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Background: Inflammatory bowel disease (IBD) is a chronic disease in which macrophages play an important role in its pathogenesis. Platelet-derived growth factor-BB (PDGF-BB) secreted by macrophages is involved in the repair of vascular endothelial injury during inflammatory reactions., Methods: The expression levels of M1 macrophages and PDGF-BB in serum and colonic mucosa of 30 patients with Crohn's disease (CD) and 30 patients with ulcerative colitis (UC) were measured using enzyme-linked immunosorbent assays and immunohistochemistry. Logistic regression was used for univariate and multivariate analyses, and receiver operating characteristic curves were used to evaluate diagnostic value. Associations were evaluated using Spearman correlation analysis., Results: The expression of serum PDGF-BB and M1 macrophages with positive CXCL9 expression in patients with active-stage IBD [206.55(160.41,262.90)and 337.30(217.73,472.28) pg/ml] was higher than that in patients with remission stage [153.42(107.02,219.68)and 218.37(144.49,347.33)pg/ml] and controls [156.19(91.16,216.08)and 191.20(121.42,311.76)pg/ml](P < 0.05). The expression of PDGF-BB, CD86, and CXCL9 in the colon of patients with active-stage IBD [0.380(0.266,0.542) 0.663(0.480,0.591) and 0.564(0.378,0.765) /µm 2 ] was higher than that in the remission stage [0.308(0.214,0.420), 0.376(0.206,0.591) and 0.413(0.275,0.570) /µm 2 ] and controls [0.265(0.185,0.384), 0.416(0.269,0.534) and 0.497(0.415,0.642) /µm 2 ] (P < 0.05). A positive correlation was observed between CD86 and PDGF-BB, and CXCL9 and PDGF-BB levels in patients with IBD (P < 0.05). CD86 and PDGF-BB in the colonic mucosa were independent risk factors for active IBD, and the area under the curve for their combined diagnosis was 0.754 (95%CI: 0.654-0.852, P < 0.05)., Conclusions: PDGF-BB was associated with M1 macrophages and has a potential diagnostic value for active IBD., Trial Registration: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: The study had been performed in accordance with the Declaration of Helsinki and had been approved by the medical ethics committee of The Second Hospital of Jiaxing (No. JXEY-2021SW095). Informed consent to participate in the study had all been obtained from participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Micronutrient deficiencies are common in inflammatory bowel disease (IBD). The aim of this study was to evaluate micronutrient deficiencies and identify muscular status of patients with IBD. From June 2019 to October 2021, a total of 105 patients with IBD were enrolled prospectively. To obtain objective data, micronutrients were measured in the patients' serum, and body composition analysis was performed using bioelectrical impedance analysis. There were 51 patients with ulcerative colitis (UC) and 54 with Crohn's disease (CD), while the gender ratio (M: F) was 54:51. The average age was 37 ± 18 years, which was significantly lower in patients with CD than UC (29 ± 16 vs. 45 ± 16, p < 0.001). Iron and magnesium were lower in patients with CD compared to UC, respectively (63.3 ± 42.5 vs. 82.8 ± 44.0 µg/dL, p = 0.024, 2.08 ± 0.15 vs. 2.15 ± 0.19 mg/dL, p = 0.036). Vitamin D levels showed insufficiency in patients with UC and deficiency (below 20 ng/mL) in patients with CD (20.1 ± 10.6 vs. 19.0 ± 9.9 ng/mL, p = 0.567). In the UC and CD patient groups, skeletal muscle index (SMI) and adjusted skeletal muscle mass were lower in patients with CD compared to UC (SMI: 32.8 ± 4.7 vs. 35.8 ± 5.5%, p < 0.004, adjusted skeletal muscle: 7.0 ± 1.5 vs. 8.2 ± 1.9 kg/m 2 , p < 0.001). In conclusion, decreased trace elements, specifically iron, magnesium, and vitamin D, as well as skeletal muscle mass were observed to be prominent in patients with CD as compared to UC.

Oxidative stress is believed to play an important role in the pathogenesis of inflammatory bowel disease (IBD), specifically Crohn's disease (CD) and ulcerative colitis (UC). This meta-analysis aimed to identify and quantify the oxidative stress-related biomarkers in IBD and their associations with disease activity. We systematically searched Ovid MEDLINE, Ovid Embase, and Web of Science databases, identifying 54 studies for inclusion. Comparisons included: (i) active IBD versus healthy controls; (ii) inactive IBD versus healthy controls; (iii) active CD versus inactive CD; and (iv) active UC versus inactive UC. Our analysis revealed a significant accumulation of biomarkers of oxidative damage to biomacromolecules, coupled with reductions in various antioxidants, in both patients with active and inactive IBD compared to healthy controls. Additionally, we identified biomarkers that differentiate between active and inactive CD, including malondialdehyde, Paraoxonase 1, catalase, albumin, transferrin, and total antioxidant capacity. Similarly, levels of Paraoxonase 1, erythrocyte glutathione peroxidase, catalase, albumin, transferrin, and free thiols differed between active and inactive UC. Vitamins and carotenoids also emerged as potential disease activity biomarkers for CD and UC, but their intake should be monitored to obtain meaningful results. These findings emphasize the involvement of oxidative stress in the pathogenesis of IBD and highlight the potential of oxidative stress-related biomarkers as a minimally invasive and additional tool for monitoring the activity of IBD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: anti-TNF drugs have revolutionized the treatment of Crohn's disease (CD) and have set new therapeutic targets. A direct correlation between anti-TNF trough levels and endoscopic healing in inflammatory bowel disease (IBD) patients has been established, but the association between drug levels and transmural healing assessed by ultrasound is not yet clearly defined., Aims: to evaluate the correlation between the serum concentration of adalimumab (ADA) and sonographic transmural healing in CD patients at different times during follow-up., Methods: in this retrospective, cross-sectional study, all patients with CD who were undergoing treatment with ADA in our center were included. Intestinal ultrasound (IUS) was performed before the initiation of the drug and for response monitoring. ADA serum-trough levels were compared between patients with and without transmural healing at different periods of time., Results: ninety-two patients were included, and all patients showed signs of inflammatory activity in the baseline IUS. During IUS monitoring of the response to ADA, 34 (34.8 %) patients presented transmural healing. Among patients in the first year of treatment, those with sonographic healing showed higher median levels than patients without transmural healing (12.0 µg/ml vs 9.3 µg/ml, respectively; p = 0.007). There was no correlation between ADA levels and sonographic healing in patients undergoing treatment for over a year., Conclusions: higher ADA trough levels correlated with transmural healing with ultrasound during the first year of treatment. This correlation was not found after one year of treatment.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gut affecting both adults and children. Neutrophil extracellular traps (NETs) are structures released by activated neutrophils, potentially contributing to tissue damage in various diseases. This study aimed to explore the presence and role of NETs in pediatric IBD. We compared intestinal biopsies and peripheral blood from 20 pediatric IBD patients (UC and CD) to controls. Biopsy staining and techniques for neutrophil activation were used to assess neutrophil infiltration and NET formation. We also measured the enzymatic activity of key NET proteins and evaluated NET formation in UC patients in remission. Both UC and CD biopsies showed significantly higher levels of neutrophils and NETs compared to controls ( p < 0.01), with UC exhibiting the strongest association. Peripheral blood neutrophils from UC patients at diagnosis displayed increased NET formation compared to controls and CD patients. Interestingly, NET formation normalized in UC patients following remission-inducing treatment. This pilot study suggests a potential role for NETs in pediatric IBD, particularly UC. These findings warrant further investigation into the mechanisms of NET involvement and the potential for targeting NET formation as a therapeutic strategy.

