Blood Of Inflammatory Bowel Disease Patients Research Articles

Assessment of anti-inflammatory efficacy of acupuncture in patients with inflammatory bowel disease: A systematic review and meta-analysis

BackgroundInflammation has a significant role in the onset and progression of inflammatory bowel disease (IBD). Increasing attention has been paid to the use of acupuncture in IBD patients; however, its regulatory effects on inflammatory factors in IBD still require validation. Here, we systematically evaluated the effects of acupuncture on inflammatory factors in IBD patients. MethodsEight electronic databases were searched for studies that met the inclusion criteria. After evaluating the quality of the studies selected by two reviewers, the meta-analysis was performed to assess the efficacy of acupuncture in IBD patients and the impact on inflammatory factors (TNF-α, IL-1, IL-8 and IL-10). ResultsFour randomized controlled trials with a total of 228 patients satisfied the inclusion criteria. Acupuncture has a positive therapeutic impact on IBD (MD = 1.22, 95% CI [1.07, 1.39], P = 0.003). Moreover, it regulates the levels of TNF-α (MD =−60.58, 95% CI [−100.30, −20.89], P = 0.003), IL-8 (MD =−56.40, 95% CI [−60.02, −52.14], P < 0.00001) and IL-10 (MD =35.96, 95% CI [11.02, 60.91], P = 0.005) in IBD patients. However, the P value of meta-analysis in IL-1 great than 0.05.(MD =−27.90, 95% CI [−97.82, 42.02], P = 0.11). ConclusionAcupuncture has a positive therapeutic impact on IBD and can effectively regulate inflammatory factors in IBD patients. TNF-α, IL-8 and IL-10 are more appropriate inflammatory indicators for clinically evaluating the anti-inflammatory response in the blood of IBD patients by acupuncture.

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides.

A "leaky" gut barrier has been implicated in the initiation and progression of a multitude of diseases, for example, inflammatory bowel disease (IBD), irritable bowel syndrome and celiac disease. Here we show how pro-hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352-372 ), the most abundant CgA-derived proteolytic peptide, affect the gut barrier. Colon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analysed by immunohistochemistry, western blot, ultrastructural and flowcytometry studies. FITC-dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250-301 ). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients. Plasma levels of CST were elevated in IBD patients. CST-KO mice displayed (a) elongated tight, adherens junctions and desmosomes similar to IBD patients, (b) elevated expression of Claudin 2, and (c) gut inflammation. Plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-KO mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-KO mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-KO mice supplementation with CST and/or PST in CgA-KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability. The pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts by antagonizing PST.

Emerging concepts in non-invasive monitoring of Crohn's disease.

Inflammatory bowel disease (IBD) is an umbrella term for Crohn’s disease (CD) and ulcerative colitis (UC). In light of evolving epidemiology of CD, its clinical management is still complex and remains a challenge for contemporary physicians. With the advent of new diagnostic and treatment paradigms, there is a growing need for new biomarkers to guide decision-making, differential diagnosis, disease activity monitoring, as well as prognosis. However, both clinical and endoscopic scoring systems, widely utilized for disease monitoring and prognosis, have drawbacks and limitations. In recent years, biochemical peptides have become available for IBD monitoring and more frequently used as surrogate markers of gut inflammation. Emerging concepts that revolve around molecular, stem cell, epigenetic, microbial or metabolomic pathways associated with vascular and epithelial gut barrier could lead to development of new CD biomarkers. Measurement of cell-derived microvesicles (MVs) in the blood of IBD patients is another emerging concept helpful in future disease management. In this review, we discuss novel concepts of non-invasive biomarkers, which may become useful in monitoring of CD activity and prognosis. We discuss metabolomics as a new powerful tool for clinicians to guide differential IBD diagnosis. In the coming years, new developments of prognostic tools are expected, aiming for breakthroughs in the management of patients with CD.

Aberrant function of myeloid-derived suppressor cells (MDSCs) in experimental colitis and in inflammatory bowel disease (IBD) immune responses

Background and aims: Myeloid-derived suppressor cells (MDSCs) encompass a novel population of suppressor cells and a potential candidate for cell-based therapies in inflammatory diseases. Herein, we investigated their immunomodulatory properties in experimental inflammatory colitis and T cell-mediated immune responses in inflammatory bowel disease (IBD) patients. Methods: MDSCs (defined as CD14−HLA−DR−/lowCD33+CD15+) numbers were determined in peripheral blood (PB) from IBD patients. PB MDSC function was assessed in vitro. Experimental colitis was induced upon 2,4,6-trinitrobenzene sulfonic acid (TNBS) treatment and MDSCs were characterized by flow cytometry. The in vivo suppressive potential of bone marrow (BM)-derived MDSCs (BM-MDSCs) was tested by using both depleting and adoptive transfer strategies. Results: MDSCs were enriched in the periphery of IBD patients during active disease. TNBS colitis induced amplification of MDSCs, particularly of the granulocytic (Ly6G+) subset during the effector phase of disease. Of interest, BM-MDSCs potently suppressed CD4+ T cell responses under steady state but failed to control colitis-associated immune responses in vivo. Mechanistically, under the colonic inflammatory milieu MDSCs switched phenotype (decreased proportion of Gr1high and increased numbers of Gr1low) and downregulated CCAAT/enhancer-binding protein beta (CEBPβ) expression, a critical transcription factor for the suppressive function of MDSCs. In accordance with the murine data, human CD33 + CD15+ MDSCs from peripheral blood of IBD patients not only failed to suppress autologous T cell responses but instead enhanced T cell proliferation in vitro. Conclusions: Our findings demonstrate an aberrant function of MDSCs in experimental inflammatory colitis and in IBD-associated immune responses in vitro. Delineation of the mechanisms that underlie the loss of MDSCs function in IBD may provide novel therapeutic targets.

Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease.

AIMTo identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTSComplete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.CONCLUSIONThiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.

Tu1882 FC Gamma Receptors Modulate the Inhibitory Efficacy of Infliximab in Blocking TNF-Mediated Responses in Blood and Intestine of IBD Patients

Background & Aims: Tumor necrosis factor (TNF) is an important cytokine in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF drugs have been implemented in IBD therapy. The efficacies of those drugs differ among individuals and they have not been tested in different tissues. The aim of this study was to evaluate their efficacies in ex vivo-treated perhipheral blood and intestine of both IBD patients and healthy individuals. Methods: Peripheral blood obtained from healthy donors and IBD patients was used for stimulation experiments with anti-TNF drugs. Peripheral blood mononuclear cells (PBMCs) were isolated and the efficacies of anti-TNFs were assessed by RT-PCR and ELISA. Expression levels of Fc receptors were examined by Western blotting and RT-PCR. To determine the activation of Fc receptors we measured the production of GM-CSF and CCL-2 mRNAs and phosphotyrosine signal in THP-1 cells. The expression levels of Fc receptors in human intestinal tissues and in PBMCs were determined by RT-PCR and Western blotting. Results: Both adalimumab (ADA) and infliximab (IFX) displayed significant limitations in blocking TNFmediated responses in ex vivo-treated peripheral blood from healthy donors as compared to certolizumab-pegol (CZP; p<0.001). ADA had significantly lower efficacy in PBMCs as compared to THP-1 cells (p<0.001), which was correlated with the increased expression levels of both low affinity Fc receptors CD16 and CD32. IFX, but no other anti-TNFs tested was less effective in peripheral blood of IBD patients as compared to healthy controls (p<0.05) when assessed by measuring the changes on mRNA levels of IL-8, TNF and ICAM as well as plasma release of IL-8 (p<0.05). These differences were correlated with an increase in mRNA levels of both low affinity Fc receptors CD16 and CD32 in PBMCs from IBD patients as compared to healthy individuals. In THP-1 cells IFX either alone or in complex with TNF, was more potent in activating Fc receptors as measured by the production of GM-CSF and CCL-2 mRNA (p<0.05). IFX/TNF but not ADA/TNF complexes induced IL8 mRNA production in THP-1 cells (p<0.05), which was accompanied by detection of distinct phospho-tyrosine signals. Increased colonic mRNA (p<0.05) and protein (p<0.001) expression levels of CD64 as well as mRNA levels of CD16 (p<0.001) were detected in inflamed tissues of IFX-non-responders as compared to IFX responders. These changes were correlated with elevated mRNA levels of cytokines regulating the expression of this receptor, namely GM-CSF (p<0.01) and IFN-γ (p<0.0001) as well as IL-8 (p<0.0001) and IL-6 (p<0.05). Conclusions: Fc receptors modulate the efficacy of IFX both exand In Vivo. These observations will help to optimize individual anti-TNF strategy in IBD patients with elevated systemic and local levels of Fc receptors.

Circulating soluble factor-inhibiting natural killer (NK) activity of fresh peripheral blood mononuclear cells (PBMC) from inflammatory bowel disease (IBD) patients.

This study was performed in order to assess the cytotoxic activity, both natural (NK) and antibody-dependent (ADCC), of PBMC from 38 IBD patients and correlate it with their clinical features. Cytotoxicity assays were performed using sensitive target cells for NK and ADCC activities. In some experiments, highly purified NK cells, obtained both by Percoll density gradient and by co-culturing non-adherent PBMC with RPMI 8866 feeder cells, were used as effector cells. Furthermore, we evaluated NK cell parameters such as number, surface expression of adhesion molecules (CD11a/CD18, CD49d and CD54) and response to different stimuli. We observed a decreased NK cytotoxicity of PBMC from IBD patients, both in ulcerative colitis (UC) and Crohn's disease (CD), independently of the clinical activity of disease. In contrast, the ADCC lytic activity was within normal range. The lower NK cytotoxic activity observed in our IBD patients cannot be related to a decreased number of NK cells, surface expression of adhesion molecules, defective response to IL-2 and maturative defect. Decreased NK activity was induced in PBMC of controls when serum of patients was added and this was unrelated to monocyte-derived modulating factor(s). Our data show a decreased natural killing by fresh PBMC from IBD patients. This lower activity seems to be unrelated to a primary NK cell defect, since purified NK cells exhibited normal levels of killing. It might be hypothesized that serum factors, possibly derived from lymphocytes, with inhibitory properties on NK activity, might be functionally active in the blood of IBD patients, thus modulating NK activity.