International Journal of Molecular Sciences

Research

Jump to: Review

16 pages, 1884 KB

Open AccessArticle

Serum Oncostatin M in Ulcerative Colitis Patients and Its Relation to Disease Activity

by Alina-Ecaterina Jucan, Georgiana-Elena Sarbu, Vasile-Claudiu Mihai, Carmen Atodiresei, Simona Juncu, Ioana-Ruxandra Mihai, Mariana Pavel-Tanasa, Daniela Constantinescu, Mihaela Dranga, Otilia Nedelciuc, Diana-Gabriela Iosep, Mihai Danciu, Smaranda Diaconescu, Georgiana-Emmanuela Gîlca-Blanariu, Andrei Mihai Andronic, Elena Toader, Vasile-Liviu Drug, Cristina Cijevschi Prelipcean and Catalina Mihai

Int. J. Mol. Sci. 2026, 27(1), 307; https://doi.org/10.3390/ijms27010307 - 27 Dec 2025

Viewed by 171

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease; non-invasive biomarkers that accurately reflect the endoscopic and histological activity of UC require validation. Therefore, our study focused on exploring the potential of serum oncostatin M (OSM) as a biomarker for evaluating UC [...] Read more.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease; non-invasive biomarkers that accurately reflect the endoscopic and histological activity of UC require validation. Therefore, our study focused on exploring the potential of serum oncostatin M (OSM) as a biomarker for evaluating UC severity. A total of UC 89 eligible participants (≥18 years) underwent extensive clinical and paraclinical evaluation. Clinical, endoscopic, and histological activity were assessed using the partial Mayo score (pMS), the Mayo endoscopic score (MES), and the Nancy Histological Index (NHI), respectively. Serum OSM levels were determined by ELISA test and measured in pg/mL; fecal calprotectin (FC) was measured in µ/g. In our study, serum OSM was significantly associated with all four outcome measures: higher OSM levels predicted higher pMS (β = 0.471, p < 0.001, R² = 0.222), MES (β = 0.422, p < 0.001, R² = 0.178), NHI (β = 0.422, p < 0.001, R² = 0.256), and FC (β = 0.431, p < 0.001, R² = 0.186). Furthermore, ROC curve analyses demonstrated that OSM had excellent diagnostic accuracy for active disease, particularly in relation to histological inflammation (AUC = 0.967). In comparison, FC showed good but slightly lower accuracy (AUC = 0.875). Notably, OSM also outperformed FC in discriminating histological remission. Pairwise ROC curve analyses using DeLong’s test further confirmed the diagnostic accuracy of OSM, FC, and combined biomarker scores (OSM+FC) across clinical, endoscopic, and histological endpoints. The combined score PRE1 (OSM + FC based on NHI) achieved perfect discrimination (AUC = 1.000, p < 0.001). Composite models PRE2 and PRE3 (OSM+FC based on MES and pMS) improved diagnostic accuracy relative to OSM, confirming the value of combining OSM with FC. Although both outperformed OSM (p < 0.05), neither achieved a superior advantage over FC. Serum OSM is strongly associated with histological activity in UC and demonstrates superior performance compared with FC in assessing histological remission. Full article

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

► Show Figures

Figure 1

16 pages, 2931 KB

Open AccessArticle

Oral Nano-Delivery of Crotoxin Modulates Experimental Ulcerative Colitis in a Mouse Model of Maximum Acute Inflammatory Response

by Raquel Guedes de Oliveira Brito, Fernanda Narangeira de Araujo Neves, Larissa Ferreira de Almeida, Bruna Cristina Favoretto, Wafa Hanna Koury Cabrera, Nancy Starobinas, Jamile Macedo Garcia, Natália Coelho Couto de Azevedo Fernandes, José Luiz de Souza Lopes, Marcia Carvalho de Abreu Fantini, Pedro Leonidas Oseliero Filho, Olga Martinez Ibañez, Osvaldo Augusto Sant’Anna, Solange Massa and Orlando Garcia Ribeiro

Int. J. Mol. Sci. 2026, 27(1), 185; https://doi.org/10.3390/ijms27010185 - 24 Dec 2025

Viewed by 140

Abstract

The incorporation of drugs into nanostructured silica has proven to be an effective strategy for delaying drug release, protecting against enzymatic degradation, and enhancing therapeutic efficacy. Specifically, crotoxin, a component derived from the venom of Crotalus durissus terrificus, exhibits notable analgesic and [...] Read more.

The incorporation of drugs into nanostructured silica has proven to be an effective strategy for delaying drug release, protecting against enzymatic degradation, and enhancing therapeutic efficacy. Specifically, crotoxin, a component derived from the venom of Crotalus durissus terrificus, exhibits notable analgesic and immunomodulatory properties. Previous studies have demonstrated that encapsulating crotoxin within SBA-15 nanostructured mesoporous silica not only reduces its toxicity and enhances its analgesic effects but also enables effective oral administration. Given its promising efficacy and the expanding interest in its application across various experimental models and potential therapeutic uses, this study aimed to conduct a detailed analysis of the physicochemical properties of crotoxin when incorporated into SBA-15 silica. Following characterization, the crotoxin–SBA-15 complex was orally administered to mice in an experimental model of ulcerative colitis (UC). The most widely adopted experimental model for studying UC involves the administration of dextran sodium sulfate (DSS) in drinking water to induce colonic inflammation in susceptible animals. In this study, we hypothesized that crotoxin incorporated into ordered mesoporous silica (SBA-15) could modulate DSS-induced UC. Crotoxin was successfully incorporated into SBA-15 and administered orally, as its physicochemical properties supported this route of delivery. Mice received the crotoxin–SBA-15 complex either at the onset of UC induction or on days 1 and 4 after DSS exposure. Seven days after the start of DSS administration, we observed a substantial reduction (approximately 50%) in Disease Activity Index (DAI) scores, accompanied by marked improvements in the histopathological features of the colon. These findings indicate for the first time that crotoxin incorporated into SBA-15 exhibits significant therapeutic potential in the treatment of experimentally induced ulcerative colitis. Full article

