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.

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).

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.

Lipopolysaccharide-binding protein in Crohn's disease patients: a promising noninvasive biomarker monitoring disease activity.

BACKGROUND: Following STRIDE-II recommendations, the discovery of novel noninvasive biomarkers, beyond the use of C-reactive protein (CRP) and fecal calprotectin, remains a medical need to further improve the monitoring of patients with inflammatory bowel disease (IBD). This study aims to evaluate the potential of serum lipopolysaccharide-binding protein (LBP) in monitoring IBD activity. METHODS: This retrospective cross-sectional study included 69 IBD patients (43 Crohn's disease and 26 ulcerative colitis) and 82 controls. Serum LBP levels were measured by ELISA. Clinical, biological and endoscopic parameters were analyzed for IBD patients with no reports of missing data. Statistical tests, including nonparametric tests and receiver operating characteristic (ROC) curve analysis, were used to evaluate the diagnostic accuracy of LBP. RESULTS: IBD patients displayed a significantly higher LBP median [29.6 µg/ml (19.8-38.8) in Crohn's disease and 22.8 (13.7-38.8) in ulcerative colitis] than controls [5.8 (4.7-7.3), P  < 0.001] with little overlapping distributions. In Crohn's disease patients, LBP levels gradually increased with endoscopic activity scores demonstrating a 1.7-fold rise in active patients compared to remitter patients ( P  = 0.02). LBP level exhibited a positive correlation with CRP ( ρ  = 0.75, P  < 0.001) as well as fecal calprotectin ( ρ  = 0.42, P  < 0.01), both of which further increased when excluding cases that did not match endoscopic activity. CONCLUSION: LBP might be a promising noninvasive biomarker for monitoring disease activity, especially in Crohn's disease patients. In clinical situations where current biomarkers lack sensitivity, LBP could be discriminative and help filling the gap for reliable therapeutic decisions.

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.

Assessing seasonal variations of biomarkers in inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel diseases are chronic pathologies characterized by a complex interplay of genetic and environmental factors, as well as aberrant immune responses. This study aimed to investigate inflammation markers' seasonality and association with disease exacerbation episodes in patients with Crohn's disease and ulcerative colitis. METHODS: 284 patients were classified based on clinical, endoscopic, and histopathological criteria. Systemic inflammation was evaluated using C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and chitotriosidase, while fecal calprotectin was measured to assess intestinal inflammation. Serum vitamin D levels and the seasonality of an activity score that combines several clinical and biological parameters were also evaluated. RESULTS: The peak number of patients reporting endoscopic activity occurred in autumn for Crohn's disease (82%) and spring for ulcerative colitis (95%). Regarding histological activity, spring saw the highest number of patients for both diseases (72% for Crohn's disease; 87% for ulcerative colitis). Most of the inflammatory markers exhibited lower values during winter. Systemic inflammatory markers follow a slightly different trend than fecal calprotectin and differ in the two pathologies. The maximum values of intestinal inflammation were observed in autumn for Crohn's disease (784 µg/g) and in spring for ulcerative colitis (1269 µg/g). Serum vitamin D concentrations were consistently low throughout the year. Statistical analysis revealed differences between the seasons for CRP and ESR (P < 0.05). CONCLUSION: The evolution of flares and inflammatory markers in Crohn's disease and ulcerative colitis displayed distinct seasonal patterns. Systemic inflammation did not consistently parallel intestinal inflammation.

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.

RNA methylation machinery and m6A target genes as circulating biomarkers of ulcerative colitis and Crohn's disease: Correlation with disease activity, location, and inflammatory cytokines.

