Early induction of C/EBPß expression as a potential marker of steroid responsive colitis.

The precise mechanism of hydrocortisone immune regulation in the management of colitis is poorly understood. Whilst not without limitations, its ability to suppress pathology and rapidly improve patient clinical outcome is key. We were interested in identifying early markers of therapeutic responsiveness in order to identify patients' refractory to therapy. Chronic Th1-driven colitis was induced in AKR/J mice using a parasite infection, Trichuris muris. 35 days post infection, mice were treated with low dose hydrocortisone (2 mg/kg/) i.p. on alternate days. Response to therapy was assessed at a systemic and tissue level day 45 post infection. Histopathology, gene and protein analysis was conducted to determine cytokine and transcriptional profiles. The colonic transcriptional profile in steroid treated mice showed significant upregulation of a small subset of T cell associated genes, in particular C/EBPß, CD4, IL7R and STAT5a. Despite no change in either transcription or protein production in downstream cytokines IFN γ, TNFα IL-17 and IL-10, hydrocortisone treatment significantly reduced colonic pathology and restored colonic length to naïve levels. As expected, steroid treatment of chronic gut inflammation generated significant immunosuppressive effects characterized by histological improvement. Low dose hydrocortisone induced significant upregulation of a subset of genes associated with T cell maintenance and regulation, including C/EBPß. These data suggest that enhanced expression of C/EBPß may be one of a subset of early markers demonstrating an immune regulatory response to hydrocortisone therapy, potentially by stabilization of Treg function. These observations contribute to our understanding of the immune landscape after steroid therapy, providing a potential markers of therapeutic responders and those refractory to hydrocortisone treatment.

A retrospective observational study of early experiences of vedolizumab treatment for inflammatory bowel disease in the UK: The REVIVE study.

Results from clinical trials show that vedolizumab is an efficacious treatment for inflammatory bowel disease, namely Crohn's disease (CD) and ulcerative colitis (UC). However, there is limited evidence from real-world clinical practice, especially on early clinical experiences in the UK.To describe real-world early experiences of vedolizumab to treat CD and UC in the UK.A retrospective, chart review study of patients with CD or UC treated with vedolizumab across 5 UK hospitals. All eligible adults (≥18 years at initiation) with a diagnosis of CD and ≥14 weeks of data or UC and ≥10 weeks of data available following vedolizumab initiation were included.Data were analyzed for 112 patients (CD: 66; UC: 46). Patients with CD had a median of 7.4 (interquartile range 5.7-9.4) months follow-up and patients with UC had a median of 7.4 (5.6-10.2) months follow-up post-vedolizumab initiation. Most patients, 80% (53/66) with CD and 89% (41/46) with UC, remained on vedolizumab treatment at the time of data collection. No new safety signals were identified during the study.These results add to the body of evidence supporting vedolizumab as an effective and well-tolerated treatment for CD and UC in real-world clinical practice.

Human monocytes and macrophages regulate immune tolerance via integrin αvß8-mediated TGFß activation.

Monocytes are crucial immune cells involved in regulation of inflammation either directly or via differentiation into macrophages in tissues. However, many aspects of how their function is controlled in health and disease are not understood. Here we show that human blood monocytes activate high levels of the cytokine TGFß, a pathway that is not evident in mouse monocytes. Human CD14+, but not CD16+, monocytes activate TGFß via expression of the integrin αvß8 and matrix metalloproteinase 14, which dampens their production of TNFα in response to LPS. Additionally, when monocytes differentiate into macrophages, integrin expression and TGFß-activating ability are maintained in anti-inflammatory macrophages but down-regulated in pro-inflammatory macrophages. In the healthy human intestine, integrin αvß8 is highly expressed on mature tissue macrophages, with these cells and their integrin expression being significantly reduced in active inflammatory bowel disease. Thus, our data suggest that integrin αvß8-mediated TGFß activation plays a key role in regulation of monocyte inflammatory responses and intestinal macrophage homeostasis.

A real-world, long-term experience on effectiveness and safety of vedolizumab in adult patients with inflammatory bowel disease: The Cross Pennine study.

