Systemic Inflammation in Preclinical Ulcerative Colitis

Bergemalm, Daniel; Andersson, Erik; Hultdin, Johan; Eriksson, Carl; Rush, Stephen; Kalla, Rahul; Adams, Alexander T.; Keita, Åsa V.; D’Amato, Mauro; Gomollón, Fernando; Jahnsen, Jørgen; Arnott, Ian; Bayés, Mònica; Bonfiglio, Ferdinando; Boyapati, Ray; Carstens, Adam; Casèn, Christina; Ciemniejewska, Ewa; Dahl, Fredrik A.; Detlie, Trond Espen; Drummond, Hazel E.; Ekeland, Gunn S.; Ekman, Daniel; Frengen, Anna B.; Gullberg, Mats; Gut, Ivo; Gut, Marta; Heath, Simon; Hjelm, Fredrik; Hjortswang, Henrik; Ho, Gwo‐Tzer; Jonkers, Daisy; Söderholm, Johan D.; Kennedy, Nicholas A.; Lees, Charlie W; Lindahl, Torbjørn; Lindqvist, Carl Mårten; Merkel, Angelika; Modig, Eddie; Moen, Aina Elisabeth Fossum; Nilsen, Hilde; Nimmo, Elaine R.; Noble, Colin; Nordberg, Niklas; O'Leary, Kate; Ocklind, Anette; Olbjørn, Christine; Pettersson, Erik; Pierik, Marieke; Dominique,; Ricanek, Petr; Satsangi, Jack; Repsilber, Dirk; Karling, Pontus; Halfvarson, Jonas

doi:10.1053/j.gastro.2021.07.026

Cited by 81 publications

(55 citation statements)

References 56 publications

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“…Furthermore, investigations on healthy individuals suggest that regulatory variants, implicated in the majority of GWAS signals, act before disease onset [51]. In line with this, six proteins were upregulated in plasma samples obtained from individuals that developed UC later in life [52]. Three of these proteins were encoded by genes present among upregulated core enriched genes of the non-inflamed UC mucosa (CCL2, CCL11 and CXCL11), and two of these (CCL2 and CCL11) were present among the IBD GWAS-related genes.…”

Section: Differential Expression and Ibd Susceptibility Locimentioning

confidence: 61%

Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis

Söderman

Berglind

Almér

2022

IJMS

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Ulcerative colitis (UC) arises from a complex interplay between host and environmental factors, but with a largely unsolved pathophysiology. The pathophysiology was outlined by RNA-sequencing of mucosal biopsies from non-inflamed and inflamed colon of UC patients (14 and 17, respectively), and from 27 patients without intestinal inflammation. Genes differentially expressed (DE), or present in enriched gene sets, were investigated using statistical text analysis of functional protein information. Compared with controls, inflamed and non-inflamed UC mucosa displayed 9360 and 52 DE genes, respectively. Seventy-three non-pseudogenes were DE relative to both gender and inflammation. Mitochondrial processes were downregulated in inflamed and upregulated in non-inflamed UC mucosa, whereas angiogenesis and endoplasmic reticulum (ER) stress were upregulated in both tissue states. Immune responses were upregulated in inflamed mucosa, whereas the non-inflamed UC mucosa presented both up- and downregulated gene sets. DE and enriched genes overlapped with genes present in inflammatory bowel disease genome-wide associated loci (p = 1.43 × 10−18), especially regarding immune responses, respiratory chain, angiogenesis, ER stress, and steroid hormone metabolism. Apart from confirming established pathophysiological mechanisms of immune cells, our study provides evidence for involvement of less described pathways (e.g., respiratory chain, ER stress, fatty-acid oxidation, steroid hormone metabolism and angiogenesis).

