The causal relationship between cholecystectomy and IBD/IBS and the role of bile acids and gut microbiota: a two-sample Mendelian randomization study.

OBJECTIVE: This study aims to explore the causal relationship between cholecystectomy and inflammatory bowel disease (IBD)/irritable bowel syndrome (IBS) and the role of serum bile acids and gut microbiota in this context. METHODS: Utilizing genetic variant data from previous Genome-Wide Association Studies (GWAS), this study employed a two-sample MR approach to assess the causal effect of cholecystectomy on IBD/IBS. RESULTS: The MR analysis suggested a potential negative causal relationship between cholecystectomy and UC (p = 0.0233, OR 0.9773, 95%CI 0.9581-0.9969) and a positive causal relationship between cholecystectomy and IBS (p = 0.0395, OR 4.077, 95%CI 1.0699-15.5362). Various sensitivity analyses reinforced the reliability of the causal relationship. However, the analysis did not find definitive results between serum bile acids or gut microbiota and cholecystectomy or IBD/IBS, possibly due to insufficient statistical power. MVMR find a causal relationship between bile acids and IBS (p = 0.0015, b = 0.4085) and UC (p = 0.0198, b = 0.0029). CONCLUSION: This study provides evidence of a causal relationship between cholecystectomy and IBD/IBS, highlighting the potential risk reduction for UC and increased risk for IBS following cholecystectomy. The role of bile acids and gut microbiota in this relationship remains unclear, necessitating further research to validate the causality and explore underlying mechanisms.

Unravelling the role of beta-CGRP in inflammatory bowel disease and its potential role in gastrointestinal homeostasis.

BACKGROUND: The role of beta calcitonin gene-related peptide (beta-CGRP) in gastrointestinal tract is obscure, but experimental models suggest an effect on the homeostasis of the intestinal mucosa. We measured beta-CGRP circulating levels in a large series of subjects with a recent diagnosis of inflammatory bowel disease (IBD), in order to assess the potential role of this neuropeptide in IBD pathogenesis. METHODS: Morning serum beta-CGRP levels were measured by ELISA (CUSABIO, China) in 96 patients recently diagnosed of IBD and compared with those belonging from 50 matched healthy controls (HC) and 50 chronic migraine (CM) patients. RESULTS: Beta-CGRP levels were lower in patients with IBD (3.1 ± 1.9 pg/mL; 2.9 [2.4-3.4] pg/mL) as compared to HC (4.7 ± 2.6; 4.9 [4.0-5.8] pg/mL; p < 0.001) and to CM patients (4.6 ± 2.6; 4.7 [3.3-6.2] pg/mL; p < 0.001). Beta-CGRP levels in CM were not significantly different to those of HC (p = 0.92). Regarding IBD diagnostic subtypes, beta-CGRP levels for ulcerative colitis (3.0 ± 1.9pg/mL; 2.5 [2.1-3.4] pg/mL) and Crohn's disease (3.3 ± 2.0 pg/mL; 3.2 [2.4-3.9] pg/mL) were significantly lower to those of HC (p < 0.01 and p < 0.05, respectively) and CM (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: We have found a significant reduction in serum beta-CGRP levels in patients with a recent diagnosis of all kinds of IBD as compared to two control groups without active intestinal disease, HC and CM, which may suggest a role for this neuropeptide in the pathophysiology of IBD. Our data indicate a protective role of beta-CGRP in the homeostasis of the alimentary tract.

Procalcitonin in inflammatory bowel disease: A diagnostic or prognostic marker.

Serological biomarkers have been rapidly progressing as non-invasive tests for the early detection of inflammatory bowel disease (IBD). Procalcitonin (PCT) is a novel acute-phase reactant protein that is elevated in the inflammatory process, especially in bacterial infections. This study aimed to review the diagnostic value of PCT in IBD activity. However, there were controversies about the role of PCT in the detecting of IBD disease activity. Studies showed varied diagnostic cut-points (ranging from 0.13 to 1.0 ng/dl) and sensitivity up to 93 %. Although the clear role of PCT as a valuable diagnostic marker was not identified in determining disease activity, PCT measurement in addition to other inflammatory markers can improve the diagnostic value of these markers. Moreover, further studies are required to confirm PCT's value in distinguishing IBD disease activity.