Accurate diagnosis of ulcerative colitis (UC) and Crohn's disease (CD), the main subtypes of inflammatory bowel disease (IBD), has been challenging due to the constraints of the current techniques. N6-methyl adenosine (m6A) regulators have evolved as key players in IBD pathogenesis; however, their relation to its clinical setting is largely unexplored. This study investigated the potential of selected RNA methylation machinery and m6A target genes as serum biomarkers of UC and CD, their predictive and discriminating capabilities, and their correlations with laboratory data, interleukin (IL)-6, interferon-γ, disease activity scores, and pathological features. Fifty UC and 45 CD patients, along with 30 healthy volunteers were enlisted. The mRNA expression levels of the m6A writers methyltransferase-like 3 (METTL3) and Wilms-tumor associated protein (WTAP), and the reader YTH domain family, member 1 (YTHDF1), along with the m6A candidate genes sex determining region Y-box 2 (SOX2), hexokinase 2 (HK2), and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) were upregulated in UC patients, whereas only METTL3, HK2, and UBE2L3 were upregulated in CD patients versus controls. Serum WTAP (AUC = 0.94, 95 %CI = 0.874-1.006) and HK2 (AUC = 0.911, 95 %CI = 0.843-0.980) expression levels showed excellent diagnostic accuracy for UC, METTL3 showed excellent diagnostic accuracy for CD (AUC = 0.91, 95 %CI = 0.828-0.992), meanwhile, WTAP showed excellent discriminative power between the two diseases (AUC = 0.91, 95 %CI = 0.849-0.979). Multivariate logistic analysis unveiled the association of METTL3 and UBE2L3 expression with the risk of CD and UC diagnosis, respectively, controlled by age and sex as confounders. Remarkable correlations were recorded between the gene expression of studied m6A regulators and targets in both diseases. Among UC patients, serum METTL3 and WTAP were correlated with UC extent/type, while WTAP was correlated with IL-6. Among CD patients, serum METTL3 and HK2 were correlated with CD activity index (CDAI) and CD location. In conclusion, m6A regulators and target genes are distinctly expressed in UC and CD clinical samples, correlate with disease activity and extent/location, and could serve as a novel approach to empower the diagnosis and stratification of IBD subtypes.

Reduced Taurine Serum Levels in Inflammatory Bowel Disease.

Taurine is a semi-essential micronutrient that acts as an anti-inflammatory molecule. The oral administration of taurine to colitic mice attenuates ongoing mucosal inflammation. This study aimed to determine whether inflammatory bowel diseases (IBDs) are marked by changes in the circulating levels of taurine. We measured the serum concentrations of taurine in 92 IBD patients [46 with ulcerative colitis (UC) and 46 with Crohn's disease (CD)] and 33 healthy controls with a commercial ELISA kit. The taurine levels were significantly decreased in both patients with UC and patients with CD compared to the controls, while there was no difference between CD and UC. Taurine levels declined with age in healthy controls but not in IBDs. IBD patients younger than 50 years had levels of taurine reduced compared to their age-matched controls. In the IBD group, taurine levels were not influenced by the body mass index of the patients and the consumption of taurine-rich nutrients, while they were significantly reduced in UC patients with clinically active disease compared to those in clinical remission. These findings indicate that IBDs are marked by serum taurine deficiency, which would seem to reflect the activity of the disease, at least in UC.

Effectiveness of a novel diet in attenuation of clinical activity of disease in patients with ulcerative colitis: a randomized, clinical trial.

Dietary intake plays a pivotal role in ulcerative colitis (UC) initiation and prognosis. The aim of this study was to investigate the effect of a combined Mediterranean, low-FODMAP diet accompanied with partial enteral nutrition (PEN) on clinical and para-clinical characteristics of patients with UC. Fifty patients with active mild to moderate UC were received either a combined diet or a regular diet for 6 weeks. Before and after the intervention, disease activity index, quality of life and some inflammatory and oxidative stress factors were measured using valid and reliable questionnaires and blood sampling. Disease activity index was significantly decreased in the combined diet group in comparison to control diet group (p = 0.043), and baseline data (p < 0.001). Moreover, the quality of life score increased significantly in the combined diet group compared to the control group, and the baseline data (p < 0.001). Serum level of high sensitive C-reactive protein (hs-CRP) decreased significantly in the combined group (p < 0.01), while it increased in the control group non-significantly. Serum total anti-oxidant capacity (TAC) changes were not statistically significant in two groups. This study indicates that this combination diet has the potential to be used as a safe and highly effective approach in patients with significant intestinal symptoms. Further clinical trial studies with different duration of intervention are needed to confirm these results.Trial registration: The study was registered on IRCT.ir with registration number of IRCT20100524004010N38, on 25/04/2023.

Factors associated with changes in tacrolimus blood concentration after food initiation in patients with ulcerative colitis.

