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Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 November 2025 | Viewed by 11286

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Special Issue Editor

Prof. Dr. Rafał Filip

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Guest Editor

1. Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
2. Department of Gastroenterology with IBD Unit, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
Interests: crohns disease; UIcerative colitis; GI endoscopy; GI immunology; gastrointestinal diseases

Special Issue Information

Dear Colleagues,

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are chronic diseases with periods of activity and remission. Despite the great progress made in understanding the etiology of IBD, it is not fully elucidated. However, many studies point to important genetic, environmental, and immunological factors in the occurrence of these conditions. Understanding the molecular and immunological mechanisms in the pathogenesis process can influence the therapeutic process.

The purpose of this Special Issue is to deepen knowledge and gather information on molecular and pathophysiological mechanisms of inflammatory bowel disease and also to present the complete current situation of this field and its future prospects.

To ensure the diversity of approaches and viewpoints of the authors, we will collect different types of articles, such as original articles, systematic reviews, and communication.

This Special Issue is supervised by Prof. Dr. Rafał Filip and assisted by our Guest Editor’s assistant editors Dr. Sara Jarmakiewicz-Czaja, sjczaja@ur.edu.pl, and Dr. Aneta Sokal-Dembowska, asokal@ur.edu.pl (Institute of Health Sciences, Medical College of Rzeszów University, Rzeszów, Poland).

Prof. Dr. Rafał Filip
Guest Editor

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Keywords

Crohn’s disease
inflammatory bowel disease
immunologic and molecular mechanisms
therapies for IBD
ulcerative colitis

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Published Papers (9 papers)

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Research

Jump to: Review

28 pages, 5350 KB

Open AccessArticle

Galactooligosaccharides Promote Gut Barrier Integrity and Exert Anti-Inflammatory Effects in DSS-Induced Colitis Through Microbiota Modulation

by Lucila A. Godínez-Méndez, Alejandra Natali Vega-Magaña, Marcela Peña-Rodríguez, Gisela Anay Valencia-Hernández, Germán Muñoz-Sánchez, Liliana Iñiguez-Gutiérrez, Rocío López-Roa, Martha Eloisa Ramos-Márquez, Mary Fafutis-Morris and Vidal Delgado-Rizo

Int. J. Mol. Sci. 2025, 26(16), 7968; https://doi.org/10.3390/ijms26167968 - 18 Aug 2025

Viewed by 565

Abstract

Ulcerative colitis is a chronic inflammatory bowel disease characterized by persistent inflammation, immune dysregulation, gut microbiota alterations, and impaired epithelial barrier function. Lupinus albus is a legume rich in galactooligosaccharides (GOS) that functions as a prebiotic capable of modulating the gut microbiota and mitigating ulcerative colitis-related damage. This study aimed to elucidate the effect of GOS on gut microbiota modulation and the molecular mechanisms involved in epithelial restoration and inflammation reduction. Fifteen C57BL/6 mice were randomly assigned to three groups (n = 5 per group): control (CTL), ulcerative colitis (UC), and ulcerative colitis + GOS (UC + GOS). UC was induced by administering 2% dextran sulfate sodium (DSS) in drinking water for seven days. The UC + GOS group received 2.5 g/kg BW of GOS via gavage for 14 days. GOS administration improved mucus layer thickness, regulated the expression of tight junction proteins, reduced pro-inflammatory cytokine levels, and modulated the gut microbiota, preventing the loss of richness and diversity. Additionally, the expression of monocarboxylate transporters (MCTs) MCT1 and MCT4 was evaluated, and significant differences were observed between the groups across colon and cecum tissues. These findings suggest that GOS supplementation may play a potential role in attenuating ulcerative colitis by regulating the gut microbiota and the metabolic state of intestinal cells. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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31 pages, 4867 KB

Open AccessArticle

Cannabidiol Enhances the Therapeutic Efficacy of Olsalazine and Cyclosporine in a Murine Model of Colitis

by Dinesh Thapa, Mohan Patil, Leon N. Warne, Rodrigo Carlessi and Marco Falasca

Int. J. Mol. Sci. 2025, 26(16), 7913; https://doi.org/10.3390/ijms26167913 - 16 Aug 2025