Predicting treatment response in Crohn's disease (CD) patients initiating biological therapy is crucial. The first step involves considering symptom control and normalization of C-reactive protein (CRP). However, data on the actual rates of achieving CRP normalization and the appropriate timeframe are lacking. Therefore, we aim to investigate the rate of attaining CRP normalization and identify its optimal timeframe in CD patients initiating biological therapy. In this retrospective multi-center study, we analyzed moderate to severe CD patients initiating biological therapy from January 2012 to July 2023. The primary outcome was the rate and timeframe for achieving CRP normalization. Secondary outcomes included clinical outcomes in patients who achieved CRP normalization and factors associated with early CRP normalization. Of 183 patients, 123 (67.2%) achieved CRP normalization, with a median duration of 3.8 months (interquartile range 1.4 to 7.4 months). The duration and value difference for CRP normalization between anti-tumor necrosis factor agents, ustekinumab, and vedolizumab were statistically insignificant. Cumulative rates of CD-related hospitalization, intestinal resection, and drug discontinuation over 8 years were 11.4%, 2.4%, and 12.2%, respectively. The duration of CRP normalization correlates with drug discontinuation (area under the curve: 0.64). Treatment with 5-aminosalicylic acid (HR 2.77; 95% confidence interval [CI] 1.26-6.11) and high albumin level (HR 1.64, 95% CI 1.04-2.61) favored early CRP normalization, whereas structuring behavior less likely than inflammatory behavior (HR 0.43, 95% CI 0.19-0.96). We have provided the actual rate of achieving CRP normalization and its appropriate timeframe as an initial target in CD treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Increasing evidence links a worldwide bacterial infection of cattle and other animal species by Mycobacterium avium ssp. paratuberculosis (MAP) to Crohn's disease (CD). A large, FDA phase 2/3 controlled clinical trial of combination antimycobacterial antibiotic therapy for CD has been completed, and the report describing the trial is pending publication. The identification of MAP infection in CD patients will become increasingly important. Thus, it is desirable to develop MAP-based tests that accurately predict which CD patients have a MAP infection. A prospective, case-control laboratory test study of 199 subjects (61 CD patients and 138 non-CD controls) was performed using a panel of MAP antigens, including Hsp65, PknG, PtpA, CL1, and MAP IDEXX, which were measured under blind conditions in the plasma of the 199 subjects. Results showed that compared to any individual MAP antigen, combinations of antigens showed improved CD classification performance. For the Hsp65 antigen, the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), correct classification (CC), and area under the curve (AUC) were 59.02%, 58.70%, 38.71%, 76.42%, 59.3% and 0.606, respectively. For the best combination of MAP antibodies (Hsp65 and PknG), the SEN, SPE, PPV, NPV, CC, and AUC were 59.02%, 60.87%, 40.00%, 77.06%, 60.30%, and 0.631, respectively. Further improvement of the CD classification performance was achieved by combining IFN-γ, IL-8, and IL-17 cytokines with antibodies against MAP antigens, yielding SEN, SPE, PPV, NPV, CC, and AUC of 62.3%, 62.32%, 42.22%, 78.9%, 62.31% and 0.708, respectively. Thus, combinations of antibodies against MAP antigens and cytokine levels yield better CD diagnostic predictive performance than any individual antibodies against MAP antigens., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JTK, JMG, HB, PZ, and RP have ownership in US and international patents which have been filed with claims based on the findings of this study., (Copyright: © 2024 Kuenstner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Matrix γ-carboxyglutamic acid (MGLA) protein is a vitamin K dependent peptide which contributes to the immunomodulatory activity of mesenchymal stromal cells. There is a possible association between MGLA protein and inflammatory bowel disease (IBD) which is divided into Crohn's disease (CD) and ulcerative colitis (UC). However, little is known about the clinical utility of MGLA protein in IBD patients. This study aimed to assess the impact of achieving remission on the serum MGLA protein levels in IBD patients. This prospective observational study included 60 newly diagnosed IBD patients. All patients were subjected to full clinical, laboratory, radiological, and histopathological assessment of IBD at baseline and six months after initiating treatment. Serum MGLA protein level was assessed using an enzyme-linked immunosorbent assay. There were 29 (48.3%) UC cases and 31 (51.67%) CD cases. We observed a significant decrease in serum MGLA protein levels after 6 months of treatment compared to pretreatment values in UC patients (120.490 ± 26.273 vs. 26.320 ± 17.378 nmol/L, p <0.001) and CD patients (125.576 ± 28.208 vs. 28.520 ± 18.443 nmol/L, p <0.001). Serum MGLA protein levels were significantly higher in non-remittent patients compared to remittent UC patients before treatment (142.556 ± 17.096 vs. 110.560 ± 23.659 nmol/L, p <0.001) and after six months of treatment (51.222 ± 4.410 vs. 15.114 ± 3.302 nmol/L, p <0.001). Serum MGLA protein levels were significantly higher in non-remittent patients compared to remittent CD patients before treatment (150.727 ± 7.198 vs. 111.743 ± 25.718 nmol/L, p <0.001) and after six months of treatment (52.182 ± 5.269 vs. 15.506 ± 4.475 nmol/L, p <0.001). This response was irrespective of the therapeutic modality. In conclusion, achievement of remission in IBD patients resulted in a significant decrease in serum MGLA protein levels., (Copyright© by the Egyptian Association of Immunologists.)