The therapeutic effect of tacrolimus against ulcerative colitis (UC) is correlated with its trough blood concentration. Conventionally, oral tacrolimus for the treatment of UC is initiated under fasting conditions; once the symptoms improve, food intake is resumed. Tacrolimus blood concentration decreases with food intake compared with that under fasting conditions. The aim of this study was to explore the characteristics of patients with UC whose tacrolimus blood concentrations tended to decrease after food initiation. Medical data of 13 patients with UC and treated with tacrolimus were retrospectively obtained. The participant characteristics associated with the changes in tacrolimus blood concentrations after food initiation were analyzed using regression analysis based on the rate of decrease in the concentration/dose (C/D) ratio after food initiation. Single regression analysis showed that the number of days required from tacrolimus initiation to food resumption (P = 0.0071) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0247) were significantly associated with the rate of decrease in the C/D ratio after food initiation. Furthermore, multiple regression analysis showed a significant effect of the number of days to food resumption (P = 0.0004) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0012). The results suggest that the degree of change in blood tacrolimus concentration after food initiation may be related to the severity of the symptoms and pathology of UC. Early identification of participant characteristics may help control tacrolimus blood concentration fluctuations after food initiation.

Correlation of Blood and Intestinal Mucosa miR-34a Expressions with Disease Severity in Ulcerative Colitis Patients.

BACKGROUND: miR-34a has been implicated in many autoimmune diseases and gastrointestinal diseases. However, the expression of miR-34 in ulcerative colitis (UC) patients were not fully studied. This study was performed to in-vestigate the association of blood and intestinal tissue miR-34a expression of patients with disease severity in UC patients. METHODS: Our study enrolled 82 patients with UC and 80 age- and gender- matched healthy individuals. Blood miR-34a expressions were detected using reverse transcription-polymerase chain reaction (RT-PCR). Local intestinal miR-34a, STAT3 mRNA and IL-23 mRNA expressions were also detected in the lesioned area and adjacent non-affected intestinal tissue in patients. Disease severity of UC was assessed by Mayo score. The diagnostic value of both blood and local miR-34a expression for UC patients was assessed by receiver operating characteristic (ROC) curve. RESULTS: Blood miR-34a was increased in UC patients in contrast with healthy individuals with statistical significance. In UC patients, local intestinal miR-34a expressions were markedly upregulated compared to adjacent non-affected intestinal tissue. Local intestinal miR-34a expressions were positively correlated with STAT3 mRNA and IL-23 mNRA. Both blood and local miR-34a expressions were significantly and positively related to Mayo scores. ROC curve analysis indicated that both blood and local miR-34a expressions may act as decent marker for Mayo grade. CONCLUSIONS: Blood and intestinal tissue miR-34a expressions are correlated with disease severity in UC patients. Both blood and intestinal tissue miR-34a expressions may serve as potential diagnostic and prognostic makers for UC. Therapeutic methods targeting miR-34a may act as potential ways for UC treatment.

Fecal calprotectin and platelet count predict histologic disease activity in pediatric ulcerative colitis: results from a projection-predictive feature selection.

Especially for pediatric patients, proxies of mucosal inflammation are needed. The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been established to predict clinical and endoscopic disease activity. However, histologic inflammation might persist. We applied a special variable selection technique to predict histologic healing in pediatric ulcerative colitis (UC) as parsimoniously (but still as precisely) as possible. The retrospective analysis included data from two study cohorts, comprising 91 visits from 59 pediatric patients with UC. A Bayesian ordinal regression model was used in combination with a projection-predictive feature selection (PPFS) to identify a minimal subset of clinical and laboratory parameters sufficient for the prediction of histologic disease activity. Following the PPFS, CEDATA-GPGE patient registry data were analyzed to investigate the relevance of the selected predictors in relation to PUCAI and Physician Global Assessment (PGA) in up to 6697 patient visits. Fecal calprotectin (FC) and platelet count were identified as the minimal subset of predictors sufficient for prediction of histologic disease activity in pediatric UC. FC and platelet count also appeared to be associated with increasing disease activity as measured by PUCAI and PGA in the CEDATA-GPGE registry. Based on the selected model, predictions can be performed with a Shiny web app.  Conclusion: Our statistical approach constitutes a reproducible and objective tool to select a minimal subset of the most informative parameters to predict histologic inflammation in pediatric UC. A Shiny app shows how physicians may predict the histologic activity in a user-friendly way using FC and platelet count. To generalize the findings, further prospective studies will be needed. What is Known: • Histologic healing is a major endpoint in the therapy of ulcerative colitis (UC). • The PUCAI score has been established to predict disease activity in pediatric UC but is not suitable for the prediction of histologic healing. What is New: • Our Bayesian ordinal regression model in combination with a projection-predictive feature selection is a reproducible and objective tool to select the minimal subset of clinical and laboratory parameters to predict histologic inflammation in pediatric UC. • Histologic inflammation in pediatric UC can be non-invasively predicted based on the combination of fecal calprotectin levels and platelet count.

