Molecular Biomarkers in Inflammatory Bowel Disease: Pathophysiology and New Therapeutic Strategies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 13624

Special Issue Editor


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Guest Editor
Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia
Interests: inflammatory bowel disease; biomarkers; pathophysiology

Special Issue Information

Dear Colleagues,

Inflammatory bowel disease (IBD) is a comprehensive medical term that represents a spectrum of chronic, idiopathic and immunologically mediated digestive tract disorders, with the main representatives being Crohn’s disease and ulcerative colitis. Although there are still many unknowns regarding the etiology and pathophysiology of IBD, it is considered to involve a complex interplay between genetic, epithelial, environmental, microbial and immunological factors.

Considering that the number of affected patients is increasing worldwide, and that overall disease management often requires complex and expensive testing, there is a need for convenient, non-invasive and economical solutions. Hence, recent developments suggest that molecular biomarkers are starting to become a main point of IBD studies, as they could fill these gaps and potentially improve numerous areas in IBD management, including in terms of timely diagnosis, treatment response, monitoring disease activity or mucosal healing. Furthermore, as most of the biomarkers that are currently widely used in IBD have certain shortcomings, there is vast space for improvements and new studies in this field.

Therefore, the main goal of the present Special Issue is to feature the most comprehensive and up-to‑date original research and specialized reviews helping to encompass and improve knowledge regarding molecular biomarkers that have significant roles in the complex pathophysiological pathways of IBD development as well as their potential for becoming new effective and reliable tools in disease monitoring, treatment strategies and precision medicine.

Dr. Marino Vilović
Guest Editor

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Keywords

  • inflammatory bowel disease (IBD)
  • Crohn’s disease
  • ulcerative colitis
  • biomarkers
  • molecular biomarkers in IBD
  • pathophysiology
  • therapeutic approaches in IBD
  • precision medicine

Published Papers (9 papers)

