipulated mouse model of IBD. Mice homozygous for the severe combined immunodeficiency (scid) mutation develop IBD with adoptive transfer of CD4+ T cells expressing high levels of CD45RB (CD45RB(high) CD4+ T cells). These mice do not develop IBD in germfree conditions, implicating undefined intestinal flora in the pathogenesis of lesions. In controlled duplicate studies, the influence of a single murine pathogen, Helicobacter hepaticus, in combination with the abnormal immunological response on the development of IBD was assessed. The combination of H. hepaticus infection and CD45RB(high) CD4+ T-cell reconstitution resulted in severe disease expression similar to that observed in human IBD. This study demonstrates that IBD develops in mice as a consequence of an abnormal immune response in the presence of a single murine pathogen, H. hepaticus. The interaction of host immunity and a single pathogen in this murine system provides a novel model of human IBD, an immunity-mediated condition triggered by bacterial infection.

Animals↗

PubMed2000

Results of multiple diagnostic tests for Mycobacterium avium subsp. paratuberculosis in patients with inflammatory bowel disease and in controls.

Mycobacterium avium subsp. paratuberculosis has been incriminated as a cause of Crohn's disease (CD); however, studies to date have been relatively small and generally only used a single diagnostic assay. The objective of the study was to reexamine the association of M. avium subsp. paratuberculosis and CD using multiple diagnostic tests. Five methods were used to detect M. avium subsp. paratuberculosis infections in 439 inflammatory bowel disease (IBD) patients and 324 control subjects in the United States and Denmark. Most assays were adaptations of diagnostic tests for this infection performed routinely on animals. PCR for IS900, a genetic element unique to M. avium subsp. paratuberculosis, was positive significantly more often on resected bowel and lymph node tissues from CD patients (19.0%) and ulcerative colitis (UC) patients (26.2%) than from controls (6. 3%) (P < 0.05). Positive IS900 PCR results occurred more often in U. S. than in Danish IBD patients, 32.0 versus 13.3% (P = 0.025). The majority of Danish patients were bacillus Calmette-Guérin (Mycobacterium bovis BCG) vaccinated (CD, 77.5%; UC, 86.6%; controls, 83.0%) whereas none of the U.S. patients with IBD and only 2% of U. S. controls were vaccinated. Among Danish IBD patients, positive PCR findings were four times more common among subjects who were not BCG vaccinated (33.3%) than among BCG vaccinates (8.8%, P = 0.02). Culture of the same tissues tested by PCR using modified BACTEC 12B medium failed to grow M. avium subsp. paratuberculosis from patients or controls. U.S. CD patients had the highest serological evidence (enzyme-linked immunosorbent assay [ELISA] for serum antibodies) of M. avium subsp. paratuberculosis infection (20.7% of patients positive) which was higher than for all UC patients studied (6.1%) or healthy controls (3.8%, P < 0.005). Among Danish patients alone, however, no significant differences in rates of ELISA-positive results among CD, UC, or control patients were found. For 181 study subjects, both IS900 PCR and ELISA were performed. Although 11 were ELISA positive and 36 were PCR positive, in no instance was a patient positive by both tests, suggesting that these states are mutually exclusive. Evaluation of cytokine-mediated immune responses of IBD patients was complicated by the influence of immunosuppressive therapy given most IBD patients. Gamma interferon (IFN-gamma) release by peripheral blood leukocytes after M. avium purified protein derivative PPD antigen stimulation showed significantly lower responses in CD patients than in UC patients or controls in both U.S. (by ex vivo assay) and Danish (by in vitro assay) populations (P < 0.05). Interleukin-5 responses were not different among CD, UC, or control groups. Collectively, the PCR, ELISA, and IFN-gamma tests for M. avium subsp. paratuberculosis together with the unexpected observation that BCG vaccination influenced M. avium subsp. paratuberculosis detection, lead us to conclude that M. avium subsp. paratuberculosis, or some similarly fastidious mycobacterial species, infects at least a subset of IBD patients. Whether the infection is primary (causal) or secondary, it may contribute to the etiopathogenesis of IBD.

Adult↗