Characterization of faecal microbiota and serum inflammatory markers in dogs diagnosed with chronic enteropathy or small-cell lymphoma: a pilot study.

Dogs diagnosed with chronic enteropathy (CE) or small-cell lymphoma (SCL) exhibit marked differences in faecal microbiota and organic acid profiles compared with healthy dogs, as well as immune abnormalities in intestinal mucosal tissue. However, few studies have analysed trace organic acids, such as succinic acid, which have been suggested to be associated with IBD in humans. Therefore, in this study, we compared the faecal microbiota and organic acid profiles as well as serum inflammatory markers between dogs with disease (n = 11; 6 with CE and 5 with SCL) and healthy controls (n = 16). We also performed machine learning and correlation analysis to obtain more detailed insights into the characteristics of affected dogs. These results revealed that dogs with CE and SCL had lower levels of Erysipelotrichaceae (e.g. Turicibacter and Allobaculum), exhibited abnormalities in the succinic acid metabolism (i.e. succinic acid accumulation and decreased levels of Phascolarctobacterium as succinic acid-utilising bacteria) and increased levels of pathobiont bacteria such as Escherichia-Shigella. Additionally, the presence of Dubosiella was significantly negatively correlated with Canine Inflammatory Bowel Disease Activity Index scores. These findings are expected to aid the development of microbiome-based medications and/or supplements, although further verification is needed.

Evaluating the causal effect of circulating proteome on the risk of inflammatory bowel disease-related traits using Mendelian randomization.

Objective: This study sought to identify circulating proteins causally linked to Inflammatory Bowel Disease (IBD) traits through a Mendelian Randomization (MR) analytical framework. Methods: Using a large-scale, two-sample MR approach, we estimated the genetic links of numerous plasma proteins with IBD and its subtypes, leveraging information from the Inflammatory Bowel Disease Genetics Consortium. To assess the robustness of MR findings, methods like Bayesian colocalization, and Steiger filtering analysis, evaluation of protein-altering variants. Further insights into IBD's underlying mechanisms and therapeutic targets were gleaned from single-cell sequencing analyses, protein-protein interaction assessments, pathway enrichment analyses, and evaluation of drug targets. Results: By cis-only MR analysis, we identified 83 protein-phenotype associations involving 27 different proteins associated with at least one IBD subtype. Among these proteins, DAG1, IL10, IL12B, IL23R, MST1, STAT3 and TNFRSF6B showed overlapping positive or negative associations in all IBD phenotypes. Extending to cis + trans MR analysis, we further identified 117 protein-feature associations, including 44 unique proteins, most of which were not detected in the cis-only analysis. In addition, by performing co-localization analysis and Steiger filtering analysis on the prioritized associations, we further confirmed the causal relationship between these proteins and the IBD phenotype and verified the exact causal direction from the protein to the IBD-related feature. Conclusion: MR analysis facilitated the identification of numerous circulating proteins associated with IBD traits, unveiling protein-mediated mechanisms and promising therapeutic targets.

Liver enzyme profiles after initiating biological treatment in children with inflammatory bowel diseases.

OBJECTIVES: Biological treatments (BTs) are essential in managing pediatric inflammatory bowel diseases (PIBDs). Elevated liver enzymes sometimes succeed BT, yet elucidating studies are scarce. We addressed liver biochemistry after introducing BT and searched for their determinants. METHODS: We identified PIBD patients receiving infliximab, adalimumab, vedolizumab, or ustekinumab at the Children's Hospital, University of Helsinki, Finland, in 2000-2023, and followed their alanine transaminase (ALT) and γ-glutamyl transpeptidase (GT) levels for 24 months. ALT was categorized based on the age- and sex-specific upper limit of normal. We disregarded 46 patients with underlying primary sclerosing cholangitis with/without autoimmune hepatitis (AIH), pretreatment AIH diagnosis, and elevated liver enzymes at the beginning of BT from the analyses. RESULTS: Of 618 BT episodes in 403 patients, 22.2% exhibited increased ALT or GT (ALT in 117, GT in 4, and both ALT/GT in 16 episodes). Of all ALT elevations (n = 133), 41.4% occurred within the first 3 months. ALT elevation was more common after infliximab (representing 59.5% of BTs) than other BTs (25.9% vs. 14.2%, adjusted odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.23-4.72). AIH followed 1.5% (n = 9) of BT episodes. Ninety-five percent of ALT elevations resolved within 6 months. Antibiotic exposure (particularly to metronidazole) was associated with ALT elevation in general (adjusted OR: 5.76, 95% CI: 2.40-13.9) and short disease duration before starting BT with notable ALT elevation (adjusted OR: 1.10, 95% CI: 1.01-1.22). CONCLUSIONS: Benign ALT elevation is common within 3 months after starting BT (especially infliximab) and scarcely led to cessation of the treatment. AIH is a rare finding during the first year of BT.

