Evaluation of Monocarboxylate Transporter 4 in Inflammatory Bowel Disease and Its Potential Use as a Diagnostic Marker.
Ontology highlight
ABSTRACT: Monocarboxylate transporter 4 (MCT4), encoded by SLC16A3 gene, is responsible for exporting lactic acid into the extracellular microenvironment, and an acidic microenvironment promotes cytokine production and remodels chronic inflammation, providing a link from glycolysis to inflammatory bowel disease (IBD).The aim of this study is to explore the value of MCT4 as a potential biomarker in IBD.The study group consisted of 39 cases with UC and 15 cases with CD. The centration of lactate level in serum was assessed by blood gas analysis, and MCT4 expression was analyzed by IHC.Lactate level was increased in the forty-three of 54 patients (79.6%) with IBD by blood gas analysis compared with normal level (P < 0.001), in line with the result that showed increased MCT4 expression in inflamed colonic mucosa analyzed by immunohistochemistry. Most importantly, abundance of MCT4 expression was significantly associated with mucosal inflammation, which could be a clinical prognosis marker.The data suggested that increased lactate level in blood was possibly due to highly expressed MCT4 expression caused by inflammation in intestinal mucosal epithelial tissue, which could be a prognosis indicator of IBD in children.
<h4>Background</h4>Monocarboxylate transporter 4 (MCT4), encoded by SLC16A3 gene, is responsible for exporting lactic acid into the extracellular microenvironment, and an acidic microenvironment promotes cytokine production and remodels chronic inflammation, providing a link from glycolysis to inflammatory bowel disease (IBD).<h4>Objective</h4>The aim of this study is to explore the value of MCT4 as a potential biomarker in IBD.<h4>Methods</h4>The study group consisted of 39 cases with UC and 15 ...[more]
Project description:NLRP3 inflammasome has emerged as a crucial regulator of inflammatory bowel disease (IBD) characterized by a chronic inflammatory disease of the gastrointestinal tract. The expression of MCT4 is significantly increased in intestinal mucosal tissue of IBD, which has been identified to regulate intestinal barrier function. However, the function of MCT4 in cell pyroptosis remained unknown. In this study, we have established a stable cell line with MCT4 overexpression in HT-29 and CaCO2 cells, respectively. Functional analysis revealed that ectopic expression of MCT4 in CaCO2 cells contributed to cell pyroptosis as evidenced by LDH assay, which is largely attributed to Caspase-1-mediated canonical pyroptosis, but not Caspase-4 and Caspase-5, leading to cleave pro-IL-1β and IL-18 into mature form and release mediated by cleaved GSDMD. Mechanically, MCT4 overexpression in HT-29 and CaCO2 cell triggered the phosphorylation of ERK1/2 and NF-κB p65, while inhibition of MCT4 by MCT inhibitor α-Cyano-4-hydroxycinnamic acid (α-CHCA) in HT-29 and CaCO2 cells led to a significant downregulation of ERK1/2 and NF-κB activity. What's more, blockade of ERK1/2-NF-κB pathway could reverse the promotion effect of MCT4 on IL-1β expression. Importantly, both MCT4 and Caspase-1, GSDMD were significantly increased in patients with IBD, and a positive clinical correlation between MCT4 and Caspase-1 expression was observed (p < 0.001). Taken together, these findings suggested that MCT4 promoted Caspase-1-mediated canonical cell pyroptosis to aggravate intestinal inflammation in intestinal epithelial cells (IECs) through the ERK1/2-NF-κB pathway.
Project description:The gut microbiome serves as a signaling hub that integrates environmental inputs with genetic and immune signals to influence the host's metabolism and immunity. Gut bacteria are intricately connected with human health and disease state, with specific bacteria species driving the characteristic dysbiosis found in gastrointestinal conditions such as inflammatory bowel disease (IBD); thus, gut bacteria changes could be harnessed to improve IBD diagnosis, prognosis, and treatment. The advancement in next-generation sequencing techniques such as 16S rRNA and whole-genome shotgun sequencing has allowed the exploration of the complexity of the gut microbial ecosystem with high resolution. Current microbiome data is promising and appears to perform better in some studies than the currently used fecal inflammation biomarker, calprotectin, in predicting IBD from healthy controls and irritable bowel syndrome (IBS). This study reviews current data on the differential potential of gut bacteria within IBD cohorts, and between IBD and other gastrointestinal diseases.