Introduction: Neutrophilic calprotectin (CP) and myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and eosinophil-derived neurotoxin (EDN) are suggested proxy markers for gut inflammation. However, there are insufficient supporting data for MPO, NGAL, and EDN., Methods: In a cross-sectional investigation including adult patients, we studied the ability of CP, MPO, NGAL, and EDN, measured in fecal and serum samples, to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and to predict disease activity., Results: Fifty-nine patients had ulcerative colitis (UC), 38 had Crohn's disease, and 100 patients had IBS. The protein concentrations were higher in patients with IBD in the fecal samples ( P < 0.001) and the serum samples ( P < 0.01), and they correlated weakly (r s ≤0.38) between the sample sources. Fecal EDN was higher in patients with Crohn's disease compared with UC (1.79 vs 0.50 mg/kg, P = 0.016). The neutrophilic proteins were superior to EDN in the fecal samples for differentiating between patients with IBD and IBS. Fecal MPO (cutoff: 0.86 mg/kg) had the highest sensitivity (74.7%) and specificity (84.6%). Combining fecal CP and MPO increased the sensitivity to 82.3% (specificity: 73.6%). NGAL (cutoff: 196.9 μg/L) showed the best discriminating performance in serum (sensitivity: 62.9%; specificity: 68.0%). Serum NGAL (cutoff: 272.4 μg/L) predicted active disease in UC (Partial Mayo Score ≥2) with a sensitivity and specificity of 57.1% and 83.3%, respectively., Discussion: Fecal MPO and serum NGAL are promising novel biomarkers, in addition to fecal CP, for differentiating between IBD and IBS. Serum NGAL may also predict disease activity in patients with UC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Aims: Refeeding syndrome (RFS) is defined by the presence of acute electrolyte disturbances, including hypophosphatemia. Underlying disease(s), malnutrition and hospitalisation are known risk factors for RFS. It can occur in patients with inflammatory bowel disease (IBD). We aimed to determine the frequency of hypophosphatemia and the relationship between hypophosphatemia, disease severity and nutritional status in hospitalized patients with IBD., Methods: This study was performed prospectively in hospitalized adult patients for the treatment of IBD in a tertiary-care hospital. Disease severity was assessed using Truelove and Witts score for ulcerative colitis (UC) and Crohn's Disease Activity Index for Crohn's disease (CD). Nutritional status was determined using Subjective Global Assessment (SGA). Serum phosphate concentration was recorded for first 7 days after hospitalization, and less than 0.65 mmol/l was defined as hypophosphatemia., Results: Fifty participants (33 with UC and 17 with CD) were included in the study. The mean age of the study sample was 43.4±14.9 years, of which 64% were male. A total of 8.8% of patients with UC and 37.5% of patients with CD had severe (>moderate) disease upon study admission. Seventeen patients (34%) were malnourished. During the 7 study days, 23 participants (46%) had at least one episode of hypophosphatemia. Serum phosphate concentration was significantly and moderately correlated with serum potassium concentration in both the patients and the hypophosphatemia group on study day 3 (p<0.05). Multivariate logistic regression analysis showed that the presence of malnutrition [odds ratio (OR) = 3.64, 95% confidence interval (CI): 1.52-5.58, p=0.008), the administration of parenteral nutrition (OR=2.91, 95%Cl: 1.37-4.63, p=0.015), and severe IBD (OR=1.74, 95%CI: 1.03-3.42, p=0.020) were associated with hypophosphatemia., Conclusions: Approximately half of the participants exhibited at least one instance of hypophosphatemia during the study period. Hypophosphatemia was found to be associated with malnutrition, parenteral nutrition, and severe disease in patients with IBD requiring hospitalization.

Background: Considering the increasing worldwide prevalence of inflammatory bowel disease (IBD), the early diagnosis of this disease is extremely important. However, non-invasive diagnostic methods remain limited, while invasive techniques are the most commonly used in daily practice. Therefore, there is a serious need to find new non-invasive biomarkers of IBD., Methods: The serum profiles of occludin, claudin-2, and zonulin were assessed in IBD patients using the ELISA method. The levels of the analyzed biomarkers were measured before and after a year of anti-inflammatory treatment, which was a tumor necrosis factor α (TNF-α) inhibitor (adalimumab) in patients with ulcerative colitis (UC) and conventional therapy in patients with Crohn's disease (CD)., Results: In IBD patients, the serum level of occludin ( p < 0.001) decreased compared to healthy individuals, while the level of claudin-2 ( p < 0.001) increased. Additionally, zonulin ( p < 0.01) concentration increased in CD patients compared to the control group. The highest diagnostic ability was presented by occludin measurements with the area under the curve (AUC) of 0.959 (95% CI 0.907-1) in UC and 0.948 (95% CI 0.879-1) in CD. Claudin-2 also demonstrated very good ability in diagnosing UC and CD with AUC values of 0.864 (95% CI 0.776-0.952) and 0.896 (95% CI 0.792-0.999), respectively. The ability of zonulin to diagnose CD was estimated as good with an AUC of 0.74 (95% CI 0.598-0.881). Moreover, a significant correlation was identified between C-reactive protein (CRP), claudin-2 (r = -0.37; p < 0.05), and zonulin (r = -0.44; p < 0.05) in UC patients. Treatment with adalimumab improved the level of occludin, claudin-2, and zonulin in UC patients, while anti-inflammatory conventional therapy decreased the concentration of zonulin in CD., Conclusions: Occludin and claudin-2 measurements present significant utility in diagnosing both UC and CD, while zonulin assessments may be useful in CD diagnosis. Additionally, claudin-2 and zonulin measurements may be helpful in evaluating the intensity of the inflammatory process. Anti-TNF-α treatment improved the value of occludin, claudin-2, and zonulin, indicating its beneficial effect on the integrity of tight junctions in UC.

Objective: Serum amyloid A (SAA) was found to be positively correlated with the activity of Crohn's disease (CD); however, its prognostic value remains uncertain. Here, we examined its predictive ability in newly diagnosed CD and explored genetic association., Methods: This retrospective cohort study included patients newly diagnosed as CD at the First Affiliated Hospital of Sun Yat-sen University between June 2010 and March 2022. We employed receiver operating characteristic curve, Cox proportional hazard regression models and restricted cubic splines to investigate the prognostic performance of SAA for surgery and disease progression. To assess possible causality, a two-sample Mendelian randomisation (MR) of published genome-wide association study data was conducted., Results: During 2187.6 person-years (median age, 28 years, 72.4% male), 87 surgery and 153 disease progression events were documented. A 100-unit increment in SAA level generated 14% higher risk for surgery (adjusted HR (95% CI): 1.14 (1.05-1.23), p=0.001) and 12% for disease progression (1.12 (1.05-1.19), p<0.001). Baseline SAA level ≥89.2 mg/L led to significantly elevated risks for surgery (2.08 (1.31-3.28), p=0.002) and disease progression (1.72 (1.22-2.41), p=0.002). Such associations were assessed as linear. Adding SAA into a scheduled model significantly improved its predictive performances for surgery and disease progression (p for net reclassification indexes and integrated discrimination indexes <0.001). Unfortunately, no genetic causality between SAA and CD was observed in MR analysis. Sensitivity analyses showed robust results., Conclusion: Although causality was not found, baseline SAA level was an independent predictor of surgery and disease progression in newly diagnosed CD, and had additive benefit to existing prediction models., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: It is still unclear whether Crohn's disease (CD) might be associated with diminished ovarian reserve (OvR) and factors influencing anti-Mullerian hormone (AMH) levels in CD are poorly known., Material and Methods: We conducted a comprehensive literature search of multiple electronic databases from inception to June 2022 to identify all studies reporting AMH levels or factors associated with diminished OvR in patients with CD., Results: Of the 48 studies identified in our search, eight (including 418 patients with CD) were finally included. The mean difference (95% confidence interval [CI]) in the AMH level between pooled CD patients and controls was -0.56 (-1.14 to 0.03) (p = 0.06). A history of CD-related surgery was not associated with a lower OvR (odds ratio, OR [95% CI] 1.34, [0.66-2.7]; p = 0.4). While disease activity and perianal disease seems associated with a low OvR, disease location (L2 vs. L1, OR [95% CI] = 95% CI [0.47-7.4]; p = 0.4) and L3 vs. L1 (OR [95% CI] = 1.44 [0.67-3.12]; p = 0.3), CD medication, and disease behavior were not., Conclusions: Our systematic review and meta-analysis did not identify a significantly low OvR in patients with CD. Contrary to CD-related surgery risk factor, active disease was associated lower AMH levels., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Introduction: Recent studies have identified a critical role of stromal-immune cell interactions in immunity and immune tolerance. Transcriptomic profiling has implicated stromal cells in immune-mediated disorders including the 2 common forms of inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). Stromal-immune interactions may edify inflammatory state and the development of IBD-related complications such as fibrosis, yet the lack of protein markers has hampered studying stromal-immune perturbation., Methods: In this study, we designed a 40-color spectral flow cytometry assay to characterize hematopoietic and nonhematopoietic cells in intestinal biopsies and matched blood samples from patients with CD or UC., Results: We identified circulating stromal-like cells that are significantly more abundant in IBD blood samples than in healthy controls. Those cells expressed podoplanin (PDPN), a commonly used marker for fibroblasts, and they were associated with activated and memory T and B cells and altered natural killer cell, monocyte, and macrophage populations. PDPN + cells in the blood correlated with PDPN + cells in the colon. Principal component analysis distinctly separated healthy blood samples from IBD blood samples, with stromal-like cells and B-cell subtypes dominating the IBD signature; Pearson correlation detected an association between PDPN + stromal-like cells and B-cell populations in IBD blood and gut biopsies., Discussion: These observations suggest that PDPN + cells in the blood may serve as a biomarker of IBD. Understanding the relationship between stromal cells and immune cells in the intestine and the blood may provide a window into disease pathogenesis and insight into therapeutic targets for IBD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Osteoporosis prevalence is increased in Crohn's disease (CD). Its pathogenesis in these patients is incompletely understood., Objectives: To identify factors associated with decreased bone mineral density (BMD) status in CD patients on a time-line course., Methods: A retrospective study was performed that followed CD patients who underwent at least two bone mineral density scans (DEXAs). Follow-up began one year prior to the first DEXA test and lasted at least one year after a second test. Possible correlations between baseline and follow-up variables and changes in BMD status were examined. Change in BMD was defined as a transition from one bone density category to another (normal vs. osteopenia vs. osteoporosis). Binary variables were assessed using the Cochrane-Armitage test. Categorical variables were assessed using the chi-squared test. A multivariate analysis was performed., Results: The study included 141 patients. At baseline, 33 patients (23.4%) had normal BMD, 75 (53.2%) had osteopenia, and 33 (23.4%) had osteoporosis. Patients with low BMD had a lower baseline BMI compared to those with normal BMD ( p < 0.0001). After a median follow-up of 48 months (IQR 29-71), BMD status worsened in 19 (13.5%) patients, whereas in 95 (67.3%) and 27 (19.1%) patients, BMD remained unchanged or improved, respectively. On the multivariate analysis, elevated median CRP throughout follow-up (OR = 0.8, 95% CI: 0.68-0.93) and low baseline BMI (OR = 0.9, 95% CI: 0.83-0.98) were associated with a lack of BMD status improvement., Conclusions: Persistently elevated CRP and low BMI are associated with a lack of improvement in BMD. These findings underscore the importance of effective inflammation control and nutritional support to maintain and improve bone health.