Assessment of IBD disease activity by Interleukin-6 and serum amyloid A in relation with fecal calprotectin and endoscopic indices.

BACKGROUND AND STUDY AIMS: Close monitoring of disease activity in IBD patients is essential to avoid long term complications. Although endoscopic assessment is the ideal monitoring tool, the usage of noninvasive biomarkers is more practical and patient friendly. We aimed to study the performance of Interleukin-6(IL-6) and Serum Amyloid A(SAA) as serum biomarkers in assessment of the disease activity of IBD patients in correlation to C-reactive protein (CRP), Fecal Calprotectin (FC) and endoscopic indices. METHODS: 83 IBD (26 CD and 57 UC) patients on stable treatment regimen were recruited. Serum markers included CRP, CBC, IL-6, SAA were analyzed, together with FC. These markers were compared with the endoscopic and clinical disease parameters. Harvey-Bradshaw Index (HBI) and the Simple Clinical Colitis Activity Index (SCCAI) were used to assess clinical activity in CD and UC patients, respectively. Endoscopic activity was recorded using the Simple Endoscopic Score (SES) for Crohn's disease or the Mayo Endoscopic Score (MES) for ulcerative colitis. RESULTS: In prediction of disease activity, IL-6, SAA and CRP demonstrated good area under receiver operating characteristics (AUC) (>0.7), with FC being the best (0.94) for endoscopically active disease (P < 0.01). Combining FC and IL-6 or SAA improved its discriminative accuracy with an AUC (∼0.96). CONCLUSIONS: FC most accurately predicts endoscopic disease activity in IBD patients, in comparison to other studied serological biomarkers. The serum IL-6 and SAA are potential predictors of endoscopic disease activity, and they might be valuable for assessment of disease activity. Finally, a composite score of FC and SAA or IL-6 can increased its diagnostic accuracy.

Vitamin D and CRP are associated in hospitalized inflammatory bowel disease (IBD) patients in Shanghai.

BACKGROUND AND OBJECTIVES: Patients with inflammatory bowel disease (IBD) are more likely to be confirmed with vitamin D deficiency. However, the association between inflammation and vitamin D remains unclear. The purpose of this study was to evaluate the association between inflammation and vitamin D in hospitalized patients with IBD. METHODS AND STUDY DESIGN: All the participants were recruited from one teaching hospital from June 2018 to October 2022. Inflammation was evaluated by serum concentration of C-reactive protein (CRP), using an immunoturbidimetric method at admission. We further divided the participants into five groups based on serum CRP levels: <5, 5-9.9, 10-19.9, 20-39.9, and >40mg/L. Serum 25-hydroxy-vitamin D (25-(OH)-D) was assessed by liquid chromatography tandem mass spectrometry. Addi-tional information, including age, sex, body mass index (BMI), IBD (ulcerative colitis vs. Crohn's disease) subtype, was abstracted from medical records. RESULTS: This study included 1,989 patients with IBD (average age was 39.4 years, 33.8% of them were women, 1,365 CD and 624 UC patients). The median CRP was 5.49 mg/L (range of quartiles: 1.64~19.5 mg/L) and the prevalence of 25-(OH)-D deficiency was 69.8%. CRP was significantly associated with serum level of 25-(OH)-D. The difference in 25-(OH)-D was -4.28 ng/ml (-5.27 ng/ml, -3.31 ng/ml) between two extremist CRP groups after adjustment of potential covariates (age, sex, BMI, type of IBD, dietary type, season, and lymphocyte count). Subgroup analysis in sex, type of IBD, and age, were similar to the main analysis results. CONCLUSIONS: There was a negative association between CRP levels and vitamin D in hospitalized patients with IBD.