BACKGROUND: Real-life data on vedolizumab effectiveness in inflammatory bowel disease (IBD) are still emerging. Data on the comparative safety of the gut selective profile are of particular interest. AIMS: To assess clinical outcome and safety in IBD patients treated with vedolizumab. METHODS: We retrospectively collected data of patients treated with vedolizumab at eight UK hospitals (August 2014-January 2018). Clinical response and remission at 14 and 52 weeks evaluated through Physician Global Assessment (PGA) and adverse events were recorded. Possible predictors of clinical response were examined. RESULTS: Two hundred and three IBD patients (mean treatment 16 ±â€¯8 months) were included. Of these, 135 patients (mean age 40.6 ±â€¯16.0 years; F:M 1.9:1) had CD and 68 (mean age 44.5 ±â€¯18.1 years; F:M 1:1.2) had UC. According to PGA, 106/135 (78.5%) CD and 62/68 (91.2%) UC patients (p = 0.02) had a clinical response/remission at 14 weeks, whereas 76/119 (63.9%) CD and 52/63 (82.5%) UC patients (p < 0.01) showed a sustained response or remission at 52 weeks, with a high adherence rate (97%). No predictors of clinical response were found. The cumulative incidence of infectious diseases was 11.9 per 100 person-years. CONCLUSION: Vedolizumab is an effective therapy for inducing and maintaining remission of IBD, with better results for UC, and with a good safety profile.

Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation.

BACKGROUND: Genetic susceptibility to colonic inflammation is poorly defined at the gene level. Although Genome Wide Association studies (GWAS) have identified loci in the human genome which confer susceptibility to Inflammatory Bowel Disease (Crohn's and Ulcerative Colitis), it is not clear if precise loci exist which confer susceptibility to inflammation at specific locations within the gut e.g. small versus large intestine. Susceptibility loci for colitis in particular have been defined in the mouse, although specific candidate genes have not been identified to date. We have previously shown that infection with Trichuris muris (T. muris) induces chronic colitis in susceptible mouse strains with clinical, histological, and immunological homology to human colonic Crohn's disease. We performed an integrative analysis of colitis susceptibility, using an F2 inter-cross of resistant (BALB/c) and susceptible (AKR) mice following T. muris infection. Quantitative Trait Loci (QTL), polymorphic and expression data were analysed alongside in silico workflow analyses to discover novel candidate genes central to the development and biology of chronic colitis. RESULTS: 7 autosomal QTL regions were associated with the establishment of chronic colitis following infection. 144 QTL genes had parental strain SNPs and significant gene expression changes in chronic colitis (expression fold-change ≥ +/-1.4). The T. muris QTL on chromosome 3 (Tm3) mapped to published QTL in 3 unrelated experimental models of colitis and contained 33 significantly transcribed polymorphic genes. Phenotypic pathway analysis, text mining and time-course qPCR replication highlighted several potential cis-QTL candidate genes in colitis susceptibility, including FcgR1, Ptpn22, RORc, and Vav3. CONCLUSION: Genetic susceptibility to induced colonic mucosal inflammation in the mouse is conserved at Tm3 and overlays Cdcs1.1. Genes central to the maintenance of intestinal homeostasis reside within this locus, implicating several candidates in susceptibility to colonic inflammation. Combined methodology incorporating genetic, transcriptional and pathway data allowed identification of biologically relevant candidate genes, with Vav3 newly implicated as a colitis susceptibility gene of functional relevance.

Paraneoplastic oesophageal dysmotility-renal cell carcinoma presenting as dysphagia: a case report.

INTRODUCTION: Dysphagia and weight loss are alarming symptoms that warrant urgent assessment. CASE PRESENTATION: We present a case report of dysphagia secondary to oesophageal dysmotility attributed to a paraneoplastic manifestation of an occult renal cell carcinoma. CONCLUSION: We believe this patient's dysphagia was a paraneoplastic manifestation of the renal cell tumour, an association that has never been previously reported. This case demonstrates the need to look for alternative causes for dysphagia if initial investigation and treatment are unhelpful. Importantly, this must include the consideration of a paraneoplastic process secondary to an occult neoplasm.

Enteroendocrine cells: neglected players in gastrointestinal disorders?

Enteroendocrine cells (EEC) form the basis of the largest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and homeostatic functions, particularly postprandial secretion and motility. Their key purpose is to act as sensors of luminal contents, either in a classical endocrine fashion, or by a paracrine effect on proximate cells, notably vagal afferent fibres. They also play a pivotal role in the control of food intake, and emerging data add roles in mucosal immunity and repair. We propose that EEC are fundamental in several gastrointestinal pathologies, notably Post-infectious Irritable Bowel Syndrome, infectious enteritis, and possibly inflammatory bowel disease. Further work is needed to fully illustrate the importance, detailed biology and therapeutic potential of these frequently overlooked cells.