Correlation Between Serum and Fecal Biomarkers and Patient-Reported Outcomes in Patients with Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Patient-reported outcomes (PROs), such as the short CD activity index (sCDAI) and partial Mayo Score (PMS), are used to define clinical remission in IBD, but may not represent the true degree of inflammation and endoscopy is invasive. Non-invasive testing options include c-reactive protein (CRP) and fecal calprotectin (FCP). AIM: The aim of this study was to assess the degree of correlation of non-invasive biomarkers with PROs and the impact other clinical variables can have on their levels. METHODS: We reviewed data collected from the prospective cohort, Study of a Prospective Adult Research Cohort with IBD (SPARC-IBD), comprised of over 3000 patients from 17 tertiary referral centers. Demographic and clinical variables were analyzed by disease type, disease severity was based on PROs, and baseline CRP and FCP were measured. For comparative analysis, we performed Fisher's exact test and Welch's t test, where p < 0.05 was significant. RESULTS: 1547 patients were included; 63% had CD, 56% were female, with an average disease duration of 13.6 years. CRP and FCP were associated with symptom severity in inflammatory CD. CRP was useful to differentiate symptoms across different disease locations in CD, whereas FCP was associated with symptom severity in Crohn's colitis only. For UC, FCP was able to distinguish symptom severity better in distal UC, whereas in extensive or pancolitis, it was useful only to distinguish severe symptoms from other categories of symptom severity. CONCLUSION: PROs correlate with CRP and FCP; however, disease location and phenotype impact their ability to distinguish symptom severity.

Investigating the concomitance of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides and inflammatory bowel disease (IBD).

OBJECTIVE: To assess relationship between Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and inflammatory bowel disease (IBD). METHODS: This is a retrospective study design. The patients were identified using a preset criteria of patients who have the diagnosis of ANCA associated vasculitis including a diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA) with overlapping inflammatory bowel disease (Crohn's disease or ulcerative colitis) in the time period from 01/01/2020 to 08/03/2023. Subsequently data from each patient was collected that will include baseline demographics, disease characteristics, disease activity, treatment information, multiorgan involvement, and pathology findings which were then analyzed. RESULTS: 39 patients were identified that met criteria. 20 patients carried a diagnosis of GPA, 6 had MPA and 4 patients had EGPA. 20 patients with GPA had inflammatory bowel disease, 13 with ulcerative colitis and 6 with Crohn's disease while 1 GPA patient had unspecified inflammatory bowel disease. 4 patients with EGPA had inflammatory bowel disease, 2 with ulcerative colitis and 2 with Crohn's disease. 6 patients with MPA had inflammatory bowel disease, 4 with ulcerative colitis and 2 with Crohn's disease. IBD diagnosis preceded the diagnosis of ANCA vasculitis in 77.8 % of the cases. CONCLUSION: Objective observation and deductions from this study raise the concern for a possible pathogenic association of ANCA associated vasculitis and inflammatory bowel disease and more research is needed to identify any causal association or influence of the two systemic disease on each other.

Growth differentiation factor-15 serum concentrations reflect disease severity and anemia in patients with inflammatory bowel disease.

BACKGROUND: Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality. Growth-differentiation factor-15 (GDF-15) is often over-expressed under stress conditions, such as inflammation, malignancies, heart failure, myocardial ischemia, and many others. AIM: To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases. An additional aim was to determine possible associations between GDF-15 and multiple clinical, anthropometric and laboratory parameters in patients with IBD. METHODS: This cross-sectional study included 90 adult patients diagnosed with IBD, encompassing both Crohn's disease (CD) and ulcerative colitis (UC), and 67 healthy age- and sex-matched controls. All patients underwent an extensive workup, including colonoscopy with subsequent histopathological analysis. Disease activity was assessed by two independent gastroenterology consultants specialized in IBD, employing well-established clinical and endoscopic scoring systems. GDF-15 serum concentrations were determined following an overnight fasting, using electrochemiluminescence immunoassay. RESULTS: In patients with IBD, serum GDF-15 concentrations were significantly higher in comparison to the healthy controls [800 (512-1154) pg/mL vs 412 (407-424) pg/mL, P < 0.001], whereas no difference in GDF-15 was found between patients with CD and UC [807 (554-1451) pg/mL vs 790 (509-956) pg/mL, P = 0.324]. Moreover, multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age, sex, and C-reactive protein levels (P = 0.016 and P = 0.049, respectively). Finally, an association between GDF-15 and indices of anemia was established. Specifically, negative correlations were found between GDF-15 and serum iron levels (r = -0.248, P = 0.021), as well as GDF-15 and hemoglobin (r = -0.351, P = 0.021). Accordingly, in comparison to IBD patients with normal hemoglobin levels, GDF-15 serum levels were higher in patients with anemia (1256 (502-2100) pg/mL vs 444 (412-795) pg/mL, P < 0.001). CONCLUSION: For the first time, we demonstrated that serum concentrations of GDF-15 are elevated in patients with IBD in comparison to healthy controls, and the results imply that GDF-15 might be involved in IBD pathophysiology. Yet, it remains elusive whether GDF-15 could serve as a prognostic indicator in these patients.

Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study.

Background: Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Method: Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. Results: E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Conclusion: Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

The diagnostic performance of serum αvß6 autoantibodies for ulcerative colitis: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Currently, there is no single golden standard for diagnosing ulcerative colitis (UC). Now serum αvß6 autoantibodies have shown promise as a diagnostic tool for UC. Here the aim was to determine the diagnostic performance of serum αvß6 autoantibodies for UC. METHODS: PubMed, the Cochrane Library, the Embase, and the Web of Science were searched comprehensively. STATA software was utilized to analyze the relevant data. RESULTS: 9 studies from 6 articles with 1827 subjects were eligible. The summary sensitivity and specificity of serum αvß6 autoantibodies to diagnose UC were 0.82 (95 % confidence interval (CI): 0.65-0.92) and 0.94 (95 % CI: 0.90-0.97) with an area under the summary receiver operating characteristic curve of 0.96 (95 % CI: 0.94-0.97). Subgroup analysis was conducted owning to substantial heterogeneity between studies (I2 = 97 % and P < 0.001). The aggregate sensitivity and specificity to diagnose UC in adults were 0.75 (95 % CI: 0.61-0.86) and 0.95 (95 % CI: 0.90-0.97), and when using a threshold of mean control+3SD, 0.80 (95 % CI: 0.60-0.91) and 0.96 (95 % CI: 0.90-0.99), respectively. Additionally, to differentiate UC from healthy participants, non-inflammatory bowel disease, and Crohn's disease, the overall specificity was 0.96, 0.88, and 0.80, respectively. CONCLUSIONS: serum αvß6 autoantibodies, as a non-invasive tool, demonstrated good diagnostic accuracy for UC. However, their application may be limited in some immune-related disorders, and further studies are needed for validation.

Comparing the efficacy of vedolizumab between males and females: a post-hoc analysis of GEMINI-1 and VARSITY.

Vedolizumab is a first-line treatment option for ulcerative colitis. There are differences in incidence of ulcerative colitis between males and females, but whether sex affects treatment outcomes is less clear. We examined sex-based differences in patients with ulcerative colitis initiated on vedolizumab from two major randomized controlled trials (RCTs). We conducted a post-hoc analysis on participants with ulcerative colitis from the VARSITY and GEMINI-1 RCTs who received vedolizumab. Outcomes of interest were rates of clinical improvement, clinical remission, and endoscopic improvement at weeks 6, 14, and 52 in male and female participants, as were differences in concentrations of trough vedolizumab and C-reactive protein; 1009 persons in GEMINI-1 and VARSITY trials were included. Male and female patients had similar disease characteristics aside from males being more likely to have Mayo 3 grade endoscopic severity at baseline (62.8 vs. 48.9%, P  < 0.001). At week 6, females were more likely to have endoscopic improvement (47.4 vs. 35.2%, P  = 0.001) and increased vedolizumab trough levels [34.0 (23.0-44.5) vs. 28.9 (19.0-34.6), P  < 0.001]. The probability of achieving clinical remission (28.9 vs. 34.5%, P  = 0.057) or endoscopic improvement (35.5 vs. 39.3%, P  = 0.212) at week 52 was not different between males and females. Females with ulcerative colitis treated with vedolizumab appear more likely to achieve early endoscopic improvement than males, though longer-term outcomes demonstrated no difference. Further studies are required to better understand mechanisms through which sex or sex-associated factors could influence response to therapy in ulcerative colitis.