Purpose: Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-naive IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes. Patients and methods: Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohns disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map (TM) technology at diagnosis and after therapy in IBD patients. Results: Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (Pamp;lt;0.001). Only Prevotella was more abundant in patients (Pamp;lt;0.01). IBD patients with ileocolitis or total colitis had more Ruminococcus gnavus (P=0.02) than patients with colonic CD or left-sided UC. CD patients with upper gastrointestinal manifestations had higher Veillonella abundance (Pamp;lt;0.01). IBD patients (58%) who received biologic therapy had lower baseline Firmicutes and Mycoplasma hominis abundance (Pamp;lt;0.01) than conventionally treated. High Proteobacteria abundance was associated with stricturing/penetrating CD, surgery (Pamp;lt;0.01), and nonmucosal healing (Pamp;lt;0.03). Low Faecalibacterium prausnitzii abundance was associated with prior antibiotic therapy (P=0.001), surgery (P=0.02), and nonmucosal healing (Pamp;lt;0.03). After therapy, IBD patients had unchanged dysbiosis. Conclusion: Fecal microbiota profiles differentiated IBD and non-IBD symptomatic children from healthy children, but displayed similar dysbiosis in IBD and non-IBD symptomatic patients. Pretreatment fecal microbiota profiles may be of prognostic value and aid in treatment individualization in pediatric IBD as severe dysbiosis was associated with an extensive, complicated phenotype, biologic therapy, and nonmucosal healing. The dysbiosis persisted after therapy, regardless of treatments and mucosal healing.

  Background: The genetic influence on disease course in inflammatory bowel disease (IBD) remains unknown. We therefore aimed to study longitudinal concordance for clinical characteristics and longitudinal stability using the Montreal Classification in an IBD twin population.Methods: A total of 158 twins with ulcerative colitis (UC) (18 belonging to 9 concordant monozygotic pairs) and 141 twins with Crohn's disease (CD) (34 belonging to 17 concordant monozygotic pairs) were enrolled. Medical notes were scrutinized for clinical characteristics at diagnosis and after 10 years. Using the binominal distribution, we tested the hypothesis that clinical characteristics were independent within individuals in disease concordant monozygotic pairs.Results: In CD, location was identical in 11/17 monozygotic concordant pairs at diagnosis (P = 0.008) and in 11/16 pairs after 10 years (P = 0.02). Behavior at diagnosis was identical in 13/17 pairs (P = 0.03) and in 11/16 pairs after 10 years (P = 0.01). Monozygotic UC twins were concordant (within 5 years) for age at diagnosis (6/9 pairs; P < 0.001) and symptomatic onset (4/9 pairs; P = 0.02) but not for extent of disease at diagnosis or after 10 years. The Montreal Classification did not demonstrate longitudinal stability, either regarding location or behavior of CD or extent of UC.Conclusions: The high phenotypic concordance, both at diagnosis and longitudinally, in monozygotic twins with CD supports a genetic influence not only on disease occurrence but also on disease course. This contrasts with UC, where the genetic impact appears less. Montreal Classification characteristics changed over time and should be used cautiously.

OBJECTIVES:  Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative colitis (UC). The long-term prognosis in this patient group is not well described. We studied the long-term colectomy and relapse rates in patients given intensive intravenous corticosteroid treatment (IIVT) for acute UC.

METHODS:  A retrospective clinical study of 158 patients with UC treated in 1975–1982 with IIVT. Patients were followed-up to death, colectomy or last visit.

RESULTS:  A total of 11 patients were excluded due to change of diagnosis (N = 10) or lost to follow-up (N = 1). The indication for index IIVT in the remaining 147 patients was a severe attack (N = 61), a moderately severe attack (N = 45), a mild attack (N = 29) or chronic continuous disease (N = 12). The median (range) duration of follow-up was 173 (4–271) months in patients escaping colectomy during the first 3 months. Three months after IIVT, the colectomy rates were 28/61 (46%) in a severe attack, 4/45 (9%) in a moderately severe, and 1/29 (3%) in a mild attack. After 10 yr, the colectomy rates were 39/61 (64%), 22/45 (49%), and 8/29 (28%), respectively. During follow-up, neither colectomy incidence beyond 3 months, time to first relapse nor relapse incidence was influenced by severity of initial attack, except for a lower relapse incidence after a severe attack.

