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The Anti-inflammatory Immune Regulation Induced by Butyrate Is Impaired in Inflamed Intestinal Mucosa from Patients with Ulcerative Colitis.

ABSTRACT: Altered gut microbiota composition and reduced levels of short-chain fatty acids, such as butyrate, have been identified as key components of ulcerative colitis (UC). We aimed to determine and compare effects of butyrate on the intestinal immune profile of UC patients with active disease and non-inflamed controls. Biopsies were cultivated during 6 h with or without butyrate. Cytokines were measured in supernatants and mRNA gene expression was analyzed in biopsies using Qiagen RT² Profiler PCR Arrays. The intestinal immune profile of cultured biopsies, as determined by mRNA gene expression and secreted cytokines, differed between inflamed UC samples and controls. Principal component analysis revealed that addition of butyrate differently regulated mRNA expression in inflamed biopsies from UC and non-inflamed biopsies from controls. Highly discriminant and predictive orthogonal partial least squares discriminant analyses identified 29 genes for UC (R2 = 0.94, Q2 = 0.86) and 23 genes for controls (R2 = 0.90, Q2 = 0.71) that were most regulated by butyrate. UC displayed more up-regulation of genes as compared with controls, and controls displayed the most prominent down-regulations. Ingenuity Pathway Analysis identified a down regulation of the Neuroinflammation Signaling pathway and predicted inhibition of the categories Inflammatory response, cellular movement, and cellular development as top diseases and functions, respectively, for controls but not for UC. In conclusion, butyrate has a different effect on gene regulation and more potently down-regulates gene expression of inflammatory pathways in non-inflamed controls than in inflamed tissue of UC patients. These discrepancies may at least partly explain why anticipated anti-inflammatory effects of local butyrate induction or supplementation are not always obtained.

SUBMITTER: Magnusson MK

PROVIDER: S-EPMC7170981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Ulcerative colitis (UC) is a complicated disease caused by the interaction between genetic and environmental factors that affect mucosal homeostasis and triggers inappropriate immune response. The purpose of the study was to identify significant biomarkers with potential therapeutic targets and the underlying mechanisms. Methods:The gene expression profiles of GSE48958, GSE73661, and GSE59071 are from the GEO database. Differentially expressed genes (DEGs) were screened by the GEO2R tool. Next, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was applied to analyze gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Then, protein-protein interaction (PPI) was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Results:There were a total of 128 common DEGs genes, including 86 upregulated genes enriched in extracellular space, regulation of inflammatory response, chemokine-mediated signaling pathway, response to lipopolysaccharide, and cell proliferation, while 42 downregulated genes enriched in the integral component of the membrane, the integral component of the plasma membrane, apical plasma membrane, symporter activity, and chloride channel activity. The KEGG pathway analysis results demonstrated that DEGs were particularly enriched in cytokine-cytokine receptor interaction, TNF signaling pathway, chemokine signaling pathway, pertussis, and rheumatoid arthritis. 18 central modules of the PPI networks were selected with Cytotype MCODE. Furthermore, 18 genes were found to significantly enrich in the extracellular space, inflammatory response, chemokine-mediated signaling pathway, TNF signaling pathway, regulation of cell proliferation, and immune response via reanalysis of DAVID. Conclusion:The study identified DEGs, key target genes, functional pathways, and pathway analysis of UC, which may provide potential molecular targets and diagnostic biomarkers for UC.

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The Anti-inflammatory Immune Regulation Induced by Butyrate Is Impaired in Inflamed Intestinal Mucosa from Patients with Ulcerative Colitis.

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