The relationship between Glasgow Prognostic Score and hospital duration in patients with inflammatory bowel diseases.

BACKGROUND AND OBJECTIVES: Both hypoalbuminemia and inflammation were common in patients with inflammatory bowel diseases (IBD), however, the combination of the two parameters on hospital duration re-mained unknown. METHODS AND STUDY DESIGN: This is a retrospective two-centre study performed in two tertiary hospitals in Shanghai, China. Serum levels of C-Reactive Protein (CRP) and albumin (ALB) were measured within 2 days of admission. Glasgow prognostic score (GPS), based on CRP and ALB, was calculated as follows: point "0" as CRP <10 mg/L and ALB ≥35 g/L; point "1" as either CRP ≥10 mg/L or ALB <35 g/L; point "2" as CRP ≥10 mg/L and ALB <35 g/L. Patients with point "0" were classified as low-risk while point "2" as high-risk. Length of hospital stay (LOS) was defined as the interval between admission and discharge. RESULTS: The proportion of low-risk and high-risk was 69.3% and 10.5% respectively among 3,009 patients (65% men). GPS was associated with LOS [ß=6.2 d; 95% CI (confidence interval): 4.0 d, 8.4 d] after adjustment of potential co-variates. Each point of GPS was associated with 2.9 days (95% CI: 1.9 d, 3.9 d; ptrend<0.001) longer in fully adjusted model. The association was stronger in patients with low prealbumin levels, hypocalcaemia, and hypokalaemia relative to their counterparts. CONCLUSIONS: GPS was associated with LOS in IBD patients. Our results highlighted that GPS could serve as a convenient prognostic tool associated with nutritional status and clinical outcome.

Evaluation of the fatty acid-based erythrocyte membrane lipidome in cats with food responsive enteropathy, inflammatory bowel disease and low-grade intestinal T-cell lymphoma.

Feline chronic enteropathies (FCE), include food-responsive-enteropathy (FRE), inflammatory bowel disease (IBD), and low-grade intestinal T-cell lymphoma (LGITL), and are common causes of chronic gastrointestinal signs in cats. Distinguishing between different subgroups of FCE can be challenging due to the frequent overlap of anamnestic, clinical, and laboratory data. While dysregulation in lipid metabolism has been reported in humans and dogs with chronic IBD, similar changes in cats are not yet completely understood. Assessing the fatty acid (FA) profile of red blood cell (RBC) membranes offers a valuable method for evaluating the quantity and quality of structural and functional molecular components in the membranes. Therefore, this study aimed to examine the FA composition of RBC membranes in FCE in comparison to healthy cats (HC). Gas-chromatography was used to quantitatively analyze a cluster of 11 FA, and based on these results, parameters of lipid homeostasis and enzyme activity indexes were calculated. A total of 41 FCE cats (17 FRE, 15 IBD, 9 LGITL) and 43 HC were enrolled. In FCE cats, the values of docosapentaenoic acid (p = 0.0002) and docosahexaenoic acid (p = 0.0246), were significantly higher, resulting in an overall increase in ω-3 polyunsaturated fatty acids (PUFA) (p = 0.006), and that of linoleic acid (p = 0.0026) was significantly lower. Additionally, FCE cats exhibited an increased PUFA balance (p = 0.0019) and Δ6-desaturase index (p = 0.0151), along with a decreased ω-6/ω-3 ratio (p = 0.0019). No differences were observed among cats affected by FRE, IBD and LGITL. Like humans and dogs, the results of this study indicate that FCE cats also display changes in their FA lipid profile at the level of the RBC membrane. The non-invasive analysis of RBC membrane shows promise as a potential tool for gaining a better understanding of lipid imbalances in this disease.

Platelet indices and inflammatory bowel disease: a Mendelian randomization study.

