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Background: Alterations in kidney function and increased risk of kidney diseases in patients with inflammatory bowel disease (IBD) have been reported, but the causal relationship remains unclear. Herein, Mendelian randomization was employed to identify the causal effect of inflammatory bowel disease on kidney function and the risk of chronic kidney disease (CKD), urolithiasis, and IgA nephropathy., Methods: The International Inflammatory Bowel Disease Genetics Consortium provided the summary-level genome-wide association study (GWAS) data that correlates with Crohn's disease (CD) and ulcerative colitis (UC). GWAS data for estimated glomerular filtration rate from serum creatinine (eGFRcrea), urine albumin-creatinine ratio (uACR), and CKD were obtained from the CKDGen Consortium, and GWAS data for urolithiasis were obtained from the FinnGen consortium. The summary-level GWAS data for IgA nephropathy were obtained from the meta-analysis of UK-biobank, FinnGen, and Biobank Japan. Inverse-variance weighted was used as the primary estimate. Furthermore, the Steiger test was used to validate the direction of causality., Results: The inverse-variance weighted data revealed that genetically predicted UC significantly increased uACR levels, while genetically predicted CD significantly increased the risk of urolithiasis., Conclusions: UC increases the levels of uACR, and CD increases the risk of urolithiasis., (© 2023. The Author(s).)

Introduction: Patients with inflammatory bowel disease (IBD) might be at an increased risk for the development of cardiovascular disease (CVD). The present protocol is developed to review and analyse published data to determine if patients with IBD have an increased CVD burden., Methods and Analysis: We will conduct a systematic review of all observational studies that examine endothelial function, arterial stiffness and carotid intima-media thickness in patients with IBD. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and study quality will be assessed using the Newcastle-Ottawa Scale. If sufficient data are available, a meta-analysis will be conducted. The overall effect sizes will be estimated using both fixed effects models and random effects models. Statistical heterogeneity will be calculated using Higgin's (I 2 ) tests. Subgroup analyses, conditional number of studies retrieved and their sample size, will be stratified according to participant disease category or gender or disease activity., Ethics and Dissemination: Formal ethics approval is not required as individual data will not be collected. The results will be disseminated through peer-reviewed publications, conference presentations and scientific news releases., Prospero Registration Number: CRD42021274093., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To investigate the role of Coxsackie-adenovirus receptor (CAR) in inflammatory bowel disease (IBD)., Background: CAR, a type I transmembrane protein with functions in virus attachment, has been shown to be associated with epithelial tight junctions (TJs) and mediates cell adhesion, implying its potential roles in the pathogenesis of IBD., Methods and Materials: To determine the effect of CAR in IBD using QPCR and Western blotting to determine the expression of CAD in TNF- α induced NCM460 and SW480 cells and IBD tissues compared to control groups. Furthermore, TJs dysregulation, FITC-Dextran permeability assay, qRT-PCR, Western blot, and IF assessed the permeability in CAR overexpressed cells treated with TNF- α . HE, qRT-PCR, Western blot, and IHC assay were used to assess the CAR overexpressed cells whether they have the effect to cure DSS induced ulcerative colitis rat model in vivo ., Result: We found CAR levels in human colon cell lines are significantly downregulated under the treatment of tumor necrosis factor-alpha (TNF- α ). Furthermore, overexpression of CAR markedly prevented TNF- α induced inflammatory response, TJs dysregulation, and permeability disruption (FITC-Dextran permeability assay) in cells. Consistent with these findings in vitro , we found that CAR overexpression could suppress gut inflammation, attenuate the downregulation of TJ protein ZO-1 and Occludin, and limit the induction of barrier permeability in a DSS induced ulcerative colitis rat model in vivo . Together, our findings strongly suggest that CAR could protect tight junctions and has an anti-inflammatory effect during the pathogenesis of IBD. Thus CAR may serve as a therapeutic target for the diagnosis and treatment of IBD.