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Research

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11 pages, 1587 KiB  
Article
T Cell-Induced Colitis Is Exacerbated by Prolonged Stress: A Comparison in Male and Female Mice
by Ross M. Maltz, Pedro Marte-Ortiz, Madeline G. McClinchie, Miranda E. Hilt and Michael T. Bailey
Biomedicines 2024, 12(1), 214; https://doi.org/10.3390/biomedicines12010214 - 18 Jan 2024
Viewed by 1041
Abstract
Psychological stress exposure is well recognized to exacerbate inflammatory bowel disease (IBD) but the mechanisms involved remain poorly understood. In this study, chronic T cell-mediated colitis was induced by adoptively transferring CD4+CD45RBhigh splenic T cells from C57BL/6 WT donor mice [...] Read more.
Psychological stress exposure is well recognized to exacerbate inflammatory bowel disease (IBD) but the mechanisms involved remain poorly understood. In this study, chronic T cell-mediated colitis was induced by adoptively transferring CD4+CD45RBhigh splenic T cells from C57BL/6 WT donor mice into Rag1tm1Mom mice. Two weeks after T cell transfer, mice were exposed to a prolonged restraint stressor (RST) for 8 h per day for 6 consecutive days. The colitis phenotype was assessed via histopathology and semi-quantitative rt-PCR at humane endpoints or 10 weeks post-T-cell transfer. Mice that received the T cell transplant developed chronic colitis marked by increases in colonic histopathology and inflammatory cytokines. Colonic histopathology was greater in males than females regardless of RST exposure but RST exposure increased histopathology scores in females such that they reached scores observed in the males. This pattern was consistent with cytokine gene expression and protein levels in the colon (especially for IFN-γ, IL-17A, and TNF-α). Serum cytokine levels were not strongly affected by exposure to the stressor. Using a murine model of chronic T cell-mediated colitis, this study demonstrates that biological sex strongly influences colonic inflammation and exposure to chronic stress has a more pronounced effect in females than in males. Full article
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14 pages, 2374 KiB  
Article
Effects of Golimumab and Ustekinumab on Circulating Dendritic Cell Migratory Capacity in Inflammatory Bowel Disease
by Irene Soleto, Cristina Ramirez, Cristina Gómez, Montse Baldan-Martin, Macarena Orejudo, Jorge Mercado, María Chaparro and Javier P. Gisbert
Biomedicines 2023, 11(10), 2831; https://doi.org/10.3390/biomedicines11102831 - 18 Oct 2023
Cited by 1 | Viewed by 1099
Abstract
Inflammatory bowel disease (IBD) is a chronic condition which includes ulcerative colitis (UC) and Crohn’s disease (CD), the origins of which are not yet fully understood. Both conditions involve an exacerbated immune response in the intestinal tract, leading to tissue inflammation. Dendritic cells [...] Read more.
Inflammatory bowel disease (IBD) is a chronic condition which includes ulcerative colitis (UC) and Crohn’s disease (CD), the origins of which are not yet fully understood. Both conditions involve an exacerbated immune response in the intestinal tract, leading to tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells crucial for maintaining tolerance in the gastrointestinal mucosa. Previous research has indicated that DC recruitment to the intestinal mucosa is more pronounced in individuals with IBD, but the specific mechanisms governing this migration remain unclear. This study aimed to assess the expression of various homing markers and the migratory abilities of circulating DC subsets in response to intestinal chemotactic signals. Additionally, this study examined how golimumab and ustekinumab impact these characteristics in individuals with IBD compared to healthy controls. The findings revealed that a particular subset of DCs known as type 2 conventional DCs (cDC2) displayed a more pronounced migratory profile compared to other DC subsets. Furthermore, the study observed that golimumab and ustekinumab had varying effects on the migratory profile of cDC1 in individuals with CD and UC. While CCL2 did not exert a chemoattractant effect on DC subsets in this patient cohort, treatment with golimumab and ustekinumab enhanced their migratory capacity towards CCL2 and CCL25 while reducing their migration towards MadCam1. In conclusion, this study highlights that cDC2 exhibits a heightened migratory profile towards the gastrointestinal mucosa compared to other DC subsets. This finding could be explored further for the development of new diagnostic biomarkers or the identification of potential immunomodulatory targets in the context of IBD. Full article
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16 pages, 3192 KiB  
Article
Effect of Carbamylated Erythropoietin in a Chronic Model of TNBS-Induced Colitis
by Inês Silva, Mário Gomes, Carolina Alípio, Jéssica Vitoriano, João Estarreja, Priscila Mendes, Rui Pinto and Vanessa Mateus
Biomedicines 2023, 11(9), 2497; https://doi.org/10.3390/biomedicines11092497 - 9 Sep 2023
Viewed by 873
Abstract
Background: Inflammatory bowel disease (IBD) is a public health issue with a growing prevalence, which can be divided into two phenotypes, namely Crohn’s disease (CD) and ulcerative colitis (UC). Currently, used therapy is based only on symptomatic and/or palliative pharmacological approaches. These treatments [...] Read more.