Background: Platelets play a significant role in the innate and adaptive processes of immunity and inflammation. Inflammatory bowel disease (IBD) is an autoimmune disease that is widely understood to be caused by a combination of genetic predisposition, aberrant immune responses, etc. Methods: To examine the relationships between genetically determined platelet indices and IBD, we conducted a Mendelian randomization (MR) study. Data associated with platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT) were used from the UK Biobank. The outcome data, including IBD, Crohn's disease (CD), ulcerative colitis (UC), were from the FinnGen database. The inverse variance-weighted (IVW), MR-Egger, weighted median methods were used for MR analyses. Results: The MR estimations from the IVW approach show a significant connection between PLT and IBD. Similarly, PCT and IBD have a relationship following the IVW and MR-Egger approaches. While PLT and PCT have strong relationships with CD, according to the findings of all three approaches respectively. Nevertheless, PDW was the only relevant indicator of UC. The only significant result was IVW's. Conclusion: Our findings suggest that the fluctuation of platelet indicators is of great significance in the development of IBD. PLT and PCT have a close association with IBD and CD, respectively; PDW only has a connection with UC. Platelets play an important role in the progression of IBD (UC, CD).

Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease.

BACKGROUND: Adipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency. METHODS: The study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants. RESULTS: Children with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines. CONCLUSIONS: Whether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.

Interaction between inflammatory bowel disease, physical activity, and myokines: Assessment of serum irisin levels.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, showed a wide spectrum of intestinal and extra-intestinal manifestations, which rendered the patients physically inactive and impaired their quality of life. It has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those patients. Irisin is one member of the myokines secreted by muscle contraction during exercise and could be used as an anti-inflammatory biomarker in assessing the physical activity of IBD patients. In addition, experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental colitis. Furthermore, irisin produces changes in the diversity of the microbiota. Therefore, endogenous or exogenous irisin, via its anti-inflammatory effects, will improve the health of IBD patients and will limit the barriers to physical activity in patients with IBD.

Improved high-performance liquid chromatography tandem mass spectrometry method for quantification of infliximab in pediatric plasma and its application in therapeutic drug monitoring.

RATIONALE: The application of infliximab (IFX) to immune-mediated disease is limited by the significant individual variability and associated clinical nonresponse, emphasizing the importance of therapeutic drug monitoring (TDM). Because of the cross-reactivity, limited linear range, and high costs, the clinical application of the previous reported methods was limited. Here, an improved high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to address the issues. METHODS: This study developed an improved bioanalytical HPLC-MS/MS method coupling nanosurface and molecular-orientation limited proteolysis technology. The commercially available compound P14R was selected as the internal standard. This method was developed with fewer volume of reagents and was thoroughly validated. The validated method was applied to TDM in pediatric inflammatory bowel disease (IBD). RESULTS: Chromatography was performed using a Shim-pack GISS-HP C18 metal-free column (3 µm, 2.1 × 100 mm) with a gradient elution of 0.1% formic acid in water and acetonitrile at 0.4 mL/min. Detection and quantitation were performed using electrospray ionization (ESI) and multiple reaction monitoring in the positive ion mode. The method was validated to demonstrate its selectivity, linearity, accuracy, precision, recovery, matrix effect, and stability. The method exhibited a linear dynamic range of 0.3-100 µg/mL, with intra- and inter-day precision and relative errors below 15%. The recovery and matrix effect were measured as 87.28%-89.72% and 41.98%-67.17%, respectively, which were effectively compensated by the internal standard. A total of 32 samples collected from 24 pediatric patients with IBD were analyzed using the validated method, and only 46.9% achieved the reported targeted trough level. CONCLUSION: This study developed an improved HPLC-MS/MS method for the quantitative determination of IFX concentration in human plasma. The accurate, reliable, and cost-effective method was validated and utilized in the analysis of clinical samples. The results confirmed the importance of TDM on IFX and the clinical application prospects of the improved method.