Viewed by 513

Abstract

Current therapies for inflammatory bowel disease (IBD), such as olsalazine and cyclosporine, often exhibit limited long-term efficacy and are associated with adverse effects. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, shows promise for its anti-inflammatory properties, though its effectiveness as a monotherapy remains inconclusive. This study investigates the therapeutic potential of combining low-dose CBD (10 mg/kg) with olsalazine (50 mg/kg) or cyclosporine (2.5, 5 mg/kg) in dextran sulphate sodium (DSS)-induced acute and chronic colitis models in mice. Disease severity was assessed via disease activity index (DAI), colon morphology, cytokine and chemokine expression, myeloperoxidase (MPO) activity, systemic inflammatory markers, and glucagon-like peptide-1 (GLP-1) regulation. Safety evaluations included haematology and plasma biochemistry. DSS-treated mice showed elevated DAI scores, colon shortening, heightened inflammation, and organ enlargement. Combination therapies significantly ameliorated colitis, reducing DAI, MPO activity, and inflammatory cytokines, while restoring colon length and GLP-1 levels—without inducing liver or kidney toxicity. These findings demonstrate that combining a low dose of CBD with standard IBD drugs enhances therapeutic efficacy while minimizing side effects, supporting its integration into future combination strategies for more effective and safer IBD management. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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20 pages, 2762 KB

Open AccessArticle

The Role of GPX Enzymes, Lipid Profiles, and Iron Accumulation in Necrotizing Enterocolitis

by Grant H. Gershner, Chase Calkins, Alena Golubkova, Camille Schlegel, Aslan Massahi, Megan Lerner, Alex N. Frickenstein, Sarah Bonvicino, Martin-Paul Agbaga and Catherine J. Hunter

Int. J. Mol. Sci. 2025, 26(13), 6077; https://doi.org/10.3390/ijms26136077 - 25 Jun 2025

Viewed by 533

Abstract

Necrotizing enterocolitis (NEC) is a serious GI disease of premature infants, marked by intestinal inflammation and necrosis. Recent research has highlighted the potential role of oxidative stress (OS) and ferroptosis in its pathogenesis. We previously identified a deficiency in Glutathione Peroxidase (GPX) 4 and lipid radical accumulation, prompting further investigation. Human intestinal tissue from a prior study was processed, and it underwent RNA and protein isolation, Immunohistochemistry, Immunofluorescence, and acid digestion for iron and selenium analysis via Inductively coupled mass spectrometry (ICP-MS). NEC was induced in human enteroids using lipopolysaccharide (LPS) and hypoxia, followed by RNA/protein isolation and lipidomic analysis. Humans with NEC had significantly higher levels of GPX2 (p = 0.0003). Enteroids exposed to NEC conditions had significantly decreased amounts of NADPH compared to initial controls (p = 0.0091), but similar levels compared to post-24 h controls (p = 0.3520). Patients with NEC had significantly higher levels of iron compared to controls via the bathophenanthroline-based assay (p = 0.0102) and with ICP-MS (p = 0.0148). There were several significant alterations in lipid distribution between NEC and control patients, but not in the fatty acid profiles. Our study suggests that oxidative stress, iron dysregulation, and altered lipid metabolism contribute to NEC pathogenesis. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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19 pages, 8104 KB

Open AccessArticle

Exploring the Clinical Implication of S100A9 in Ulcerative Colitis and Its Progression to Cancer: A Journey from Inflammation to Cancer

by Jaehwan Cheon, Sang Hyun Kim, Jaehyung Park and Tae Hoon Kim

Int. J. Mol. Sci. 2025, 26(12), 5693; https://doi.org/10.3390/ijms26125693 - 13 Jun 2025