Background: Inflammatory bowel disease (IBD) is a public health issue with a growing prevalence, which can be divided into two phenotypes, namely Crohn’s disease (CD) and ulcerative colitis (UC). Currently, used therapy is based only on symptomatic and/or palliative pharmacological approaches. These treatments seek to induce and maintain remission of the disease and ameliorate its secondary effects; however, they do not modify or reverse the underlying pathogenic mechanism. Therefore, it is essential to investigate new potential treatments. Carbamylated erythropoietin (cEPO) results from the modification of the Erythropoietin (EPO) molecule, reducing cardiovascular-related side effects from the natural erythropoiesis stimulation. cEPO has been studied throughout several animal models, which demonstrated an anti-inflammatory effect by decreasing the production of several pro-inflammatory cytokines. Aim: This study aimed to evaluate the efficacy and safety of cEPO in a chronic TNBS-induced colitis model in rodents. Methods: Experimental colitis was induced by weekly intrarectal (IR) administrations of 1% TNBS for 5 weeks in female CD-1 mice. Then, the mice were treated with 500 IU/kg/day or 1000 IU/kg/day of cEPO through intraperitoneal injections for 14 days. Results: cEPO significantly reduced the concentration of alkaline phosphatase (ALP), fecal hemoglobin, tumor necrosis factor (TNF)-α, and interleukin (IL)-10. Also, it demonstrated a beneficial influence on the extra-intestinal manifestations, with the absence of significant side effects of its use. Conclusion: Considering the positive results from cEPO in this experiment, it may arise as a new possible pharmacological approach for the future management of IBD. Full article
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17 pages, 11413 KiB  
Article
Therapeutic Potential of BMP7 in the Treatment of Osteoporosis Caused by the Interaction between Inflammation and Corticosteroids in Inflammatory Bowel Disease
by Ivana Smoljan, Dijana Detel, Suncica Buljevic, Igor Erjavec and Ivana Marić
Biomedicines 2023, 11(8), 2161; https://doi.org/10.3390/biomedicines11082161 - 1 Aug 2023
Cited by 1 | Viewed by 1237
Abstract
Individuals with inflammatory bowel disease (IBD) have an increased risk of bone impairment, which is a process controlled by the RANKL/RANK/OPG system, mostly due to chronic inflammation and corticosteroid treatment. Bone morphogenic protein 7 (BMP7) has a complex role in maintaining inflammation and [...] Read more.
Individuals with inflammatory bowel disease (IBD) have an increased risk of bone impairment, which is a process controlled by the RANKL/RANK/OPG system, mostly due to chronic inflammation and corticosteroid treatment. Bone morphogenic protein 7 (BMP7) has a complex role in maintaining inflammation and bone remodeling but little is known about its anti-inflammatory potential in chronic colitis. We investigated the effect of systemically administered BMP7 and corticosteroids on the severity of inflammation, macrophage differentiation, and bone regeneration in a chronic IBD model. Methods: Chronic colitis was induced in male Sprague Dawley rats via weekly administration of 2,4,6-trinitrobenzenesulfonic acid over 21 days following BMP7 or corticosteroid treatment for five days. The levels of serum and colon tissue inflammatory cytokines, RANKL/OPG system, as well as markers of macrophage polarization, were detected using RT-PCR, ELISA, or immunohistochemistry. Long bone and spine analyses were performed using microcomputed tomography (micro-CT). Results: The administration of BMP7 reduced the adverse effects of colitis and led to elevated OPG and RANK in the colon with a simultaneous decrease in TNF-α and an increase in IL-10 and TGF-β. Decreased expression of the M2 macrophage marker CD163 was found in the BMP7-treated rats compared with the colitis group, whereas the number of M1 marker iNOS-positive cells did not differ between the groups. As a result of the BMP7 treatment, morphometric parameters of trabecular bone increased, and increased trabecular separation noted in the colitis group did not appear. Conclusions: We showed that BMP7 suppressed the inflammatory response in chronic colitis, mainly by shifting the cytokine balance and by triggering alterations in the RANKL/OPG system rather than through a macrophage polarization imbalance. In addition, considering the demonstrated effect of BMP7 on bone morphology and structure, it can be suggested that BMP7 plays a role in the managing of osteoporosis in chronic colitis, and thus, its therapeutic potential in the treatment of IBD should be further evaluated. Full article
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14 pages, 657 KiB  
Article
Transcriptomic Context of RUNX3 Expression in Monocytes: A Cross-Sectional Analysis
by Emilia Dybska, Jan Krzysztof Nowak and Jarosław Walkowiak
Biomedicines 2023, 11(6), 1698; https://doi.org/10.3390/biomedicines11061698 - 13 Jun 2023
Cited by 1 | Viewed by 1270
Abstract
The runt-related transcription factor 3 (RUNX3) regulates the differentiation of monocytes and their response to inflammation. However, the transcriptomic context of RUNX3 expression in blood monocytes remains poorly understood. We aim to learn about RUNX3 from its relationships within transcriptomes of bulk CD14+ [...] Read more.
The runt-related transcription factor 3 (RUNX3) regulates the differentiation of monocytes and their response to inflammation. However, the transcriptomic context of RUNX3 expression in blood monocytes remains poorly understood. We aim to learn about RUNX3 from its relationships within transcriptomes of bulk CD14+ cells in adults. This study used immunomagnetically sorted CD14+ cell gene expression microarray data from the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1202, GSE56047) and the Correlated Expression and Disease Association Research (CEDAR, n = 281, E-MTAB-6667) cohorts. The data were preprocessed, subjected to RUNX3-focused correlation analyses and random forest modeling, followed by the gene ontology analysis. Immunity-focused differential ratio analysis with intermediary inference (DRAIMI) was used to integrate the data with protein–protein interaction network. Correlation analysis of RUNX3 expression revealed the strongest positive association for EVL (rmean = 0.75, pFDR-MESA = 5.37 × 10−140, pFDR-CEDAR = 5.52 × 10−80), ARHGAP17 (rmean = 0.74, pFDR-MESA = 1.13 × 10−169, pFDR-CEDAR = 9.20 × 10−59), DNMT1 (rmean = 0.74, pFDR-MESA = 1.10 × 10−169, pFDR-CEDAR = 1.67 × 10−58), and CLEC16A (rmean = 0.72, pFDR-MESA = 3.51 × 10−154, pFDR-CEDAR = 2.27 × 10−55), while the top negative correlates were C2ORF76 (rmean = −0.57, pFDR-MESA = 8.70 × 10−94, pFDR-CEDAR = 1.31 × 10−25) and TBC1D7 (rmean = −0.55, pFDR-MESA = 1.36 × 10−69, pFDR-CEDAR = 7.81 × 10−30). The RUNX3-associated transcriptome signature was involved in mRNA metabolism, signal transduction, and the organization of cytoskeleton, chromosomes, and chromatin, which may all accompany mitosis. Transcriptomic context of RUNX3 expression in monocytes hints at its relationship with cell growth, shape maintenance, and aspects of the immune response, including tyrosine kinases. Full article