Abnormal platelet parameters in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND: Platelet dysfunction plays a critical role in the pathogenesis of inflammatory bowel disease (IBD). Despite clinical observations indicating abnormalities in platelet parameters among IBD patients, inconsistencies persist, and these parameters lack standardization for diagnosis or clinical assessment. METHODS: A comprehensive search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases for relevant articles published up to December 16th, 2023. A random-effects model was employed to pool the weighted mean difference (WMD) and 95% confidence interval (95% CI) of platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) between IBD patients and healthy controls, and subgroup analyses were performed. RESULTS: The meta-analysis included 79 articles with 8,350 IBD patients and 13,181 healthy individuals. The results revealed significantly increased PLT and PCT levels (WMD: 69.910, 95% CI: 62.177, 77.643 109/L; WMD: 0.046%, 95% CI: 0.031%, 0.061%), and decreased MPV levels (WMD: -0.912, 95% CI: -1.086, -0.739 fL) in IBD patients compared to healthy individuals. No significant difference was found in PDW between the IBD and control groups (WMD: -0.207%, 95% CI: -0.655%, 0.241%). Subgroup analysis by disease type and disease activity showed no change in the differences for PLT, PCT, and MPV in the ulcerative colitis and Crohn's disease groups, as well as the active and inactive groups. Notably, the active group exhibited significantly lower PDW levels than the control group (WMD: -1.138%, 95% CI: -1.535%, -0.741%). CONCLUSIONS: Compared with healthy individuals, IBD patients display significantly higher PLT and PCT and significantly lower MPV. Monitoring the clinical manifestations of platelet abnormalities serves as a valuable means to obtain diagnostic and prognostic information. Conversely, proactive measures should be taken to prevent the consequences of platelet abnormalities in individuals with IBD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023493848.

Causal relationship between circulating immune cells and inflammatory bowel disease: A Mendelian randomization analysis.

Inflammatory bowel disease (IBD) is an immune-mediated inflammation of the gastrointestinal tract that includes Crohn disease and ulcerative colitis (UC). Although IBD is associated with elevated levels of innate and adaptive immunity, the relationship between circulating immune cells and IBD remains largely unknown. Therefore, we conducted a bidirectional 2-sample Mendelian randomization (MR) study to determine their causal relationship. Genome-wide association study summary statistics were extracted from publicly available databases regarding immune cell phenotypes and IBD traits (including IBD, Crohn disease, and UC). MR analysis was conducted using 5 MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. False discovery rate correction (FDR) was used to reduce the likelihood of type 1 errors. We also conducted MR-Egger-intercept tests to evaluate horizontal pleiotropy. After FDR adjustment of the P values for the IVW method, the results indicated no causal relationship between immune cell phenotypes and IBD or UC, but 4 immune characteristics were causally associated with Crohn disease. The percentage of human leukocyte antigen DR+ CD4+ T cells in lymphocytes was positively associated with the development of Crohn disease (odd ratio [OR], 1.13; 95% confidence interval [CI], 1.07-1.21; P < .001; PFDR = 0.019), whereas the percentage of IgD- CD27- B cells in lymphocytes (OR, 0.85; 95% CI, 0.79-0.92; P < .001; PFDR = 0.014), CD28 on CD39+ secreting CD4 regulatory T cells (OR, 0.92; 95% CI, 0.89-0.96; P < .001; PFDR = 0.019), and the percentage of naïve CD4+ T cells in all CD4+ T cells (OR, 0.90; 95% CI, 0.85-0.95; P < .001; PFDR = 0.027) were negatively related to the risk of Crohn disease. MR analysis of the above 4 immune cell phenotypes revealed no horizontal pleiotropy. In the reverse MR analysis, Crohn disease was not causally associated with any of these immune cell phenotypes. The findings provide insight into the relationship between immune cells and IBD pathogenesis, and may serve as a basis for developing novel immunotherapies.

Serum calgranulin C as a non-invasive predictor of activity among inflammatory bowel disease.