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Section: Differential Expression and Ibd Susceptibility Locimentioning

confidence: 61%

Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis

Söderman

Berglind

Almér

2022

IJMS

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“…All these observations can be translated to other inflammatory diseases such as IBDs (inflammatory bowel diseases). In addition, for IBDs, a pro-inflammatory phase that precedes the onset of the disease has been described [93,94]. Dietary attitudes and Crohn's disease [95] have a strong link.…”

Section: The Reduction Of Gluten Load During Intestinal Infectionsmentioning

confidence: 99%

Pivotal Role of Inflammation in Celiac Disease

Barone

Auricchio

Nanayakkara

et al. 2022

IJMS

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Celiac disease (CD) is an immune-mediated enteropathy triggered in genetically susceptible individuals by gluten-containing cereals. A central role in the pathogenesis of CD is played by the HLA-restricted gliadin-specific intestinal T cell response generated in a pro-inflammatory environment. The mechanisms that generate this pro-inflammatory environment in CD is now starting to be addressed. In vitro study on CD cells and organoids, shows that constant low-grade inflammation is present also in the absence of gluten. In vivo studies on a population at risk, show before the onset of the disease and before the introduction of gluten in the diet, cellular and metabolic alterations in the absence of a T cell-mediated response. Gluten exacerbates these constitutive alterations in vitro and in vivo. Inflammation, may have a main role in CD, adding this disease tout court to the big family of chronic inflammatory diseases. Nutrients can have pro-inflammatory or anti-inflammatory effects, also mediated by intestinal microbiota. The intestine function as a crossroad for the control of inflammation both locally and at distance. The aim of this review is to discuss the recent literature on the main role of inflammation in the natural history of CD, supported by cellular fragility with increased sensitivity to gluten and other pro-inflammatory agents.

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“…Inhibition of MMP-10 activity via siRNA or blocking associated signaling resulted in the amelioration of colitis. Recent findings indicated that increased levels of serum MMP-10 represent an early event in the pathogenesis of UC ( 66 ). MMPs are also known to influence macrophage behavior, potentially involving their antigen-presenting function.…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis

Kong

Chen

et al. 2022

Front. Immunol.

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BackgroundUlcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and its incidence is steadily increasing worldwide. Intestinal immune dysfunction has been identified as a central event in UC pathogenesis. However, the underlying mechanisms that regulate dysfunctional immune cells and inflammatory phenotype remain to be fully elucidated.MethodsTranscriptome profiling of intestinal mucosa biopsies were downloaded from the GEO database. Robust Rank Aggregation (RRA) analysis was performed to identify statistically changed genes and differentially expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. CIBERSORT was used to evaluate the proportion of 22 immune cells in biopsies. Weighted co-expression network analysis (WGCNA) was used to determine key module-related clinical traits. Protein-Protein Interaction (PPI) network and Cytoscape were performed to explore protein interaction network and screen hub genes. We used a validation cohort and colitis mouse model to validate hub genes. Several online websites were used to predict competing endogenous RNA (ceRNA) network.ResultsRRA integrated analysis revealed 1838 statistically changed genes from four training cohorts (adj. p-value < 0.05). GSEA showed that statistically changed genes were enriched in the innate immune system. CIBERSORT analysis uncovered an increase in activated dendritic cells (DCs) and M1 macrophages. The red module of WGCNA was considered the most critical module related to active UC. Based on the results of the PPI network and Cytoscape analyses, we identified six critical genes and transcription factor NF-κB. RT-PCR revealed that andrographolide (AGP) significantly inhibited the expression of hub genes. Finally, we identified XIST and three miRNAs (miR-9-5p, miR-129-5p, and miR-340-5p) as therapeutic targets.ConclusionsOur integrated analysis identified four hub genes (CXCL1, IL1B, MMP1, and MMP10) regulated by NF-κB. We further revealed that AGP decreased the expression of hub genes by inhibiting NF-κB activation. Lastly, we predicted the involvement of ceRNA network in the regulation of NF-κB expression. Collectively, our results provide valuable information in understanding the molecular mechanisms of active UC. Furthermore, we predict the use of AGP and small RNA combination for the treatment of UC.

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Systemic Inflammation in Preclinical Ulcerative Colitis

Cited by 81 publications

References 56 publications

Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis

Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis

Pivotal Role of Inflammation in Celiac Disease

Identification of Immune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis

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