Simple Summary: The present study examines the effect of experimental inflammatory bowel disease on femoral artery endothelial function and limb ischemia recovery in female mice using a chronic colitis model induced by dextran sodium sulfate exposure. As expected, plasma levels of proinflammatory cytokines, including interleukin-6, interleukin-17, tumor necrosis factor alpha, and chemokine ligand 1, were significantly increased in the chronic colitis model. However, ROS levels in the ischemic muscle tissues were not significantly increased in mice with colitis as compared to controls. There were no significant changes in endothelium-dependent or -independent vasodilation of femoral artery between the colitis model and the control. Recovery of function and blood flow of the ischemic limb and capillary density in the ischemic muscle were preserved in the colitis model as compared with the control. Inflammatory bowel disease (IBD) produces significant systemic inflammation and increases the risk of endothelial dysfunction and peripheral artery disease. Our recent study demonstrated that abdominal aortic endothelial cell function was impaired selectively in female mice with chronic colitis. This study aimed to test the hypothesis that experimental colitis leads to femoral artery endothelial cell dysfunction and impairs limb ischemia recovery in female mice. An experimental chronic colitis model was created in female C57BL/6 mice with dextran sodium sulfate (DSS) treatment. Unilateral hind limb ischemia was produced by femoral artery ligation. Limb blood perfusion, vascular density, tissue ROS levels, and plasma levels of proinflammatory cytokines were assessed. Femoral artery endothelium-dependent and -independent vasodilation of the contralateral limb were evaluated ex vivo using acetylcholine and nitroglycerin, respectively. As expected, the plasma levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-17, were significantly increased in the DSS-induced colitis model. However, ROS levels in the ischemic muscle tissues were not significantly increased in colitis model as compared to the controls. There were no significant changes in endothelium-dependent or -independent vasodilation of the femoral artery between colitis model and the control. Recovery of function and blood flow in the ischemic limb and capillary density in the ischemic gastrocnemius muscle were preserved in the colitis model as compared with the control. The data demonstrated that DSS-induced chronic colitis had no significant impact on femoral artery endothelial function or ischemic limb recovery in female mice. [ABSTRACT FROM AUTHOR]

Population-based studies have suggested that patients with inflammatory bowel disease (IBD) might be at an increased risk for cardiovascular diseases. A meta-analysis was performed on clinical studies to evaluate endothelial function, arterial stiffness, and carotid intima-media thickness (cIMT) in patients with IBD, after searching PubMed, Embase, Cochrane library, and Web of Science databases. A random-effects model was used to allow for the pooling of studies and for determination of the overall effect. After exclusion, a total of 41 eligible studies with 2330 patients with IBD and 2032 matched controls were identified and included for the analysis. It was found that cIMT was significantly increased in patients with IBD as compared with that in matched controls (Cohen's d: 0.63; 95% CI: 0.34, 0.93; I2 = 91.84%). The carotid–femoral pulse wave velocity was significantly higher in patients with IBD compared to that in matched controls (Cohen's d: 0.76; 95% CI: 0.54, 0.98; I2 = 70.03%). The augmentation index was also significantly increased in patients with IBD compared to matched control subjects (Cohen's d: 0.35; 95% CI: 0.08, 0.63; I2 = 61.37%). Brachial artery flow-mediated dilatation was significantly decreased in patients with IBD than that in matched controls (Cohen's d: −0.73; 95% CI: −1.10, −0.36; I2 = 81.02%). Based on the meta-analysis, it was found that patients with IBD exhibit significant endothelial dysfunction, increased arterial stiffness, and cIMT. Thus, patients with IBD may benefit from aggressive risk stratification for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: The chronic infection with Helicobacter pylori (H. pylori), especially cytotoxin-associated gene A-positive (CagA+) strains, has been associated with various extragastric disorders. Evaluating the potential impacts of virulence factor CagA on intestine may provide a better understanding of H. pylori pathogenesis such as colitis. The intestinal mucosal barrier is essential for maintaining its integrity and functions. However, how persistent CagA+H. pylori colonization influences barrier disruption and thereby affects chronic colitis is not fully understood. Results: Chronic colitis models of CagA+H. pylori-colonized mice treated with 2% Dextran sulphate sodium (DSS) were established to assess the disease activity and pertinent expression of tight junction proteins closely related to mucosal integrity. The aggravating effect of CagA+H. pylori infection on DSS-induced chronic colitis was confirmed in mouse models. In addition, augmented Claudin-2 expression was detected in CagA+H. pylori infection conditions and selected for mechanistic analysis. Next, GES-1 human gastric epithelial cells were cultured with CagA+H. pylori or a recombinant CagA protein, and exosomes isolated from conditioned media were then identified. We assessed the Claudin-2 levels after exposure to CagA+ exosomes, CagA− exosomes, and IFN-γ incubation, revealing that CagA+H. pylori compromised the colonic mucosal barrier and facilitated IFN-γ-induced intestinal epithelial destruction through CagA-containing exosome-mediated mechanisms. Specifically, CagA upregulated Claudin-2 expression at the transcriptional level via a CDX2-dependent mechanism to slow the restoration of wounded mucosa in colitis in vitro. Conclusions: These data suggest that exosomes containing CagA facilitate CDX2-dependent Claudin-2 maintenance. The exosome-dependent mechanisms of CagA+H. pylori infection are indispensable for damaging the mucosal barrier integrity in chronic colitis, which may provide a new idea for inflammatory bowel disease (IBD) treatment. [ABSTRACT FROM AUTHOR]