Viewed by 883

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and debilitating symptoms that considerably impair life quality. UC is particularly prevalent in younger populations, where early diagnosis remains challenging owing to nonspecific symptoms and the potential progression to colitis-associated cancer (CAC). The GSE177044 dataset, consisting of whole blood samples, was analyzed to identify differentially expressed genes, perform gene annotation, analyze key signaling pathways, and detect key hub genes in UC using protein–protein interaction networks. Multiple UC datasets composed of colonic samples were used for validation and examination of methylation and age-related gene expression patterns. Further analyses were performed to explore the association between these key hub genes and colon adenocarcinoma (COAD). We identified four key hub genes—lipocalin-2 (LCN2), matrix metalloproteinase-9 (MMP9), S100 calcium-binding protein A9 (S100A9), and olfactomedin-4 (OLFM4)—significantly up-regulated in UC, with S100A9 showing epigenetic regulation and age-dependent expression patterns. Additionally, S100A9 was strongly associated with poor prognosis in COAD, displaying hypo-methylation and elevated expression, especially in myeloid cell types, and links to altered immune and molecular subtypes. Our findings confirmed the hypo-methylation-driven up-regulation of LCN2, S100A9, and OLFM4 in UC, suggesting their potential as blood-based diagnostic biomarkers. Notably, S100A9 has emerged as a promising biomarker for the early diagnosis of ulcerative colitis, particularly in pediatric and adolescent patients with UC. Moreover, S100A9 holds potential as a precision target to prevent progression from UC to CAC. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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17 pages, 2674 KB

Open AccessArticle

Gut Bacterial Composition and Nutritional Implications in Mexican and Spanish Individuals with Inflammatory Bowel Disease Compared to Healthy Controls

by Ricardo García-Gamboa, Osiris Díaz-Torres, Misael Sebastián Gradilla-Hernández, Vicente Pérez-Brocal, Andrés Moya and Marisela González-Avila

Int. J. Mol. Sci. 2024, 25(22), 11887; https://doi.org/10.3390/ijms252211887 - 5 Nov 2024

Cited by 4 | Viewed by 1500

Abstract

The intestinal microbiota plays a key role in the pathogenesis of inflammatory bowel disease (IBD), with its composition varying based on geographic location and dietary factors. This study was performed to examine and compare the bacterial composition of the gut microbiota in Mexican and Spanish individuals with IBD and healthy controls, while also considering the nutritional aspects. This study involved 79 individuals with IBD and healthy controls from Mexico and Spain. The fecal microbiota composition was analyzed using 16S rRNA gene sequencing, and the dietary intake and anthropometric measurements were collected. Alpha diversity analysis revealed a lower Chao1 index of the bacterial genera in the IBD groups. Beta diversity analysis showed significant differences in the bacterial composition, suggesting inter-individual variability within the healthy and IBD groups. Additionally, the relative abundance of the bacterial genera varied across the four groups. Faecalibacterium was more abundant in the IBD groups; Prevotella was found exclusively in the Mexican groups, and Akkermansia was found only in the Spanish groups. Akkermansia was positively correlated with meat and protein intake, Prevotella with lean mass, and Bacteroides with calorie intake. These findings highlight the importance of considering geographic and nutritional factors in future research on the gut microbiome’s role in IBD pathogenesis. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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13 pages, 3628 KB

Open AccessArticle

Anti-Inflammatory Effects of miR-369-3p via PDE4B in Intestinal Inflammatory Response

by Viviana Scalavino, Emanuele Piccinno, Nicoletta Labarile, Raffaele Armentano, Gianluigi Giannelli and Grazia Serino

Int. J. Mol. Sci. 2024, 25(15), 8463; https://doi.org/10.3390/ijms25158463 - 2 Aug 2024