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., (© 2024. The Author(s).)

Background and Aims: Inflammatory bowel disease (IBD) is a common chronic inflammatory bowel disease characterized by diarrhea and abdominal pain. Recently human metabolites have been found to help explain the underlying biological mechanisms of diseases of the intestinal system, so we aimed to assess the causal relationship between human blood metabolites and susceptibility to IBD subtypes., Methods: We selected a genome-wide association study (GWAS) of 275 metabolites as the exposure factor, and the GWAS dataset of 10 IBD subtypes as the outcome, followed by univariate and multivariate analyses using a two-sample Mendelian randomization study (MR) to study the causal relationship between exposure and outcome, respectively. A series of sensitivity analyses were also performed to ensure the robustness of the results., Results: A total of 107 metabolites were found to be causally associated on univariate analysis after correcting for false discovery rate (FDR), and a total of 9 metabolites were found to be significantly causally associated on subsequent multivariate and sensitivity analyses. In addition we found causal associations between 7 metabolite pathways and 6 IBD subtypes., Conclusion: Our study confirms that blood metabolites and certain metabolic pathways are causally associated with the development of IBD subtypes and their parenteral manifestations. The exploration of the mechanisms of novel blood metabolites on IBD may provide new therapeutic ideas for IBD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Wang, Tang, Zhao, Wang, Han, Xu, Chang, Li, Hu, Yu, Chang, Liu and Li.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2024. The Author(s).)

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)., (© 2024. The Author(s).)

Background: The etiopathogenesis of inflammatory bowel disease (IBD) is still unclear. Prior studies suggest genetic components that may influence the incidence and severity of the disease. Additionally, it was shown that low levels of serum vitamin D may have an impact on the clinical course of the disease due to its effect on the immunological system. Methods: We aimed to investigate the correlation between the incidence of vitamin D receptor ( VDR ) gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions). Data were obtained from 62 patients with IBD (34 with Crohn's disease, 28 with ulcerative colitis), aged 3-18 years, and compared with controls (N = 47), aged 8-18 years. Results: Although there was no difference in the incidence of individual genotypes between the study groups (IBD, C) in all the polymorphisms examined, we described a significant increase in the chance of developing IBD for heterozygotes of Cdx2 (OR: 2.3, 95% CI 0.88-6.18, p = 0.04) and BsmI (OR: 2.07, 95% CI 0.89-4.82, p = 0.048) polymorphisms. The mean serum 25OHD level in patients with IBD was significantly higher compared with the controls (19.87 ng/mL vs. 16.07 ng/mL; p = 0.03); however, it was still below optimal (>30 ng/mL). Furthermore, a significant correlation was found between vitamin D level and TaqI in patients with IBD ( p = 0.025) and patients with CD ( p = 0.03), as well as with the BsmI polymorphism in patients with IBD ( p = 0.04) and patients with CD ( p = 0.04). A significant correlation was described between the degree of disease activity and genotypes for the FokI polymorphism in patients with UC ( p = 0.027) and between the category of endoscopic lesions and genotypes for the Cdx2 polymorphism also in patients with UC ( p = 0.046). Conclusions: The results suggest a potential correlation of VDR gene polymorphism with the chance of developing IBD, and the clinical course of the disease requires further studies in larger group of patients. Vitamin D supplementation should be recommended in both children with inflammatory bowel disease and in healthy peers.

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)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li and Liu.)

Ustekinumab has been shown to be effective in inducing and maintain clinical and endoscopic remission in Crohn disease (CD). We aim to assess whether ustekinumab trough levels are associated with improved outcomes in CD in real-life. We recruited patients with CD who were treated with ustekinumab for at least 6 months from January 2017 to June 2023. Patients received ustekinumab 6 mg/kg intravenous induction followed by 90 mg every 4-, 8-, or 12-weeks during maintenance were included. We assessed clinical, biochemical, and endoscopic outcomes. Trough concentrations of ustekinumab that were taken from week 42 to week 52 were measured. Primary outcome was to evaluate the relationship between ustekinumab trough concentrations and clinical remission, biochemical normalization, and endoscopic remission. Logistic regression was conducted to assess outcomes. A total of 137 patients with CD, median age of 32 years and 83 (60.6%) males. The median serum levels of ustekinumab measured was 7.2 mcg/mL (interquartile range [IQR] 3.1-9.6). Using Spearman correlation analysis, a strong negative correlation was observed between ustekinumab drug levels and simple endoscopic score (SES-CD) (r = -0.464, P < .001). Additionally, ustekinumab drug levels demonstrated substantial negative correlations with disease severity measured by Harvey-Bradshaw index (HBI) score (r = -0.582, P < .001), C-Reactive Protein (CRP) levels (r = -0.598, P < .001) and fecal calprotectin (FC) levels (r = -0.529, P < .001). A multivariable analysis adjusted for age, sex and body mass index (BMI) showed a significant association between ustekinumab serum drug levels and predefined outcomes. Ustekinumab serum drug level above 4.5 mcg/mL was associated with 24% increase in the likelihood of having an SES-CD score <3 (OR 1.24, confidence interval [CI] 1.12-1.37, P value < .001), 44% more likely to achieve HBI score <5 (OR 1.44, CI 1.26-1.65, P value < .001), 52% higher likelihood of CRP more than 10 (OR 1.52, CI 1.31-1.77, P < .001), and 42% increased likelihood of FC more than 250 (OR 1.42, CI 1.24-1.62, P < .001). Ustekinumab trough concentrations above 4.5 mcg/mL were associated with clinical, biochemical and endoscopic remission in CD. Prospective data is warranted to confirm these findings., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Although perianal Crohn's disease (PCD) is highly associated with the exacerbated inflammation, the molecular basis and immunological signature that distinguish patients who present a history of perianal lesions are still unclear. This paper aims to define immunological characteristics related to PCD. In this cross-sectional observational study, we enrolled 20 healthy controls and 39 CD patients. Blood samples were obtained for the detection of plasma cytokines and lipopolysaccharides (LPS). Peripheral blood mononuclear cells (PBMCs) were phenotyped by flow cytometry. Leukocytes were stimulated with LPS or anti-CD3/anti-CD28 antibodies. Our results show that CD patients had augmented plasma interleukin (IL)-6 and LPS. However, their PBMC was characterized by decreased IL-6 production, while patients with a history of PCD produced higher IL-6, IL-8, and interferon-γ, along with decreased tumor necrosis factor alpha (TNF). CD patients had augmented FoxP3 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulatory markers, though the PCD subjects presented a significant reduction in CTLA-4 expression. CTLA-4 as well as IL-6 and TNF responses were able to distinguish the PCD patients from those who did not present perianal complications. In conclusion, IL-6, TNF, and CTLA-4 exhibit a distinct expression pattern in CD patients with a history of PCD, regardless of disease activity. These findings clarify some mechanisms involved in the development of the perianal manifestations and may have a great impact on the disease management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Vitamin D deficiency is common in patients with inflammatory bowel disease (IBD). In this study, we aimed to evaluate the prevalence and risk factors of vitamin D deficiency in a Taiwanese IBD cohort. Vitamin D levels were checked in adult patients with IBD who were treated at Changhua Christian Hospital, a medical center in central Taiwan, from January 2017 to December 2023. The risk factors for vitamin D deficiency were evaluated. 106 adult IBD patients were included, including 20 patients with Crohn's disease and 86 with ulcerative colitis. The median age at diagnosis was 39.2 years. The mean vitamin D level was 22.2 ± 8 ng/mL. Forty-five patients (42.5%) had vitamin D deficiency (vitamin D level < 20 ng/mL). Comparing patients with normal vitamin D levels and those with vitamin D deficiency after multivariate adjustment, female sex and early age at diagnosis were identified as statistically significant risk factors. We found a prevalence of 42.5% of vitamin D deficiency in the Taiwanese IBD population. Understanding this issue is essential for teaching patients and doctors about vitamin D deficiency screening and improving patient outcomes., (© 2024. The Author(s).)

Objectives: To explore the value of different endoscopic scoring methods in assessing disease activity in pediatric Crohn's disease (CD)., Methods: A total of 70 children diagnosed with CD at the Children's Hospital of Chongqing Medical University from January 2018 to January 2023 were included. Clinical disease activity was assessed using the Pediatric Crohn's Disease Activity Index (PCDAI), while different endoscopic scores were assigned based on endoscopic findings. Spearman rank correlation analysis was used to evaluate the correlation between each endoscopic scoring method and PCDAI as well as laboratory indicators. Kappa test was used to assess the consistency between colonoscopy/capsule endoscopy scoring methods and PCDAI in determining CD activity. Receiver operating characteristic curve analysis was performed to assess the diagnostic efficacy of laboratory indicators in predicting endoscopic activity., Results: The PCDAI score showed a moderate positive correlation with the scores of Crohn's Disease Endoscopic Index of Severity (CDEIS) ( r s =0.696, P <0.01), Simple Endoscopic Score for Crohn's Disease (SES-CD) ( r s =0.680, P <0.01), Lewis Score ( r s =0.540, P <0.01), and Capsule Endoscopy-Crohn's Disease Index (CE-CD) ( r s =0.502, P <0.01). The consistency between all endoscopic scoring methods and PCDAI in determining CD activity was poor (Kappa=0.069-0.226). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hematocrit (HCT), and serum albumin (ALB) levels showed a moderate correlation with the PCDAI score and the scores of colonoscopy scoring methods (CDEIS and SES-CD) (| r s |=0.581-0.725, P <0.01), but a weak correlation with the scores of capsule scoring methods ( P <0.05). ESR and CRP had higher area under the curve (AUC) values in predicting disease activity based on PCDAI, CDEIS, SES-CD, and Lewis Score compared to HCT and ALB ( P <0.05)., Conclusions: CDEIS, SES-CD, Lewis Score, and CE-CD can be used to evaluate disease activity in pediatric CD, but they do not fully correspond with disease activity assessed by PCDAI. Elevated levels of ESR and CRP can predict clinical and endoscopic disease activity in children with CD.

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., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

This systematic review evaluates the hypothesis that optimal serum magnesium levels may enhance remission rates in Crohn's disease (CD) and considers whether magnesium supplementation could be beneficial in CD management. This review aims to synthesize available evidence concerning the impact of serum magnesium on disease remission in CD, and to analyze the effectiveness and mechanistic roles of magnesium supplementation. Adhering to the PRISMA guidelines, we searched PubMed, Web of Science, and Scopus up to January 2024 using MeSH terms and free-text queries related to CD and magnesium. The inclusion criteria were studies that investigated serum magnesium levels, effects of supplementation, and the inflammatory mechanisms in CD remission. From the 525 records identified, eight studies met the inclusion criteria after the removal of duplicates and irrelevant records. These studies, conducted between 1998 and 2023, involved a cumulative sample of 453 patients and 292 controls. Key findings include significantly lower serum magnesium levels in CD patients (0.79 ± 0.09 mmol/L) compared to controls (0.82 ± 0.06 mmol/L), with up to 50% prevalence of hypomagnesemia in CD patients observed in one study. Notably, CD patients, particularly men, exhibited lower magnesium intake (men: 276.4 mg/day; women: 198.2 mg/day). Additionally, low magnesium levels correlated with increased sleep latency (95% CI -0.65 to -0.102; p = 0.011) and decreased sleep duration (95% CI -0.613 to -0.041; p = 0.028). Another key finding was the significant association between low serum magnesium levels and elevated CRP levels as an indicator of CD disease activity. The findings support the hypothesis that serum magnesium levels are significantly lower in CD patients compared to healthy controls and suggest that magnesium supplementation could improve CD management by enhancing remission rates and sleep quality. However, more rigorous, evidence-based research is necessary to define specific supplementation protocols and to fully elucidate the role of magnesium in CD pathophysiology.