CONCLUSIONS:  In patients escaping colectomy during the first 3 months after IIVT, the future prognosis was similar irrespective of initial disease severity.

Background and aims: Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose β1, 3 N-acetylgalactosamine α-), among the same IBD twins.

Materials and methods: Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn’s disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor κB (NFκB) activation with investigators blinded to the diagnosis.

Results: Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p<0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NFκB was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p = 0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NFκB.

Conclusions: Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect “preinflammatory” NFκB activation.

Background: Genetics and environmental factors are implicated in the etiology of inflammatory bowel disease (IBD). We studied environmental factors in a population-based Swedish-Danish twin cohort using the co-twin control method.

Subjects and Methods: A questionnaire was sent to 317 twin pairs regarding markers of exposures in the following areas: infections/colonization and diet as well as smoking, appendectomy, and oral contraceptives. Odds ratios (OR) were calculated by conditional logistic regression. When confounding appeared plausible, multivariate conditional logistic regression was added. The questions were also divided into topic groups, and adjustment was made for multiple testing within each of the groups.

Results: The response rate to the questionnaire was 83%. In consideration of the study design, only discordant pairs were included (Crohn's disease [CD], n = 102; ulcerative colitis [UC], n > = 125). Recurrent gastrointestinal infections were associated with both UC (OR, 8.0; 95% confidence interval [CI], 1.0–64) and CD (OR, 5.5; 95% CI, 1.2–25). Hospitalization for gastrointestinal infections was associated with CD (OR, 12; 95% CI, 1.6–92). Smoking was inversely associated with UC (OR, 0.4; 95% CI, 0.2–0.9) and associated with CD (OR, 2.9; 95% CI, 1.2–7.1).

Conclusions: The observed associations indicate that markers of possible infectious events may influence the risk of IBD. Some of these effects might be mediated by long-term changes in gut flora or alterations in reactivity to the flora. The influence of smoking in IBD was confirmed.

Background and aims: An increased occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) is reported in unaffected members of families with Crohn’s disease. Whether ASCA is a familial trait due to genetic factors or is caused by exposure to environmental factors is unknown. To assess the genetic influence of ASCA we studied its occurrence in a twin population.

Patients and methods: ASCA were analysed in 98 twin pairs with inflammatory bowel disease and were related to clinical phenotype and CARD15/NOD2 genotype.

Results: ASCA were more common in Crohn’s disease than in ulcerative colitis (40/70 (57%) twins v 5/43 (12%) twins). Associations with ileal Crohn’s disease, stricturing/penetrating behaviour, and young age, but not CARD15/NOD2 were confirmed. ASCA were found in 1/20 (5%) healthy siblings in discordant monozygotic pairs with Crohn’s disease compared with 7/27 (26%) in discordant dizygotic pairs. Using the intraclass correlation coefficient (ICC), no agreement in ASCA titres was observed in discordant twin pairs with Crohn’s disease, in monozygotic (ICC = −0.02) or dizygotic (ICC = −0.26) pairs. In contrast, strong agreement was seen within concordant monozygotic twin pairs with Crohn’s disease (ICC = 0.76).

Conclusions: These findings question the concept of ASCA as a marker of genetic susceptibility for Crohn’s disease. The agreement in ASCA titres within concordant monozygotic twin pairs with Crohn’s disease, suggests that the level of increase is genetically determined. We propose that ASCA are a marker of a response to an environmental antigen and that a specific gene(s) other than CARD15/NOD2 determines the level of response and perhaps also specific phenotypic characteristics.

Background.

CARD15/NOD2 polymorphisms are associated with Crohn's disease. There is a high concordance for disease and disease phenotype in monozygotic twin pairs with Crohn's disease.

Aim.

We studied CARD15/NOD2 polymorphisms in a Swedish, population-based cohort of monozygotic twins with Crohn's disease to assess whether these variants explain disease concordance.

Subjects and methods.

Twenty-nine monozygotic twin pairs (concordant n = 9, discordant n = 20) with Crohn's disease and 192 healthy controls were investigated for the CARD15/NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC.

Results.

