| 1. |
- Bergemalm, Daniel, 1977-, et al.
(författare)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 2. |
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| 3. |
- Carstens, Adam, 1975-, et al.
(författare)
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The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis
- 2019
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Ingår i: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD.METHODS: Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified.RESULTS: Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD.DISCUSSION: CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.
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| 5. |
- Juzenas, Simonas, et al.
(författare)
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Depletion of erythropoietic miR-486-5p and miR-451a improves detectability of rare microRNAs in peripheral blood-derived small RNA sequencing libraries
- 2020
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Ingår i: NAR Genomics and Bioinformatics. - Oxford, UK : Oxford University Press. - 2631-9268. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Erythroid-specific miR-451a and miR-486-5p are two of the most dominant microRNAs (miRNAs) in human peripheral blood. In small RNA sequencing libraries, their overabundance reduces diversity as well as complexity and consequently causes negative effects such as missing detectability and inaccurate quantification of low abundant miRNAs. Here we present a simple, cost-effective and easy to implement hybridization-based method to deplete these two erythropoietic miRNAs from blood-derived RNA samples. By utilization of blocking oligonucleotides, this method provides a highly efficient and specific depletion of miR-486-5p and miR-451a, which leads to a considerable increase of measured expression as well as detectability of low abundant miRNA species. The blocking oligos are compatible with common 5′ ligation-dependent small RNA library preparation protocols, including commercially available kits, such as Illumina TruSeq and Perkin Elmer NEXTflex. Furthermore, the here described method and oligo design principle can be easily adapted to target many other miRNA molecules, depending on context and research question.
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| 6. |
- Juzenas, Simonas, et al.
(författare)
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Detailed transcriptional landscape of peripheral blood points to increased neutrophil activation in treatment-naïve inflammatory bowel disease
- 2022
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 16:7, s. 1097-1109
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways.METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95).RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls.CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
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| 7. |
- Juzenas, S., et al.
(författare)
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Sequencing-based hematopoietic miRNA landscape reveals common and distinct features of autoimmune inflammatory phenotypes
- 2019
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 13:Suppl. 1, s. S614-S614
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: MiRNAs represent a class of small non-coding RNAs which are involved in regulation of protein-coding gene expression. Being implicated in various processes such as development and regu-latory circuits of cells, miRNAs also play an important role in the etiology of a variety of diseases. Imbalance of the regulatory pro-cesses within immune system development and response may lead to disturbed production of pro-inflammatory cytokines and over-reactivity of the immune cells, thus causing relapsing inflamma-tion, a characteristic feature of inflammatory bowel disease (IBD). Recent studies of colonic miRNAs employed NGS for the distinction between CD, UC and healthy controls, or among different CD sub-types. However, NGS-based profiles of blood-circulating miRNAs have thus far not been investigated in the context of IBD together with other immune-mediated diseases, including ankylosing spon-dylitis, psoriasis, systemic lupus erythematosus, rheumatoid arthritis and sarcoidosis, as well as non-immune hemolytic-uremic syndrome.Methods: Study participants were recruited in Germany and Sweden, where peripheral blood samples (PAXgene) as well as phenotypical and clinical information (such as treatment status, dis-ease activity and location) was collected. Small RNA transcriptomes of 680 individuals (Figure 1) were sequenced using Illumina NGS platform. Small RNA-seq data preprocessing and quantification were performed using cutadapt and miraligner (ref. miRBase v22), respectively. Differential expression analysis (DESeq2) and correla-tion (Spearman) analysis have been performed to identify disease activity-, trait- and treatment-specific miRNA signatures. These sig-natures were then utilized in a machine-learning approach to build classification models for IBD diagnostics.Results: The results of multiple pairwise differential expression anal-yses among different immune-mediated inflammatory conditions and healthy controls revealed inflammation-specific as well and dis-ease-specific deregulation of miRNAs. Correlation analysis identified miRNAs positively and negatively correlated with IBD activity. The preliminary results of machine learning classifiers based on miRNA profiles showed that median Matthews correlation coefficient for all model types showed remarkable predictive performance estimated as being 1.00 (median over main diagnoses), as well as ranging from 0.68 to 0.76 (median over CD location) and from 0.69 to 0.77 (median over UC extent).Conclusions: Immune-mediated inflammatory diseases share com-mon and distinct differentially expressed miRNAs, which have a potential to be used in the diagnostics of IBD, including the evalua-tion of the disease activity.
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| 9. |
- Keita, Åsa, et al.
(författare)
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Gut barrier dysfunction : a primary defect in twins with Crohn's disease predominantly caused by genetic predisposition
- 2018
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Ingår i: Journal of Crohn's & Colitis. - : Elsevier. - 1873-9946 .- 1876-4479. ; 12:10, s. 1200-1209
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The aetiology of Crohn's disease is poorly understood. By investigating twin pairs discordant for Crohn's disease we aimed to assess if the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function.Methods: Ileal biopsies from 15 twin pairs discordant for Crohn's disease (monozygotic n=9, dizygotic n=6) and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to51Chromium (Cr)-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins.Results: Healthy co-twins and affected twins displayed increased 51Cr-EDTA permeability at 120 min both with Acetylsalicylic acid (p<0.001) and without (p<0.001) when compared to controls. A significant increase in 51Cr-EDTA flux was seen already at 20 minutes in healthy monozygotic co-twins compared to controls (p≤0.05) when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins (p<0.05) and affected twins (p<0.05) compared to external controls, while ELISA only showed lower tricellulin in Crohn's disease twins (p<0.05).Conclusion: Our results suggest that barrier dysfunction is a primary defect in Crohn's disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation rather than representing a primary defect.
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| 10. |
- Ling Lundström, Maria, et al.
(författare)
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Fecal Biomarkers of Neutrophil and Eosinophil Origin Reflect the Response to Biological Therapy and Corticosteroids in Patients With Inflammatory Bowel Disease
- 2023
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Ingår i: Clinical and Translational Gastroenterology. - : Nature Publishing Group. - 2155-384X. ; 14:8
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Fecal calprotectin (FC) is anoninvasive tool for examining response to biologics in inflammatory boweldisease (IBD), but its performance in relation to other novel fecal markers of various cellular origins is unknown.Methods: We performed a prospective multicenter cohort study and included patients with active IBD who provided a fecal sample at initiation of biological therapy. Levels of FC, myeloperoxidase (MPO), human neutrophil lipocalin (HNL), and eosinophil-derived neurotoxin (EDN) were analyzed and related to clinical remission status at 3 months. Changes in levels of markers at 3 months were calculated, and the impact of concomitant use of corticosteroids at baseline was estimated.Results: In patients achieving clinical remission (n = 27), a decrease in levels of FC (P = 0.005), MPO (P < 0.001), HNL (P < 0.001), and EDN (P < 0.001) was observed, whereas no significant decrease was seen in patients not achieving remission (n = 39). There was a significant difference in the change in the level of MPO (P = 0.01) and HNL (P = 0.02) between patients achieving clinical remission and those who did not, but changes in FC and EDN could not differentiate between these groups. Patients with concomitant systemic corticosteroids at inclusion had lower levels of HNL (P = 0.01) and EDN (P < 0.001) at baseline, compared with patients without corticosteroids.Discussion: Fecal MPO, HNL, and EDN are all promising biomarkers for assessing the treatment outcome of biologics in patients with IBD. Fecal levels of EDN and HNL are significantly affected by corticosteroids indicating a greater sensitivity to the effects of corticosteroids compared with levels of FC and MPO.
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