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zou, Hu, Xu, Wang, Wu and Deng.)

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., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC., Methods: Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed., Results: Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91-0.97), vitamins D (OR = 0.65, 95% CI: 0.54-0.79) and K1 (OR = 0.93, 95% CI: 0.90-0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23-1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88-0.95), phosphorus (OR = 0.69, 95% CI: 0.58-0.82), selenium (OR = 0.91, 95% CI: 0.85-0.97), zinc (OR = 0.91, 95% CI: 0.89-0.94), folate (OR = 0.71, 95% CI: 0.56-0.92) and vitamin E (OR = 0.78, 95% CI: 0.69-0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22-1.76) and magnesium (OR = 1.24, 95% CI: 1.03-1.49) were associated with increased risk of UC., Conclusions: Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Exhaustion of CD8 T cells has been suggested to inform different clinical outcomes in Crohn's disease, but detailed analyses are lacking. This study aimed to identify the role of exhaustion on a single-cell level and identify relevant CD8 T cell populations in Crohn's disease., Methods: Blood and intestinal tissue from 58 patients with Crohn's disease (active disease or remission) were assessed for CD8 T cell expression of exhaustion markers and their cytokine profile by highly multiplexed flow and mass cytometry. Key disease-associated subsets were sorted and analyzed by RNA sequencing. CD39 inhibition assays were performed in vitro., Results: Activated CD39 + and CD39 + PD-1 + CD8 T cell subsets expressing multiple exhaustion markers were enriched at low frequency in active Crohn's disease. Their cytokine production capacity was inversely linked to the Harvey-Bradshaw Index. Subset-level protein and transcriptome profiling revealed co-existence of effector and exhaustion programs in CD39 + and CD39 + PD-1 + CD8 T cells, with CD39 + cells likely originating from the intestine. CD39 enzymatic activity controlled T cell cytokine production. Importantly, transcriptional exhaustion signatures were enriched in remission in CD39-expressing subsets with up-regulation of TOX. Subset-level transcriptomics revealed a CD39-related gene module that is associated with the clinical course., Conclusions: These data showed a role for the exhaustion of peripheral CD39-expressing CD8 T cell subsets in Crohn's disease. Their low frequency illustrated the utility of single-cell cytometry methods for identification of relevant immune populations. Importantly, the link of their exhaustion status to the clinical activity and their specific gene signatures have implications for exhaustion-based personalized medicine approaches., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-β1 plasma levels., Method: The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-β1 were determined using immunofluorimetric assay., Results: AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-β1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-β1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index., Conclusions: These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Intermittent fasting (IF) during the month of Ramadan is part of the religious rituals of Muslims. The effect of intermittent fasting on disease activity in inflammatory bowel diseases (IBD) is still unknown. This is the first study to assess the effect of IF during Ramadan on inflammatory markers in patients diagnosed with IBD. The effects on clinical disease activity, quality of life, and levels of depression were also assessed., Methods: Patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) who intended to observe Ramadan fasting were recruited. The following were assessed immediately before and at the end of Ramadan: Serum CRP and stool calprotectin, partial Mayo score, Harvey Bradshaw index (HBI), Simple IBD questionnaire (SIBDQ), and Hamilton depression scale questionnaire., Results: 80 patients diagnosed with IBD were recruited (60 UC, 20 CD). Serum CRP and stool calprotectin did not show a significant change before vs after fasting (median CRP 0.53 vs 0.50, P value = 0.27, Calprotectin 163 vs 218 respectively, P value = 0.62). The partial Mayo score showed a significant rise after fasting (median 1 before vs 1 after fasting, mean: 1.79 vs 2.33 respectively, P value = 0.02). Harvey-Bradshaw index did not show a significant change after fasting (median 4 vs 5, P value = 0.4). Multiple linear regression revealed that older age and a higher baseline calprotectin were associated with a higher change in Mayo score after fasting (P value = 0.02 and P value = 0.01, respectively). No significant change was detected in SIBDQ or Hamilton depression scale scores., Conclusions: In patients diagnosed with UC, IF during Ramadan was associated with worsening of clinical parameters, the effect was more pronounced in older patients and those with higher baseline calprotectin levels. However, IF during Ramadan was not associated with an adverse effect on objective inflammatory markers (CRP and calprotectin)., (© 2022. The Author(s).)

Background & Aims: Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD., Methods: We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD., Results: We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD., Conclusions: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The single nucleotide polymorphism (SNP) rs1042058 within the gene locus encoding tumor progression locus 2 (TPL2) has been recently identified as a risk gene for inflammatory bowel disease (IBD). TPL2 has been shown to regulate pro-inflammatory signaling and cytokine secretion, while inhibition of TPL2 decreases intestinal inflammation in vivo. However, the clinical and molecular implications of this disease-associated TPL2 variation in IBD patients have not yet been studied. Methods: We analyzed the impact of the IBD-associated TPL2 variation using clinical data of 2145 genotyped patients from the Swiss IBD Cohort Study (SIBDCS). Furthermore, we assessed the molecular consequences of the TPL2 variation in ulcerative colitis (UC) and Crohn's disease (CD) patients by real-time PCR and multiplex ELISA of colon biopsies or serum, respectively. Results: We found that presence of the SNP rs1042058 within the TPL2 gene locus results in significantly higher numbers of CD patients suffering from peripheral arthritis. In contrast, UC patients carrying this variant feature a lower risk for intestinal surgery. On a molecular level, the presence of the rs1042058 (GG) IBD-risk polymorphism in TPL2 was associated with decreased mRNA levels of IL-10 in CD patients and decreased levels of IL-18 in the intestine of UC patients. Conclusions: Our data suggest that the presence of the IBD-associated TPL2 variation might indicate a more severe disease course in CD patients. These results reveal a potential therapeutic target and demonstrate the relevance of the IBD-associated TPL2 SNP as a predictive biomarker in IBD.

Background: Fecal calprotectin has been proposed as a useful biomarker of disease activity in inflammatory bowel disease (IBD). However, the role of calprotectin in systemic circulation is not well established. Thus, this study aimed to quantify serum calprotectin levels to identify a potential inflammatory marker for IBD., Methods: Ninety-eight patients with ulcerative colitis (UC) and 105 patients with Crohn's disease (CD) were prospectively enrolled and clinically scored. Ninety-two healthy, age-matched subjects served as controls. Blood samples from UC and CD patients and controls were analyzed for serum calprotectin levels and routine laboratory parameters. Disease activity was assessed by partial Mayo score and Harvey-Bradshaw index for UC and CD, respectively., Results: Serum calprotectin levels were higher in CD and UC patients than in controls and were higher during active disease than during inactive disease in CD but not in UC. In UC, serum calprotectin levels were correlated with C-reactive protein (CRP) but not with other laboratory parameters or disease activity. In CD, serum calprotectin levels were positively correlated with disease activity, serum CRP, and platelet count. In UC and CD, serum calprotectin and CRP levels increased during the acute phase and decreased towards remission., Conclusions: Serum calprotectin is an inflammatory marker in IBD but might be more effective in evaluating patients with CD than those with UC. Further studies are needed to confirm these findings and to better determine the specific uses of serum calprotectin in routine practice.

