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IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.
Cananzi, M, Wohler, E, Marzollo, A, Colavito, D, You, J, Jing, H, Bresolin, S, Gaio, P, Martin, R, Mescoli, C, et al
Human genetics. 2021;(9):1299-1312
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Abstract
Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
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High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23.
Dahlerup, JF, Jacobsen, BA, van der Woude, J, Bark, LÅ, Thomsen, LL, Lindgren, S
Scandinavian journal of gastroenterology. 2016;(11):1332-8
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Abstract
OBJECTIVE Iron isomaltoside (Monofer(®)) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA. MATERIALS AND METHODS The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters. RESULTS Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found. CONCLUSION Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.
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Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.
Ostrowski, J, Paziewska, A, Lazowska, I, Ambrozkiewicz, F, Goryca, K, Kulecka, M, Rawa, T, Karczmarski, J, Dabrowska, M, Zeber-Lubecka, N, et al
Scientific reports. 2016;:39831
Abstract
Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10-11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components.
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Effects of Probiotics on Gut Microbiota in Patients with Inflammatory Bowel Disease: A Double-blind, Placebo-controlled Clinical Trial.
Shadnoush, M, Hosseini, RS, Khalilnezhad, A, Navai, L, Goudarzi, H, Vaezjalali, M
The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi. 2015;(4):215-21
Abstract
BACKGROUND/AIMS: Several clinical trials have revealed various advantages for probiotics in inflammatory bowel disease (IBD). The aim of this study was to further investigate the effects of probiotic yogurt consumption on gut microbiota in patients with this disease. METHODS A total of 305 participants were divided into three groups; group A (IBD patients receiving probiotic yogurt; n=105), group B (IBD patients receiving placebo; n=105), and control group (healthy individuals receiving probiotic yogurt; n=95). Stool samples were collected both before and after 8 weeks of intervention; and population of Lactobacillus, Bifidobacterium and Bacteroides in the stool specimens was measured by Taqman real-time PCR method. RESULTS By the end of the intervention, no significant variations in the mean weight and body mass index were observed between three groups (p>0.05). However, the mean numbers of Lactobacillus, Bifidobacterium, and Bacteroides in group A were significantly increased compared to group B (p<0.001, p<0.001, and p< 0.01, respectively). There were also significant differences in the mean numbers of either of three bacteria between group A and the healthy control group; however, these differences between two groups were observed both at baseline and the end of the intervention. CONCLUSIONS Consumption of probiotic yogurt by patients with IBD may help to improve intestinal function by increasing the number of probiotic bacteria in the intestine and colon. However, many more studies are required in order to prove the concept.
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Variable deficits of bone mineral despite chronic glucocorticoid therapy in pediatric patients with inflammatory diseases: a Glaser Pediatric Research Network study.
von Scheven, E, Gordon, CM, Wypij, D, Wertz, M, Gallagher, KT, Bachrach, L
Journal of pediatric endocrinology & metabolism : JPEM. 2006;(6):821-30
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OBJECTIVE To evaluate the relationship between chronic glucocorticoid (GC) exposure and bone mineral density (BMD) in children with rheumatic diseases and inflammatory bowel disease. STUDY DESIGN Lumbar spine BMD was measured by DXA in 86 GC-treated children (66% female, age 8-20 years, mixed ethnicity) screened for a multi-center intervention trial. Predictors of spine BMD z-score and vitamin D [25(OH)D] were examined by multivariable linear regression. RESULTS Mean prior year and lifetime cumulative GC exposure was 77.8 mg/kg and 224.6 mg/kg, respectively. BMD z-scores ranged from -3.7 to 2.2 SD (-1.1 +/- 1.2, mean +/- SD). Lower BMD z-scores were associated with increased prior year average daily GC dose (p = 0.03), decreased height z-score (p = 0.003), and decreased 25(OH)D concentrations (p = 0.03), but explained only a small proportion of BMD variability (adjusted R2 = 0.29). The 25(OH)D levels were <20 ng/ml in 45% of patients, and low 25(OH)D was associated with non-Caucasian ethnicity (p <0.001), increased age (p = 0.004), increased parathyroid hormone (p = 0.03), and residing in the Boston area (p <0.001). CONCLUSIONS Although GC exposure is significantly associated with BMD z-score, the association is too variable to serve as a consistent predictor of reduced BMD in children. Vitamin D insufficiency is common and may contribute to skeletal deficits in this population.