Publications

    • 26 JUL 16
    • 0
    Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis

    Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis

    Tertiary lymphoid tissue (TLT) is lymphoid tissue that forms in adult life as a result of chronic inflammation in a tissue or organ. TLT has been shown to form in a variety of chronic inflammatory diseases, though it is not clear if and how TLT develops in the inflamed colon during inflammatory bowel disease. Here, we show that TLT develops as newly formed lymphoid tissue in the colon following dextran sulphate sodium induced colitis in C57BL/6 mice, where it can be distinguished from the preexisting colonic patches and solitary intestinal lymphoid tissue. TLT in the inflamed colon develops following the expression of lymphoid tissue-inducing chemokines and adhesion molecules, such as CXCL13 and VCAM-1, respectively, which are produced by stromal organizer cells. Surprisingly, this process of TLT formation was independent of the lymphotoxin signaling pathway, but rather under neuronal control, as we demonstrate that selective surgical ablation of vagus nerve innervation inhibits CXCL13 expression and abrogates TLT formation without affecting colitis. Sympathetic neuron denervation does not affect TLT formation. Hence, we reveal that inflammation in the colon induces the formation of TLT, which is controlled by innervation through the vagus nerve.

    • 08 JUN 16
    • 0
    Peripheral blood methylation profiling of female Crohn’s disease patients

    Peripheral blood methylation profiling of female Crohn’s disease patients

    Crohn’s disease (CD) is a chronic inflammatory disorder belonging to the inflammatory bowel diseases (IBD). CD affects distinct parts of the gastrointestinal tract, leading to symptoms including diarrhea, fever, abdominal pain, weight loss, and anemia. The aim of this study was to assess whether the DNA methylome of peripheral blood cells can be associated with CD in women. Samples were obtained from 18 female patients with histologically confirmed ileal or ileocolic CD and 25 healthy age- and gender-matched controls (mean age and standard deviation: 30.5 ± 6.5 years for both groups). Genome-wide DNA methylation was determined using the Illumina HumanMethylation 450k BeadChip. Our analysis implicated 4287 differentially methylated positions (DMPs; corrected p < 0.05) that are associated to 2715 unique genes. Gene ontology enrichment analysis revealed significant enrichment of our DMPs in immune response processes and inflammatory pathways. Of the 4287 DMPs, 32 DMPs were located on chromosome X with several hits for MIR223 and PABPC5. Comparison with previously performed (epi)genome-wide studies revealed that we replicated 33 IBD-associated genes. In addition to DMPs, we found eight differentially methylated regions (DMRs). CD patients display a characteristic DNA methylation landscape, with the differentially methylated genes being implicated in immune response. Additionally, DMPs were found on chromosome X suggesting X-linked manifestations of CD that could be associated with female-specific symptoms.

    • 19 MEI 16
    • 0
    Mucosal integrity and sensitivity to acid in the proximal esophagus in patients with gastroesophageal reflux disease

    Mucosal integrity and sensitivity to acid in the proximal esophagus in patients with gastroesophageal reflux disease

    Acid reflux episodes that extend to the proximal esophagus are more likely to be perceived. This suggests that the proximal esophagus is more sensitive to acid than the distal esophagus, which could be caused by impaired mucosal integrity in the proximal esophagus. Our aim was to explore sensitivity to acid and mucosal integrity in different segments of the esophagus. We used a prospective observational study, including 12 patients with gastroesophageal reflux disease (GERD). After stopping acid secretion-inhibiting medication, two procedures were performed: an acid perfusion test and an upper endoscopy with electrical tissue impedance spectroscopy and esophageal biopsies. Proximal and distal sensitivity to acid and tissue impedance were measured in vivo, and mucosal permeability and epithelial intercellular spaces at different esophageal levels were measured in vitro. Mean lag time to heartburn perception was much shorter after proximal acid perfusion (0.8 min) than after distal acid perfusion (3.9 min) (P = 0.02). Median in vivo tissue impedance was significantly lower in the distal esophagus (4,563 Ω·m) compared with the proximal esophagus (8,170 Ω·m) (P = 0.002). Transepithelial permeability, as measured by the median fluorescein flux was significantly higher in the distal (2,051 nmol·cm(-2)·h(-1)) than in the proximal segment (368 nmol·cm(-2)·h(-1)) (P = 0.033). Intercellular space ratio and maximum heartburn intensity were not significantly different between the proximal and distal esophagus. In GERD patients off acid secretion-inhibiting medication, acid exposure in the proximal segment of the esophagus provokes symptoms earlier than acid exposure in the distal esophagus, whereas mucosal integrity is impaired more in the distal esophagus. These findings indicate that the enhanced sensitivity to proximal reflux episodes is not explained by increased mucosal permeability.

    • 11 MEI 16
    • 5
    The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC

    The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC