Crohn's Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 34797

Special Issue Editor


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Guest Editor
1. Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
2. State Key Laboratory of Silkworm Genome Biology, Key Laboratory for Sericulture Functional Genomics & Biotechnology of Agricultural Ministry, Southwest University, Beibei, Chongqing 400716, China
Interests: inflammatory bowel disease (IBD); ulcerative colitis (UC); colitis-associated cancer (CAC); drug delivery systems (DDSs); natural lipid nanoparticles; natural/genetically modified silk fibroin nanoparticles
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Special Issue Information

Dear Colleagues,

Inflammatory bowel disease (IBD) is a group of chronic conditions affecting the digestive tract, with Crohn's disease (CD) and ulcerative colitis (UC) as the two main forms. The exact cause of IBD is unknown, but a combination of genetic and environmental factors is believed to be involved. The disease is characterized by a range of symptoms, including abdominal pain, diarrhea, rectal bleeding, weight loss, and malnutrition. The pathophysiology of IBD involves an abnormal immune response in the gut, leading to chronic inflammation and damage to the intestinal lining. Treating IBD has been a challenge for the medical community due to the complexity of the disease and limited understanding of its pathophysiology. Current therapies include medications reducing inflammation, such as corticosteroids, immunosuppressants, and biologic therapies, but these can have significant side effects and may not be effective for all patients. Innovative therapeutic approaches for IBD, including stem cell transplantation, fecal microbiota transplantation, and modulation of the gut microbiome, are currently under investigation. Researchers are also exploring targeted therapies targeting the underlying causes of IBD, such as novel drug delivery platforms based on micro- and nanotechnology. Significant advances have been made in understanding the mechanisms of IBD and developing new therapeutic approaches in recent years. This Special Issue aims to publish the latest research advances in IBD and bring together researchers and clinical doctors participating in IBD research. Global experts will discuss topics such as the mechanisms of IBD, research advances in prevention, diagnosis, and treatment of IBD.

Dr. Dingpei Long
Guest Editor

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Keywords

  • inflammatory bowel disease
  • crohn's disease
  • ulcerative colitis
  • chronic inflammation
  • pathophysiological mechanisms
  • therapeutic approaches
  • stem cell transplantation
  • fecal microbiota transplantation
  • gut microbiome
  • targeted therapies

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Published Papers (11 papers)

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Editorial

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6 pages, 197 KiB  
Editorial
Crohn’s Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches
by Dingpei Long
Biomedicines 2024, 12(3), 689; https://doi.org/10.3390/biomedicines12030689 - 19 Mar 2024
Cited by 1 | Viewed by 2149
Abstract
Inflammatory bowel disease (IBD) is a non-specific autoimmune condition impacting the gastrointestinal tract, encompassing Crohn’s disease (CD) and ulcerative colitis (UC) [...] Full article

Research

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13 pages, 5659 KiB  
Article
Co-Administration of Proton Pump Inhibitors May Negatively Affect the Outcome in Inflammatory Bowel Disease Treated with Vedolizumab
by Kata Szemes, Nelli Farkas, Zoltan Sipos, Renata Bor, Anna Fabian, Zoltan Szepes, Klaudia Farkas, Tamas Molnar, Eszter Schafer, Tamas Szamosi, Agnes Salamon, Aron Vincze and Patricia Sarlos
Biomedicines 2024, 12(1), 158; https://doi.org/10.3390/biomedicines12010158 - 11 Jan 2024
Cited by 3 | Viewed by 1626
Abstract
Concomitant medications may alter the effect of biological therapy in inflammatory bowel disease. The aim was to investigate the effect of proton pump inhibitors on remission rates in patients with inflammatory bowel disease treated with the gut-selective vedolizumab. Patients from the Hungarian nationwide, [...] Read more.
Concomitant medications may alter the effect of biological therapy in inflammatory bowel disease. The aim was to investigate the effect of proton pump inhibitors on remission rates in patients with inflammatory bowel disease treated with the gut-selective vedolizumab. Patients from the Hungarian nationwide, multicenter vedolizumab cohort were selected for post hoc analysis. Primary outcomes were the assessment of clinical response and endoscopic and clinical remission at weeks 14 and 54. Secondary outcomes were the evaluation of the combined effect of concomitant steroid therapy and other factors, such as smoking, on remission. A total of 108 patients were identified with proton pump inhibitor data from 240 patients in the original cohort. Patients on steroids without proton pump inhibitors were more likely to have a clinical response at week 14 than patients on concomitant PPI (95% vs. 67%, p = 0.005). Non-smokers with IBD treated with VDZ were more likely to develop a clinical response at week 14 than smokers, particularly those not receiving PPI compared with patients on co-administered PPI therapy (81% vs. 53%, p = 0.041, and 92% vs. 74%, p = 0.029, respectively). We found that the use of PPIs in patients treated with VDZ may impair the achievement of response in certain subgroups. Unnecessary PPI prescriptions should be avoided. Full article
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12 pages, 747 KiB  
Article
Prevalence of Fibromyalgia and Chronic Fatigue Syndrome among Individuals with Irritable Bowel Syndrome: An Analysis of United States National Inpatient Sample Database
by Zahid Ijaz Tarar, Umer Farooq, Ahmad Nawaz, Mustafa Gandhi, Yezaz A. Ghouri, Asmeen Bhatt and Brooks D. Cash
Biomedicines 2023, 11(10), 2594; https://doi.org/10.3390/biomedicines11102594 - 22 Sep 2023
Cited by 4 | Viewed by 4379
Abstract
Background and Aim: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with other somatic disorders. We studied the prevalence and predictors of fibromyalgia and chronic fatigue syndrome (CFS) in IBS patients. Methods: We used the National Inpatient Sample and included hospitalization [...] Read more.
Background and Aim: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with other somatic disorders. We studied the prevalence and predictors of fibromyalgia and chronic fatigue syndrome (CFS) in IBS patients. Methods: We used the National Inpatient Sample and included hospitalization of individuals with IBS, using ICD-10 codes, from 2016–2019. The prevalence and predictors of fibromyalgia and CFS in IBS patients were studied. Univariate and multivariate patient- and hospital-level regression models were used to calculate the adjusted odds of fibromyalgia and CFS in the IBS patient population. Results: Of 1,256,325 patients with an ICD-10 code of IBS included in the study, 10.73% (134,890) also had ICD-10 codes for fibromyalgia and 0.42% (5220) for CFS. The prevalence of fibromyalgia and CFS was significantly higher in IBS patients (adjusted odds ratio (AOR) 5.33, 95% confidence interval (CI) 5.24–5.41, p < 0.001, and AOR 5.40, 95% CI 5.04–5.78, p < 0.001, respectively) compared to the general adult population without IBS. IBS-diarrhea, IBS-constipation, and IBS-mixed types were independently associated with increased odds of fibromyalgia and CFS. Increasing age (AOR 1.02, 95% CI 1.01–1.04, p 0.003; AOR 1.02, 95% CI 1.01–1.03, p 0.001), female gender (AOR 11.2, 95% CI 11.1–11.4, p < 0.001; AOR 1.86, 95% CI 1.78–1.93, p < 0.001) and white race (AOR 2.04, 95% CI 1.95–2.12, p < 0.001; AOR 1.69, 95% CI 1.34–2.13, p < 0.001) were independent predictors of increased odds of fibromyalgia and CFS, respectively. Conclusions: It appears that IBS is associated with an increased prevalence of somatic disorders such as fibromyalgia and CFS. Full article
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13 pages, 1958 KiB  
Article
Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn’s Disease: A Pilot Study
by Yoon-Zi Kim, Ben Kang, Eun-Sil Kim, Yiyoung Kwon, Yon-Ho Choe and Mi-Jin Kim
Biomedicines 2023, 11(9), 2575; https://doi.org/10.3390/biomedicines11092575 - 19 Sep 2023
Cited by 2 | Viewed by 1381
Abstract
Background: The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn’s disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more [...] Read more.
Background: The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn’s disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. Methods: In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. Results: Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). Conclusion: The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions’ circumstances. Full article
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10 pages, 1123 KiB  
Article
Endogenous Opioids in Crohn’s Disease
by Adrian Martyniak, Andrzej Wędrychowicz and Przemysław J. Tomasik
Biomedicines 2023, 11(7), 2037; https://doi.org/10.3390/biomedicines11072037 - 20 Jul 2023
Cited by 3 | Viewed by 1917
Abstract
Caring for patients with Crohn’s disease (CD) is a serious challenge in modern medicine. The increasing incidence of CD among adolescents and the severe course of the disease create the need for new methods of diagnosis and therapy. Endogenous opioids are a group [...] Read more.
Caring for patients with Crohn’s disease (CD) is a serious challenge in modern medicine. The increasing incidence of CD among adolescents and the severe course of the disease create the need for new methods of diagnosis and therapy. Endogenous opioids are a group of low molecular weight chemical compounds with analgesic and anti-inflammatory properties. Endorphins, enkephalins, and dynorphins may have potentially beneficial effects on the course of CD. Previous research data on this topic are inconsistent. Some authors have reported an increase in the concentration of leukocytes during the course of inflammatory bowel disease (IBD) while others have described a downward trend, explained by DPP-IV enzyme activity. Even fewer data are available on plasma endo-opioid level. There is also a lack of comprehensive studies that have assessed the endo-opioid system in patients with IBD. Therefore, the objective of this study was to measure the serum concentrations of human β-endorphin, human proenkephalin (A), and human big dynorphin in CD patients in the acute phase of the disease, during hospital treatment, and in the remission state. All determinations were performed using ELISA kits. The results of our study showed that the concentrations of all the tested endo-opioids, especially β-endorphin and proenkephalin (A), were reduced in adolescents with CD compared to those in the healthy control group, during the acute phase of the disease, and in the remission state. Modulation of the endogenous opioid system and the use of selective nonnarcotic agonists of opioid receptors seems to be promising goals in the future treatment of CD. Full article
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13 pages, 2206 KiB  
Article
Prophylactic vs. Therapeutic Effect of Probiotics on the Inflammation Mediated by the NF-κB Pathway in Inflammatory Bowel Conditions
by Saeideh Najafi, Fattah Sotoodehnejadnematalahi, Mohammad Mehdi Amiri, Mohammad Reza Pourshafie and Mahdi Rohani
Biomedicines 2023, 11(6), 1675; https://doi.org/10.3390/biomedicines11061675 - 9 Jun 2023
Cited by 7 | Viewed by 2081
Abstract
Probiotic supplements consumed adequately at the proper time can affect health by modulating inflammatory pathways in gastrointestinal epithelial cells and modifying the resultant inflammatory response. The current study applied in vitro models to investigate the effectiveness of probiotics in modulating inflammatory pathways and [...] Read more.
Probiotic supplements consumed adequately at the proper time can affect health by modulating inflammatory pathways in gastrointestinal epithelial cells and modifying the resultant inflammatory response. The current study applied in vitro models to investigate the effectiveness of probiotics in modulating inflammatory pathways and altering inflammatory gene expression in gastrointestinal epithelial cells, with the ultimate goal of promoting probiotic consumption as a therapeutic and preventive measure for chronic inflammatory bowel conditions. HT-29 cells were treated with Gram-negative bacteria to evaluate the changes in pathways related to inflammation activities before and after treatment with a Lactobacillus spp. cocktail (L. plantarum, L. rhamnosus, L. brevis, and L. ruteri) and a Bifidobacterium spp. cocktail (B. bifidum, B. langum, and B. breve) using the real-time PCR method and ELISA for IL-1β and IL-6 as pro-inflammatory cytokines. The results showed that the expression of NF-κB signaling pathway genes and IL-1β and IL-6 cytokines increased after exposure to Gram-negative components. In contrast, all probiotic combinations significantly decreased the expression of genes and the secretion of cytokines. However, this decrease was significantly smaller in cells that underwent probiotic treatment after inflammation induction. In addition, cocktails containing combined Lactobacillus and Bifidobacterium demonstrated robust anti-inflammatory activity relative to solo cocktails. Our observations confirm that probiotic consumption could positively impact inflammatory conditions and alleviate inflammatory symptoms; they can be particularly effective as a preventive measure. Our study provides preliminary evidence to support the lifetime consumption of probiotics. Full article
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Review

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17 pages, 740 KiB  
Review
The Impact of Obesity on Inflammatory Bowel Disease
by Patricia Kaazan, Warren Seow, Shaanan Yong, Leonie K. Heilbronn and Jonathan P. Segal
Biomedicines 2023, 11(12), 3256; https://doi.org/10.3390/biomedicines11123256 - 8 Dec 2023
Cited by 6 | Viewed by 3298
Abstract
Obesity is prevalent in the inflammatory bowel disease (IBD) population, particularly in newly developed countries where both IBD and obesity in the general population are on the rise. The role of obesity in the pathogenesis of IBD was entertained but results from available [...] Read more.
Obesity is prevalent in the inflammatory bowel disease (IBD) population, particularly in newly developed countries where both IBD and obesity in the general population are on the rise. The role of obesity in the pathogenesis of IBD was entertained but results from available studies are conflicting. It does, however, appear to negatively influence disease course whilst impacting on our medical and surgical therapies. The pro-inflammatory profile of the visceral adipose tissue might play a role in the pathogenesis and course of Crohn’s Disease (CD). Interestingly, isolating the mesentery from the surgical anastomosis using a KONO-S technique significantly decreases anastomotic recurrence rate. Anti-obesity therapy is not widely used in IBD but was suggested as an adjunctive therapy in those patients. In this review, we aimed to highlight the epidemiology of obesity in IBD and to describe its influence on disease course and outcomes. Full article
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19 pages, 1068 KiB  
Review
Evaluation of Disease Activity in Inflammatory Bowel Disease: Diagnostic Tools in the Assessment of Histological Healing
by Alina Ecaterina Jucan, Otilia Gavrilescu, Mihaela Dranga, Iolanda Valentina Popa, Ioana-Ruxandra Mihai, Vasile-Claudiu Mihai, Gabriela Stefanescu, Vasile Liviu Drug, Cristina Cijevschi Prelipcean, Radu-Alexandru Vulpoi, Oana-Bogdana Barboi, Irina Ciortescu and Catalina Mihai
Biomedicines 2023, 11(11), 3090; https://doi.org/10.3390/biomedicines11113090 - 18 Nov 2023
Cited by 2 | Viewed by 4080
Abstract
Inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn’s disease and ulcerative colitis. In long-standing ulcerative colitis disease activity, histological persistent inflammation has been linked to an increased risk of relapse, and long-term corticosteroid use, even when endoscopic remission is [...] Read more.
Inflammatory bowel disease (IBD) comprises two types of chronic intestinal disorders: Crohn’s disease and ulcerative colitis. In long-standing ulcerative colitis disease activity, histological persistent inflammation has been linked to an increased risk of relapse, and long-term corticosteroid use, even when endoscopic remission is reached. In Crohn’s disease, the discontinuous nature of lesions and transmural inflammation have limited the standardized histological assessment. The current evidence from research proposes that besides clinical and endoscopic healing, the achievement of histological healing constitutes an endpoint to assess disease activity and remission in IBD patients concerning better long-term disease outcomes. Histological alterations may persist even in the absence of endoscopic lesions. For these reasons, new advanced techniques promise to revolutionize the field of IBD by improving the endoscopic and histologic assessment, disease characterization, and ultimately patient care, with an established role in daily practice for objective assessment of lesions. This review outlines the importance of including microscopic evaluation in IBD, highlighting the clinical benefits of a deep state of disease remission using validated diagnostic methods and scoring systems for daily clinical practice. Full article
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33 pages, 790 KiB  
Review
Inflammatory Bowel Disease: Emerging Therapies and Future Treatment Strategies
by Elisabetta Bretto, Davide Giuseppe Ribaldone, Gian Paolo Caviglia, Giorgio Maria Saracco, Elisabetta Bugianesi and Simone Frara
Biomedicines 2023, 11(8), 2249; https://doi.org/10.3390/biomedicines11082249 - 11 Aug 2023
Cited by 18 | Viewed by 5346
Abstract
Inflammatory bowel disease (IBD) is a term used to represent a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major clinical forms. The global incidence and prevalence of IBD have increased [...] Read more.
Inflammatory bowel disease (IBD) is a term used to represent a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major clinical forms. The global incidence and prevalence of IBD have increased over the last 2–4 decades. Despite the specific etiopathogenesis of IBD still being unknown, it is widely recognized that immunological, genetic, and environmental factors are implicated. A greater understanding of the multiple signaling pathways involved has led to the development of biologic therapies in the last two decades. Although these treatments have dramatically transformed the course of IBD, there is not a definitive cure and available therapies may cause adverse events (AEs), limiting their use, or have an inadequate effect in some patients. In this context, emerging therapies addressing new specific pathogenetic mechanisms have shown promising efficacy and safety data in early clinical trials. The purpose of this review is to highlight the available clinical trial data for these new drugs, such as more preferential JAK inhibitors, anti-IL-23 antibodies, sphingosine-1-phosphate receptor modulators, anti-integrin therapies, and other small molecules that are currently under research. We will emphasize the potential significance of these agents in shaping future treatment options. Full article
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Other

12 pages, 2403 KiB  
Case Report
Novel Approach in Rectovaginal Fistula Treatment: Combination of Modified Martius Flap and Autologous Micro-Fragmented Adipose Tissue
by Ana Dimova, Ivana Erceg Ivkošić, Petar Brlek, Stefan Dimov, Tomislav Pavlović, Tomislav Bokun and Dragan Primorac
Biomedicines 2023, 11(9), 2509; https://doi.org/10.3390/biomedicines11092509 - 11 Sep 2023
Cited by 5 | Viewed by 3444
Abstract
In this paper, we introduce an innovative therapeutic approach for managing rectovaginal fistulas (RVF), by combining the modified Martius flap and micro-fragmented adipose tissue (MFAT) enriched with mesenchymal stem cells (MSC). This novel approach aims to deal with the difficulties associated with RVF, [...] Read more.
In this paper, we introduce an innovative therapeutic approach for managing rectovaginal fistulas (RVF), by combining the modified Martius flap and micro-fragmented adipose tissue (MFAT) enriched with mesenchymal stem cells (MSC). This novel approach aims to deal with the difficulties associated with RVF, a medically complex condition with a lack of effective treatment options. We present the case of a 45-year-old female patient with a 15-year history of Crohn’s disease (CD). During the preceding eight years, she had encountered substantial difficulties resulting from a rectovaginal fistula (RVF) that was active and considerable in size (measuring 3.5 cm in length and 1 cm in width). Her condition was accompanied by tissue alterations at both the vaginal and rectal openings. Following her admission to our hospital, the patient’s case was discussed during both surgical and multidisciplinary hospital team (IRB) meetings. The team decided to combine a modified Martius flap with autologous MFAT containing MSCs. The results were remarkable, leading to comprehensive anatomical and clinical resolution of the RVF. Equally significant was the improvement in the patient’s overall quality of life and sexual satisfaction during the one-year follow-up period. The integration of the modified Martius flap with MFAT emerges as a highly promising approach for addressing CD-related RVFs that had historically been, and still are, difficult to treat, given their often refractory nature and low healing success rates. Full article
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17 pages, 2715 KiB  
Systematic Review
The Utility of Faecal Calprotectin, Lactoferrin and Other Faecal Biomarkers in Discriminating Endoscopic Activity in Crohn’s Disease: A Systematic Review and Meta-Analysis
by Anuj Bohra, Ghada Mohamed, Abhinav Vasudevan, Diana Lewis, Daniel R. Van Langenberg and Jonathan P. Segal
Biomedicines 2023, 11(5), 1408; https://doi.org/10.3390/biomedicines11051408 - 9 May 2023
Cited by 12 | Viewed by 3513
Abstract
Introduction: Currently, faecal calprotectin (FC) is the predominate faecal biomarker utilised in clinical practice to monitor Crohn’s disease (CD) activity. However, there are several potential faecal biomarkers described in the literature. We performed a meta-analysis to determine the accuracy of faecal biomarkers in [...] Read more.
Introduction: Currently, faecal calprotectin (FC) is the predominate faecal biomarker utilised in clinical practice to monitor Crohn’s disease (CD) activity. However, there are several potential faecal biomarkers described in the literature. We performed a meta-analysis to determine the accuracy of faecal biomarkers in discriminating endoscopic activity and mucosal healing in CD. Methods: We searched the medical literature using MEDLINE, EMBASE, and PubMed from 1978 to 8 August 2022. Descriptive statistics, including sensitivity, specificity of the primary studies, their positive and negative likelihood ratios, and their diagnostic odds ratio (DOR), were calculated. The methodological quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS) criteria. Results: The search found 2382 studies, of which 33 were included for analysis after screening. FC was found to have a pooled sensitivity and specificity, DOR, and negative predictive value (NPV) in discriminating active endoscopic disease (versus inactive) of 81%, 74%, 13.93, and 0.27, respectively. Faecal lactoferrin (FL) had a pooled sensitivity and specificity, DOR, and NPV in discriminating active endoscopic disease of 75%, 80%, 13.41, and 0.34, respectively. FC demonstrated a pooled sensitivity and specificity, DOR, and NPV of 88%, 72%, 18.17, and 0.19 in predicting mucosal healing. Conclusion: FC remains an accurate faecal biomarker. Further evaluation of the utility of novel faecal biomarkers is needed. Full article
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