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13 pages, 1708 KiB  
Article
Do Vedolizumab trough Levels Predict the Outcome of Subsequent Therapy in Inflammatory Bowel Disease?
by Asaf Levartovsky, Ido Cohen, Chaya Mushka Abitbol, Miri Yavzori, Ella Fudim, Orit Picard, Uri Kopylov, Shomron Ben-Horin and Bella Ungar
Biomedicines 2023, 11(6), 1553; https://doi.org/10.3390/biomedicines11061553 - 26 May 2023
Cited by 2 | Viewed by 1414
Abstract
Background: Vedolizumab trough serum levels have been associated with clinical and endoscopic response in patients with inflammatory bowel disease (IBD). A recent study demonstrated that higher trough levels before dose escalation are associated with favorable outcomes. Objectives: We aimed to identify [...] Read more.
Background: Vedolizumab trough serum levels have been associated with clinical and endoscopic response in patients with inflammatory bowel disease (IBD). A recent study demonstrated that higher trough levels before dose escalation are associated with favorable outcomes. Objectives: We aimed to identify whether vedolizumab trough levels predict outcome of subsequent therapy. Methods: This retrospective study included IBD patients consecutively receiving vedolizumab therapy between November 2014 and June 2021. Only patients with a loss of response (LOR) to vedolizumab and available trough drug levels prior to therapy cessation were included. Clinical and endoscopic scores were recorded at 6 and 12 months post switching therapy. Results: Overall, 86 IBD patients (51 Crohn’s disease, 35 ulcerative colitis) who discontinued vedolizumab were included; of those, 72 (83.7%) were due to LOR. Upon vedolizumab discontinuation, 66.3% of patients were switched to another biologic therapy. Trough vedolizumab levels at discontinuation due to LOR did not differ between patients with clinical response and LOR regarding subsequent therapy at 6 months [median 33.8 μg/mL (IQR 13.2–51.6) versus 31.7 μg/mL (IQR 9.1–64.8), p = 0.9] and at 12 months [median 29.6 μg/mL (IQR 14.3–51.6) versus 34.1 μg/mL (IQR 12.2–64.7), p = 0.6]. Patients progressing to subsequent surgery had numerically lower vedolizumab trough levels at LOR compared with patients who were treated with an additional medical therapy (median 14.3, IQR 4–28.2 μg/mL versus 33.5, IQR 13–51.6 μg/mL, p = 0.08). Conclusions: Vedolizumab trough levels upon LOR do not predict response to subsequent medical therapy; however, lower drug levels may suggest a more aggressive disease pattern and future need for surgery. Full article
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13 pages, 2648 KiB  
Article
Inhibition of NADPH Oxidase (NOX) 2 Mitigates Colitis in Mice with Impaired Macrophage AMPK Function
by Suhrid Banskota, Huaqing Wang, Yun Han Kwon, Jaya Gautam, Sabah Haq, Jensine Grondin, Gregory R. Steinberg and Waliul I. Khan
Biomedicines 2023, 11(5), 1443; https://doi.org/10.3390/biomedicines11051443 - 14 May 2023
Cited by 5 | Viewed by 1956
Abstract
Macrophage adenosine monophosphate-activated protein kinase (AMPK) limits the development of experimental colitis. AMPK activation inhibits NADPH oxidase (NOX) 2 expression, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion in macrophages during inflammation, while increased NOX2 expression is reported in experimental models of [...] Read more.
Macrophage adenosine monophosphate-activated protein kinase (AMPK) limits the development of experimental colitis. AMPK activation inhibits NADPH oxidase (NOX) 2 expression, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion in macrophages during inflammation, while increased NOX2 expression is reported in experimental models of colitis and inflammatory bowel disease (IBD) patients. Although there are reductions in AMPK activity in IBD, it remains unclear whether targeted inhibition of NOX2 in the presence of defective AMPK can reduce the severity of colitis. Here, we investigate whether the inhibition of NOX2 ameliorates colitis in mice independent of AMPK activation. Our study identified that VAS2870 (a pan-Nox inhibitor) alleviated dextran sodium sulfate (DSS)-induced colitis in macrophage-specific AMPKβ1-deficient (AMPKβ1LysM) mice. Additionally, VAS2870 blocked LPS-induced TLR-4 and NOX2 expression, ROS production, nuclear translocation of NF-κB, and pro-inflammatory cytokine secretion in bone marrow-derived macrophages (BMDMs) from AMPKβ1LysM mice, whereas sodium salicylate (SS; AMPK β1 activator) did not. Both VAS2870 and SS inhibited LPS-induced NOX2 expression, ROS production, and pro-inflammatory cytokine secretions in bone marrow-derived macrophages (BMDMs) from wildtype (AMPKβ1fl/fl) mice but only VAS2870 inhibited these effects of LPSs in AMPKβ1LysM BMDMs. Furthermore, in macrophage cells (RAW 264.7), both SS and VAS2870 inhibited ROS production and the secretion of pro-inflammatory cytokines and reversed the impaired autophagy induced by LPSs. These data suggest that inhibiting NOX2 can reduce inflammation independent of AMPK in colitis. Full article
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Review