Project description:BackgroundInflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, are chronic inflammatory disorders that increase the risk for colorectal cancer. The mitochondrial translocator protein (TSPO) is a high-affinity drug- and cholesterol-binding protein expressed in the colon and its expression is increased in colon cancers. The aim of this study was to investigate TSPO expression in IBD biopsies and to establish an animal model of IBD to examine the role of TSPO. In addition, we evaluated the potential use of TSPO drug ligands in diagnosing and treating IBD.MethodsTSPO expression in IBD biopsies was evaluated using immunohistochemistry. IBD was induced in a rat experimental model via treatment with dextran sodium sulfate (DSS). Colon morphology, TSPO expression, and proinflammatory cytokine production were evaluated in addition to the effect of TSPO drug ligands on disease pathology.ResultsTSPO protein levels were elevated in the enterocytes of IBD biopsies. TSPO expression was localized to the enterocyte mitochondria. DSS treatment induced a time-dependent phenotype mimicking IBD with tissue injury and subsequent tissue regeneration. Coadministration of DSS and the TSPO drug ligands PK 11195 or Ro5-4864 increased both the rate of colon ulceration and regeneration, whereas administration of the TSPO drug ligand flunitrazepam partially prevented this pathology. These data correlated with changes in proinflammatory cytokine plasma levels, as well as increased cytokine production and secretion from the colon.ConclusionsTSPO may serve as a marker of the IBD repair process, and TSPO drug ligands should be further evaluated for IBD treatment.
Project description:Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure-activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth.
Project description:Azathioprine (AZA) and 6-mercaptopurine (6-MP) are the most widely used immunosuppressive therapies in inflammatory bowel disease. Pretreatment measurement of thiopurine methyltransferase (TPMT) activity is recommended and although conventional practice is to use a dose of 2 mg/kg AZA (1 mg/kg 6-MP), higher doses of 2.5 mg/kg AZA or more may be required in some patients, particularly if TPMT activity is high. Dose raising is limited by toxicity, and a robust monitoring system is mandatory. Patients with side effects to AZA may tolerate 6-MP but pancreatitis is a contraindication to switching. Metabolite monitoring is not widely available but may be useful, particularly if non-compliance is possible or where metabolite shunting to 6-methylmercaptopurine is suspected, on the basis of non-response or toxicity. It may allow dose optimisation before switching to alternative immunosuppressants. The drug appears safe in pregnancy and breast feeding. Long term duration of therapy is a balance between benefits in relation to the underlying disease extent, activity and aggressiveness, and the risk of neoplasia, particularly lymphoma.
Project description:Expression profiling of human colon mucosa samples aquired from inflammatory bowel disease patients and healthy controls. Expression profiling was done using Illumina Human HT-12 arrays, and data analysis was performed using tools from the Bioconductor package
Project description:Samples for microarray analysis were derived from terminal ileum and colonic tissues from probands with Crohn´s disease and Ulcerative Colitis and control patients, respectively. IBD tissue biopsies from non-inflamed regions 10 cm distant from pathological areas were selected. To minimize inter-individual differences in gene expression and to enrich for IBD-specific transcriptional events, 2.5 µg of total RNA from terminal ileum and colon transversum from four individuals of each patient and control group were used for pooling. Keywords = IBD Keywords = Crohn´s disease Keywords = Ulcerative Colitis Keywords: other
Project description:BackgroundData on opioid use in patients with inflammatory bowel disease and the relationship between disease, opioid use, and healthcare resource utilization are needed.MethodsThis analysis of real-world data from IBM Watson Health Commercial Claims and Encounters Database included patients with the first claim of inflammatory bowel disease (IBD) between 2007 and 2014.ResultsOpioid use was higher in patients with IBD than in the matched non-IBD cohort. Adjusted for age, gender, and Charlson Comorbidity Index score, inpatient and emergency room visits risk was higher in opioid users than non-users in both IBD cohorts.ConclusionsOpioid use could be a potential surrogate for inadequate disease control manifested by increased inpatient and emergency room visit risks. These results suggest a need exists for better disease management and the development of an outcomes measurement tool for IBD pain.
Project description:Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3?h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS (p?<?0.05). Changes in intestinal transmural impedance were correlated (p?<?0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3?h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.