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and β-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

According to several studies, women with Crohn's disease (CD) had reduced fertility, which is mostly due to voluntary decisions and reduced ovarian reserve. In our study, we aimed to compare reproductive health parameters (RHP), previous pregnancy complications and outcomes, and ovarian reserve (OR) assessed by the anti-Mullerian hormone (AMH) in CD patients with healthy controls. In CD patients, we also compared OR according to disease phenotypes. Consecutive pre-menopausal women with CD from two IBD centers were included. The control group consisted of age and BMI-matched healthy controls. We used a questionnaire that included RHP, CD phenotype, and CD activity. Serum AMH was assessed by the Elecsys AMH plus essay. We enrolled 50 patients and 56 controls with a median age of 31 years. All CD patients were in clinical remission. We observed no difference in RHP or AMH (median 2.6 vs. 2.1 ug/l, p = 0.98), or the proportion of low OR (AMH<1,77, 38 vs. 41.1 %, p=0.84). The slope of age-related decrease did not differ between the groups. The subgroup of CD patients after surgery and those older than 30 years with CD for >5years had a steeper decrease in AMH (slope -0.12 vs. -0.29, p = 0.04 and -0.31 vs. -0.2, p = 0.029). In a multivariate analysis, age was the single independent predictor of low OR (OR=1.25). In women with Crohn's disease, once the disease activity is under control, the reproductive health and ovarian reserve do not substantially differ from healthy controls.

Fatty acid (FA) profiles as potentially relevant components of Crohn's disease (CD) have been insufficiently analysed. We sought to explore the plasma profiles of n-3 and n-6 polyunsa-turated fatty acids (PUFAs) in newly diagnosed untreated active CD. We included 26 consecutive CD pediatric patients (<19 years) and 14 healthy controls (HCs). Disease characteristics, including inflammatory markers, dietary histories, and the Pediatric Crohn's Disease Activity Index (PCDAI), were obtained. The profiles of plasma FAs in plasma lipid classes were analysed by gas chromatography with FID detection of methyl esters. The erythrocyte sedimentation rate, C-reactive protein level and fecal calprotectin level (all p<0.001) were significantly higher in CD patients than in HCs. Most changes were observed in plasma phospholipids (PLs), such as a higher content of n-3 and changes in n-6 long-chain PUFAs in the CD group. The CD group had a lower ratio of n-6/n-3 PUFAs in PLs (p<0.001) and triacylglycerols (TAGs) (p<0.01). Correlations of the FA content in plasma PLs with disease activity scores of CD were also observed, which were positive for the sum of monounsaturated fatty acids (MUFAs) as well as oleic acid (18:1n-9) (both p<0.05). The metabolism of PUFAs is significantly altered even in treatment-naive newly diagnosed active pediatric CD, and the content of major FAs in PLs correlates with disease activity and inflammatory markers, thus probably contributing to the still unclear early disease pathogenesis.

Crohn's disease (CD) is characterized by malfunction of immune-regulatory mechanisms with disturbed intestinal mucosal homeostasis and increased activation of mucosal immune cells, leading to abnormal secretion of numerous pro- and anti-inflammatory mediators. MCP2/CCL8 is produced by intestinal epithelial cells and macrophages, and is a critical regulator of mucosal inflammation. NLRC4 is expressed in phagocytes and intestinal epithelial cells and is involved in intestinal homeostasis and host defense. However, no study to date has assessed the circulating levels of NLRC4 and MCP2/CCL8 in patients with CD. The study was aimed to investigate the serum levels of MCP2/CCL8 and NLRC4 in patients with active CD. Sixty-nine patients with active CD and 60 healthy participants were included in the study. Serum levels of NLRC4 and MCP2/CCL8 were determined using an enzyme-linked immunosorbent assay. The median serum NLRC4 levels were lower in the patient group than in the controls (71.02 (range, 46.59-85.51) pg/mL vs. 99.43 (range 83.52-137.79) pg/mL) (P < 0.001). The median serum levels of MCP2/CCL8 were decreased in patients with CD (28.68 (range, 20.16-46.0) pg/mL) compared with the controls (59.96 (range, 40.22-105.59) pg/mL) (P < 0.001). Cut-off points of NLRC4 (<81 pg/mL) and MCP2/CCL8 (<40 pg/mL) showed high sensitivity and specificity for identifying active CD. In conclusion, this is the first study to examine circulating levels of MCP2/CCL8 and NLRC4 in patients with active CD. Our results suggest that serum NLRC4 and MCP2/CCL8 levels may be involved in the pathogenesis of CD and may have a protective effect on intestinal homeostasis and inflammation. Serum levels of MCP2/CCL8 and NLRC4 could be used as a diagnostic tool and therapeutic target for CD., Competing Interests: The authors have declared that no competing interests exist.

Exclusive enteral nutrition (EEN) is a first-line treatment in active, mild to moderate Crohn's disease (CD) in children. The Crohn's disease exclusion diet (CDED), which avoids products known to have a pro-inflammatory effect on the intestinal mucosa, presents similar effectiveness to EEN for inducing remission in the paediatric population. The aim of the study was to evaluate the effectiveness of the CDED in inducing remission in adult patients. Between March 2020 and May 2021, 32 patients in a gastroenterology outpatient centre were treated according to the assumptions of the CDED. The patients were seen at baseline, at week 6, and at week 12 of the study. During the visits, anthropometric measurements and laboratory tests were performed, Crohn's disease activity index (CDAI) was calculated, and the Inflammatory Bowel Disease Questionnaire (IBDQ) was completed. The study included a total of 32 participants, 18 women (56.3%) and 14 men (43.7%). Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of therapy. Calprotectin levels were significantly lower in the second follow-up compared with baseline ( p = 0.021). The CDED is an effective therapy for inducing remission in the adult CD population.

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. IBD has been associated with numerous symptoms and complications, with the most common being iron deficiency anemia (IDA). Iron deficiency in IBD is caused by inadequate intake, malabsorption (including duodenal involvement and surgical removal), and chronic blood loss by mucosal ulcerations. Therefore, an appropriate diet should be enforced. Iron deficiency and iron supplementation have been associated with alterations to gut microbiota. IBD-associated anemia, in particular iron deficiency anemia, is associated with a significant decrease in quality of life and with clinical symptoms such as chronic fatigue, headaches and dizziness, reduced exercise tolerance, pale skin, nails, conjunctiva, and fainting. However, despite these numerous adverse symptoms, IDA remains undertreated. The European Crohn's and Colitis Organisation (ECCO) guidelines state that patients should be monitored for anemia. Adequate treatment, whether oral or intravenous, should be implemented while taking into consideration C-reactive protein values (CRP), hemoglobin levels, and therapeutic response. It should be stressed that every case of anemia in IBD patients should be treated. Intravenous iron formulations, which are more superior compared to the oral form, should be used. There is a need to increase awareness and implementation of international guidelines on iron supplementation in patients with IBD.