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22 pages, 1881 KiB  
Review
Cytokine Profile in Predicting the Effectiveness of Advanced Therapy for Ulcerative Colitis: A Narrative Review
by Hiroki Kurumi, Yoshihiro Yokoyama, Takehiro Hirano, Kotaro Akita, Yuki Hayashi, Tomoe Kazama, Hajime Isomoto and Hiroshi Nakase
Biomedicines 2024, 12(5), 952; https://doi.org/10.3390/biomedicines12050952 - 25 Apr 2024
Viewed by 780
Abstract
Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, [...] Read more.
Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents. Full article
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9 pages, 272 KiB  
Review
Focal Active Colitis: What Are Its Clinical Implications? A Narrative Review
by Emanuele Sinagra, Francesco Vito Mandarino, Marcello Maida, Daniela Cabibi, Francesca Rossi, Dario Raimondo and Guido Manfredi
Biomedicines 2023, 11(10), 2631; https://doi.org/10.3390/biomedicines11102631 - 25 Sep 2023
Viewed by 2485
Abstract
Focal active colitis (FAC) is described as a histolopathological term indicating the isolated finding of focal neutrophil infiltration in the colonic crypts. Currently, there exist numerous debates regarding the clinical significance of diagnosing FAC, which may or may not have clinical relevance as [...] Read more.
Focal active colitis (FAC) is described as a histolopathological term indicating the isolated finding of focal neutrophil infiltration in the colonic crypts. Currently, there exist numerous debates regarding the clinical significance of diagnosing FAC, which may or may not have clinical relevance as it is frequently detected in colorectal biopsies without any other microscopic abnormalities. The objective of this narrative review is to provide an overview of the available evidence concerning the clinical implications of FAC, both in the adult population (among five studies available in the scientific literature) and in the pediatric context (based on two available studies). Full article
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