CARD15/NOD2 mutations were found in 5/38 (13%) twins with Crohn's disease, corresponding to a total allele frequency of 6.6%. Only 2/9 concordant twin pairs carried any of the variants and the remaining seven were wild type genotype. The total allele frequency was 4.4 times higher (95% confidence interval 1.0–21.5, p = 0.06) in concordant twins than in discordant ones, 11.1% versus 2.5%. In healthy controls the total allele frequency was 2.6%.

Conclusions.

CARD15/NOD2 polymorphisms contribute but do not alone explain concordance of Crohn's disease in monozygotic twins and, at least in a Swedish population, other polymorphisms are required. The low occurrence of CARD15/NOD2 mutations in the study and other Northern European populations suggests that these variants are of less importance in Northern Europe.

The aetiology of inflammatory bowel disease (IBD) is unknown but considered to be caused by interplay of genetic and environmental factors.

The aims of this thesis were to study the influence of genetics and environmental factors in aetiology, disease phenotype and levels of Anti-Saccharomyces cerevisiae antibodies (ASCA), as well as to assess whether CARD15/NOD2 polymorphisms explain the influence of genetics in these aspects.

Twin pairs, where at least one twin in each pair had been hospitalized for IBD, were identified using a combination of the Swedish twin registry and the Swedish Hospital Discharge Register. Twin pairs with confirmed IBD were invited to take part in a questionnaire-based study on environmental factors and studies on ASCA and CARD 15/NOD2 polymorphisms.

The follow-up of the old Swedish twin group showed fairly stable concordance rates. A high degree of concordance regarding age at diagnosis, disease location and behaviour was seen in concordant monozygotic twin pairs with Crohn's disease (CD).

The three "classical" CARD15/NOD2 polymorphisms were infrequent in Swedish CD twins and healthy controls, but seemed to be more common among concordant than discordant monozygotic twins with CD.

No increased occurrence of ASCA was observed in healthy twin siblings in discordant monozygotic twin pairs, but a high degree of concordance in ASCA titres was seen in concordant monozygotic twin pairs with CD. ASCA were not associated with CARD15/NOD2.

Including both Swedish and Danish twins, associations between recurrent gastrointestinal infections up to age 20 years and both ulcerative colitis (UC) and CD were observed, whereas coffee and egg consumption was associated with UC only. Swimming in lakes in contrast with swimming pools, sea and rivers was also associated with UC.

These results confirm a stronger genetic influence in CD than in UC and suggest that genetic factors are important not only in acquiring the disease but also in determining disease characteristics of CD. The CARD15/NOD2 variants contribute, but do not fully explain concordance of CD and support the hypothesis that concordant monozygotic twins are under an increased load of susceptibility genes. Furthermore, the results question the concept of ASCA as a marker of genetic susceptibility for CD and we propose that ASCA are a marker of a response to an environmental antigen and that specific gene(s) other than CARD15/NOD2 determine the level of response and perhaps also specific phenotypic characteristics. The results also indicate, that markers of possible infectious events during childhood/adolescence and dietary factors may influence the risk of IBD. In addition, previous reported associations between smoking and IBD were confirmed.

Background & Aims:

In 1988, we reported the first twin study in inflammatory bowel disease. The aim of the current study was to follow up these twins regarding new cases of inflammatory bowel disease and Crohn’s disease characteristics using the Vienna classification.

Methods:

The official Swedish population register and the cause of death register were used to search for the twins. All living patients were interviewed.

Results:

Three monozygotic twins earlier classified as healthy had been diagnosed with inflammatory bowel disease (ulcerative colitis, n = 2; Crohn’s disease, n = 1). Retrospectively, all 3 were symptomatic at the original survey. This changed the pair concordance in monozygotic twins from 6.3% to 18.8% in ulcerative colitis and from 44.4% to 50.0% in Crohn’s disease. A high degree of concordance regarding age at diagnosis, disease location at diagnosis and during the course, and disease behavior was found in concordant monozygotic twin pairs with Crohn’s disease. Seven of 9 pairs were identical in 3 or more of these disease characteristics compared with an expected number of 1.5 (P = 0.000076).

Conclusions:

This study confirms that the genetic influence is stronger in Crohn’s disease than in ulcerative colitis. A remarkable phenotype similarity within concordant pairs with Crohn’s disease was found using the Vienna classification.