Inflammatory bowel disease is a chronic immune-mediated disorder with a relapsing and remitting course. It leads to disabling gastrointestinal symptoms, low quality of life, and a significant burden for healthcare utilization and associated costs. Therefore, non-invasive biomarkers are needed for early diagnosis and follow up to avoid the complications of invasive diagnostic procedures. Calgranulin C is a calcium binding protein with proinflammatory properties. The aim of this study was to evaluate the role of serum calgranulin C as a non-invasive biomarker for diagnosis and prediction of activity in comparison to different biomarkers and endoscopic activity scores in inflammatory bowel disease. The study included 80 inflammatory bowel disease patients (50 Ulcerative colitis and 30 Chron's patients) and 20 normal controls. Complete blood picture, C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin and serum calgranulin C were measured. Colonoscopies with histopathological examination were done and different activity scoring systems assessed. Among ulcerative colitis group, serum calgranulin C was statistically significantly higher in comparison to control group [723.640±529.055 ng/ml versus 80.850±24.416 ng/ml]. Depending on the American college of gastroenterology ulcerative colitis activity index, fecal calprotectin and serum calgranulin C were statistically significantly higher among moderate to severe ulcerative colitis than those with mild activity and those in remission (p < 0.001, for both). Regarding Crohn's disease group, serum calgranulin C was statistically significantly higher in comparison to control group [759.233±797.963 ng/ml versus 80.850±24.416 ng/mL]. Depending on Crohn's disease activity index, both serum calgranulin C and fecal calprotectin were statistically significantly higher among active disease than those in remission (p < 0.001, for both). In conclusion, serum calgranulin C could be used as a non-invasive marker to predict activity and severity and to ensure remission among inflammatory bowel disease patients.

Causality of genetically determined blood metabolites on inflammatory bowel disease: a two-sample Mendelian randomization study.

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease of the gastrointestinal tract, including two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Metabolic disorders are important factors in the development of IBD. However, the evidence for the causal relationship between blood metabolites and IBD remains limited. A two-sample MR analysis was applied to evaluate relationships between 486 blood metabolites and IBD. The inverse variance weighted method was chosen as the primary MR analysis method. False discovery rate correction was used to control for false positives in multiple testing. Following complementary and sensitivity analyses were conducted using methods such as weight median, MR-egger, weighted mode, simple mode, Cochran Q test, and MR-PRESSO. Moreover, we performed replication, meta-analysis, Steiger test, and linkage disequilibrium score regression to enhance the robustness of the results. Additionally, we performed metabolic pathway analysis to identify potential metabolic pathways. As a result, we identified four significant causal associations between four blood metabolites and two IBD subtypes. Specifically, one metabolite was identified as being associated with the development of CD (mannose: odds ratio (OR) = 0.19, 95% confidence interval (CI) 0.08-0.43, P = 8.54 × 10-5). Three metabolites were identified as being associated with the development of UC (arachidonate (20:4n6): OR = 0.18, 95% CI 0.11-0.30, P = 2.09 × 10-11; 1, 5-anhydroglucitol: OR = 2.21, 95% CI 1.47-3.34, P = 1.50 × 10-4; 2-stearoylglycerophosphocholine: OR = 2.66, 95% CI 1.53-4.63, P = 5.30 × 10-4). The findings of our study suggested that the identified metabolites and metabolic pathways can be considered as useful circulating metabolic biomarkers for the screening and prevention of IBD in clinical practice, as well as candidate molecules for future mechanism exploration and drug target selection.

Integrating plasma proteomics with genome-wide association data to identify novel drug targets for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic disease that includes Crohn's disease (CD) and ulcerative colitis (UC). Although genome-wide association studies (GWASs) have identified many relevant genetic risk loci, the impact of these loci on protein abundance and their potential utility as clinical therapeutic targets remain uncertain. Therefore, this study aimed to investigate the pathogenesis of IBD and identify effective therapeutic targets through a comprehensive and integrated analysis. We systematically integrated GWAS data related to IBD, UC and CD (N = 25,305) by the study of de Lange KM with the human blood proteome (N = 7213) by the Atherosclerosis Risk in Communities (ARIC) study. Proteome-wide association study (PWAS), mendelian randomisation (MR) and Bayesian colocalisation analysis were used to identify proteins contributing to the risk of IBD. Integrative analysis revealed that genetic variations in IBD, UC and CD affected the abundance of five (ERAP2, RIPK2, TALDO1, CADM2 and RHOC), three (VSIR, HGFAC and CADM2) and two (MST1 and FLRT3) cis-regulated plasma proteins, respectively (P < 0.05). Among the proteins identified via Bayesian colocalisation analysis, CADM2 was found to be an important common protein between IBD and UC. A drug and five druggable target genes were identified from DGIdb after Bayesian colocalisation analysis. Our study's findings from genetic and proteomic approaches have identified compelling proteins that may serve as important leads for future functional studies and potential drug targets for IBD (UC and CD).