Cited by 5 | Viewed by 1713

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) consist of a family of enzymes expressed in several types of cells, including inflammatory cells, that play a pivotal role in inflammation. Several studies have demonstrated that the inhibition of PDE4 results in a reduced inflammatory response via PKA and CREB signaling. Hence, PDE4 suppression improves the inflammatory feedback typical of several diseases, such as inflammatory bowel disease (IBD). In our previous studies, we have demonstrated that miR-369-3p regulates inflammatory responses, modulating different aspects of the inflammatory process. The aim of this study was to demonstrate an additional anti-inflammatory effect of miR-369-3p targeting PDE4B, one of the widely expressed isoforms in immune cells. We found that miR-369-3p was able to reduce the expression of PDE4B, elevating the intracellular levels of cAMP. This accumulation increased the expression of PKA and pCREB, mitigating the release of pro-inflammatory cytokines and promoting the release of anti-inflammatory cytokines. To prove that PDE4B is a good therapeutic target in IBD, we also demonstrate that the expression of PDE4B was increased in UC patients compared to healthy controls, affecting the immune infiltrate. PDE4B is considered an important player in inflammatory progression; hence, our results show the ability of miR-369-3p to ameliorate inflammation by targeting PDE4B, supporting its future application as a new therapeutic approach in IBD. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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Review

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26 pages, 2323 KB

Open AccessReview

Advances in Understanding Intestinal Homeostasis: Lessons from Inflammatory Bowel Disease and Monogenic Intestinal Disorder Pathogenesis

by Céline Petit, Aurore Rozières, Gilles Boschetti, Christophe Viret, Mathias Faure, Stéphane Nancey and Rémi Duclaux-Loras

Int. J. Mol. Sci. 2025, 26(13), 6133; https://doi.org/10.3390/ijms26136133 - 26 Jun 2025

Viewed by 1403

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract that are multifactorial in nature. The pathophysiology involves interactions between the host immune system and environmental factors, including the gut microbiota, in genetically predisposed individuals. Advances in understanding these interactions have led to the development of novel therapeutic targets, ranging from anti-TNFα to more recent anti-interleukin 23 treatments. However, some patients still experience resistance to these therapies. Monogenic intestinal diseases (MIDs), which present with more severe symptoms than IBD and typically begin early in life, result from significant disruptions of intestinal homeostasis. MIDs are driven by mutations in a single gene, offering a unique opportunity to explore the mechanisms underlying intestinal homeostasis in health. In this review, we provide a comprehensive overview of the mechanisms of intestinal homeostasis by examining the cellular and molecular features of IBD and MID pathophysiologies. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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16 pages, 517 KB

Open AccessReview

The Role of microRNAs in Inflammatory Bowel Disease

by Aneta Sokal-Dembowska, Sara Jarmakiewicz-Czaja, Kacper Helma and Rafał Filip

Int. J. Mol. Sci. 2025, 26(10), 4750; https://doi.org/10.3390/ijms26104750 - 15 May 2025

Cited by 1 | Viewed by 1310

Abstract

Deregulation of microRNAs (miRNAs) has been implicated in the development of inflammatory bowel disease (IBD). Specific miRNAs are differentially expressed in patients with IBD compared to healthy individuals. Regulation of their expression can modulate the inflammatory response, the composition of the intestinal microbiota, and intestinal barrier function. miRNAs can regulate the immune and inflammatory response via multiple mechanisms, from Th1/Th17 regulation and ferroptosis to modulation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) and control of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. The use of miRNAs as biomarkers and therapeutic targets may help monitor IBD treatment and support the development of new, more individualized therapies that minimize common side effects. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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13 pages, 531 KB

Open AccessReview

Long Non-Coding RNAs and Their Potential Role as Biomarkers in Inflammatory Bowel Disease

by Lorena Ortega Moreno, María Chaparro and Javier P. Gisbert

Int. J. Mol. Sci. 2024, 25(16), 8808; https://doi.org/10.3390/ijms25168808 - 13 Aug 2024

Cited by 1 | Viewed by 1740

Abstract

Inflammatory bowel disease is a chronic inflammatory disease that encompasses entities such as Crohn’s disease and ulcerative colitis. Its incidence has risen in newly industrialised countries over time, turning it into a global disease. Lately, studies on inflammatory bowel disease have focused on finding non-invasive and specific biomarkers. Long non-coding RNAs may play a role in the pathophysiology of inflammatory bowel disease and therefore they may be considered as potential biomarkers for this disease. In the present article, we review information in the literature on the relationship between long non-coding RNAs and inflammatory bowel disease. We especially focus on understanding the potential function of these RNAs as non-invasive biomarkers, providing information that may be helpful for future studies in the field. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies)

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