Background and Aims: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development., Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis., Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation., Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: MicroRNAs (miRNAs) are important epigenetic regulators in Crohn's disease (CD); however, their contribution to postoperative recurrence (POR) is still unknown. We aimed to characterize the potential role of miRNAs in predicting POR in patients with CD and to identify their pathogenic implications., Methods: Of 67 consecutively operated patients with CD, we included 44 with pure ileal CD. Peripheral blood samples were taken before surgery and during follow-up. The patients were classified according to the presence or absence of POR assessed by ileocolonoscopy or magnetic resonance imaging enterography. The miRNAs were profiled by reverse transcription polymerase chain reaction before surgery and during morphological POR or, for those who remained in remission, 1 year after surgery. R software and mirWalk were used., Results: Five human miRNAs (miR-191-5p, miR-15b-5p, miR-106b-5p, miR-451a, and miR-93-5p) were selected for discriminating between the 2 patient groups at presurgery (PS), with an area under the curve of 0.88 (95% confidence interval [0.79, 0.98]). Another 5 (miR-15b-5p, miR-451a, miR-93-5p, miR-423-5p, and miR-125b-5p) were selected for 1 year, with an area under the curve of 0.96 (95% confidence interval [0.91, 1.0]). We also created nomograms for POR risk estimation. CCND2 and BCL9L genes were related to PS miRNA profiles; SENP5 and AKT3 genes were related to PS and 1 year; and SUV39H1 and MAPK3K10 were related to 1 year., Discussion: Different plasma miRNA signatures identify patients at high POR risk, which could help optimize patient outcomes. We developed nomograms to facilitate the clinical use of these results. The identified miRNAs participate in apoptosis, autophagy, proinflammatory immunological T-cell clusters, and reactive oxygen species metabolism., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background/aim: Inflammatory bowel disease (IBD) mainly encompass two entities called ulcerative colitis (UC) and Crohn's disease (CD), both of which are chronic, progressive and, inflammatory conditions of the gastrointestinal tract. Various indicators and non-invasive markers have been sought and used in IBD patients to help assessing disease activity and treatment effectiveness although none of them are proven to yield definite results in full correlation with the clinical, endoscopic, and histopathological examinations. The aim of the current study was to investigate the relationship of serum neutrophil gelatinase-associated lipocalin (NGAL), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) levels with disease type and activity and to assess their potential use in establishing diagnosis and activity status of IBD, namely UC and CD., Materials and Methods: A total of 111 IBD patients with determined active and inactive disease periods and 70 matched controls were recruited. Serum NGAL levels of the patients and the control group were measured using commercially available ELISA kits. ADMA and SMDA levels were measured by high performance liquid chromatography., Results: The IBD group had significantly higher serum levels of NGAL (p = 0.001), ADMA (p = 0.0001), and SDMA (p = 0.0001) in comparison to the control group. Likewise, serum NGAL, ADMA, and SDMA levels were significantly higher in the active IBD group compared to the inactive IBD group (p = 0.0001). Active UC and active CD patients similarly had significantly higher levels of serum NGAL, ADMA, and SDMA than the respective levels in inactive UK and inactive CD patients (p = 0.0001)., Conclusion: Serum NGAL, ADMA and SMDA levels are increased in patients with IBD, and serum NGAL, ADMA and SMDA concentrations are significantly higher in active IBD patients than inactive IBD patients. Our results suggest these biomarkers may serve in estimating IBD activity and severity., Competing Interests: Authors declare that no conflicts of interest exists and all authors are responsible for the contents and creation of the paper., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

The gastrointestinal tract harbors the gut microbiota, structural alterations of which (dysbiosis) are linked with an increase in gut permeability ("leaky gut"), enabling luminal antigens and bacterial products such as nanosized bacterial extracellular vesicles (BEVs) to access the circulatory system. Blood-derived BEVs contain various cargoes and may be useful biomarkers for diagnosis and monitoring of disease status and relapse in conditions such as inflammatory bowel disease (IBD). To progress this concept, we developed a rapid, cost-effective protocol to isolate BEV-associated DNA and used 16S rRNA gene sequencing to identify bacterial origins of the blood microbiome of healthy individuals and patients with Crohn's disease and ulcerative colitis. The 16S rRNA gene sequencing successfully identified the origin of plasma-derived BEV DNA. The analysis showed that the blood microbiota richness, diversity, or composition in IBD, healthy control, and protocol control groups were not significantly distinct, highlighting the issue of 'kit-ome' contamination in low-biomass studies. Our pilot study provides the basis for undertaking larger studies to determine the potential use of blood microbiota profiling as a diagnostic aid in IBD.

Introduction: We investigated whether early adalimumab drug levels (ADL) at week 4 predicted biological remission at week 24., Methods: In a prospective study, we assessed clinical and biological remission at weeks 0, 4, 12, and 24 after induction of adalimumab in 33 patients with Crohn's disease. Disease activity was determined by the Harvey-Bradshaw Index, ileocolonoscopy reports, cross-sectional imaging, C-reactive protein (CRP), and fecal calprotectin (FC) levels. Clinical remission was defined as Harvey-Bradshaw Index <5. Biological remission was defined as a combination of FC < 200 μg/g and CRP <5 μg/mL. ADL trough levels were tested using a liquid phase, mobility shift assay., Results: At 24 weeks, 18/33 (55%) of the patients were with biological remission. Ten (30%) patients required dose escalation or withdrawal from adalimumab by week 24 because of lack of response and exhibited significantly higher FC (P = 0.003) and CRP (P = 0.002). ADL levels at week 4 (19.8 μg/mL vs 10.2 μg/mL, P = 0.001) were significantly higher in patients with biological remission vs nonresponders at week 24. ADL levels at week 4 were a good predictor of biological remission at week 24, with area under the curve 0.86, 95% confidence interval (1.1; 1.67) and for combined biological and clinical remission, with area under the curve 0.8. The best ADL cutoff at week 4 that predicted biological remission at week 24 was 13.9 μg/mL (sensitivity 94.4% and specificity 73.3%)., Discussion: In individuals with Crohn's disease, higher adalimumab drug levels at week 4 (>13.9 μg/mL) were significantly associated with biological remission at week 24., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Inflammatory bowel disease is a multifactorial etiology, associated with environmental factors that can trigger both debut and relapses. A high level of tumor necrosis factor-α in the gut is the main consequence of immune system imbalance. The aim of treatment is to restore gut homeostasis. In this study, fresh blood and serum samples were used to identify biomarkers and to discriminate between Crohn's disease and ulcerative colitis patients under remission treated with anti-TNF. Metabolomics based on Nuclear Magnetic Resonance spectroscopy (NMR) was used to detect unique biomarkers for each class of patients. Blood T lymphocyte repertories were characterized, as well as cytokine and transcription factor profiling, to complement the metabolomics data. Higher levels of homoserine-methionine and isobutyrate were identified as biomarkers of Crohn's disease with ileocolic localization. For ulcerative colitis, lower levels of creatine-creatinine, proline, and tryptophan were found that reflect a deficit in the absorption of essential amino acids in the gut. T lymphocyte phenotyping and its functional profiling revealed that the overall inflammation was lower in Crohn's disease patients than in those with ulcerative colitis. These results demonstrated that NMR metabolomics could be introduced as a high-throughput evaluation method in routine clinical practice to stratify both types of patients related to their pathology. KEY MESSAGES: NMR metabolomics is a non-invasive tool that could be implemented in the normal clinical practice for IBD to assess beneficial effect of the treatment. NMR metabolomics is a useful tool for precision medicine, in order to sew a specific treatment to a specific group of patients. Finding predictors of response to IFX would be desirable to select patients affected by IBD. Immunological status of inflammations correlates with NMR metabolomics biomarkers., (© 2021. The Author(s).)