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

► Show Figures

Figure 1

17 pages, 1689 KB

Open AccessArticle

The Cellular Effects of Di(2-ethylhexyl) Phthalate in Non-Malignant Colonic Epithelia Involve Oxidative Stress

by Zachary S. Bomstein, Kimberly F. Allred and Clinton D. Allred

Int. J. Mol. Sci. 2025, 26(23), 11716; https://doi.org/10.3390/ijms262311716 - 3 Dec 2025

Viewed by 391

Abstract

Human exposure to Di(2-ethylhexyl) Phthalate (DEHP) occurs through ingestion of contaminated food. Yet, the effects of DEHP on gastrointestinal toxicity at the cellular level are poorly understood and studies conducted to date have used malignant cell lines, limiting our understanding of molecular signaling [...] Read more.

Human exposure to Di(2-ethylhexyl) Phthalate (DEHP) occurs through ingestion of contaminated food. Yet, the effects of DEHP on gastrointestinal toxicity at the cellular level are poorly understood and studies conducted to date have used malignant cell lines, limiting our understanding of molecular signaling in intestinal epithelia of otherwise healthy individuals. The objective of our study was to use a non-transformed, colonic epithelial cell line (Young Adult Mouse Colonocytes; YAMCs) to characterize the in vitro effects of DEHP on non-malignant colonic epithelia. A 72 h DEHP exposure significantly reduced cell number and proliferation while short-term exposure increased: cellular apoptosis, BAX expression, Reactive Oxygen Species (ROS) production, gene expression linked to oxidative stress (NRF2, GCLC, HO-1, CHOP). Antioxidant pretreatment prior to DEHP exposure attenuated the phthalate’s apoptotic effect, suggesting a link between oxidative stress and apoptosis. Using YAMCs with a CRISPR-deleted Aryl Hydrocarbon Receptor (AhR) we further showed that the apoptotic and pro-oxidative effects of the phthalate are partially mediated through AhR. In conclusion, we have demonstrated that DEHP-induced toxicity in non-malignant colonocytes is due to ROS-induced oxidative stress and subsequently, apoptosis. We have further demonstrated that these effects are partly mediated by the AhR, a mechanism that deserves further investigation. Future studies should build on these findings by (a) characterizing the specific mechanisms linking ROS production to apoptosis demonstrated in our model of exposure, (b) measuring the dynamics of the receptor following DEHP exposure and (c) examining these effects over a longer exposure period. Full article

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

► Show Figures

Figure 1

24 pages, 1762 KB

Open AccessArticle

The Gut Microbial Metabolite Indole-3-Acetic Acid Reprograms Systemic Homeostasis and Ameliorates IBD-Associated Cachexia Independent of Food Intake

by Ayame Tomii, Chihiro Takei, Keisuke Yoshikiyo and Hidehisa Shimizu

Int. J. Mol. Sci. 2025, 26(23), 11260; https://doi.org/10.3390/ijms262311260 - 21 Nov 2025

Viewed by 582

Abstract

Inflammatory bowel disease (IBD) is associated with severe systemic complications, including cachexia, anemia, and renal dysfunction, which represent a significant unmet medical need. The gut microbial metabolite indole-3-acetic acid (IAA) is known to be reduced in IBD; however, its therapeutic potential remains unclear. [...] Read more.

Inflammatory bowel disease (IBD) is associated with severe systemic complications, including cachexia, anemia, and renal dysfunction, which represent a significant unmet medical need. The gut microbial metabolite indole-3-acetic acid (IAA) is known to be reduced in IBD; however, its therapeutic potential remains unclear. This study aimed to determine whether oral supplementation with IAA could ameliorate intestinal inflammation and its associated systemic complications. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we administered oral IAA and evaluated a comprehensive panel of clinical, metabolic, renal, and hematological parameters. Systemic health status was assessed using Principal Component Analysis (PCA). IAA administration significantly ameliorated DSS-induced colitis, reducing the Disease Activity Index (DAI) (3.88 vs. 3.13; p < 0.05) and significantly attenuating colon shortening (5.0 cm vs. 5.78 cm; p < 0.05) compared to the DSS-alone group. Crucially, it markedly suppressed systemic complications: IAA ameliorated DSS-induced cachexia (ΔBody weight, −3.27 g vs. −1.83 g; p < 0.05), an effect independent of food intake (N.S.). Furthermore, IAA mitigated early-stage renal dysfunction, as evidenced by a significant reduction in plasma Creatinine (Cr) levels (0.12 mg/dL vs. 0.10 mg/dL; p = 0.05), and reversed the decline in plasma iron levels associated with anemia (45.75 μg/dL vs. 63.50 μg/dL; p < 0.05). PCA revealed that IAA induced a distinct recovery profile, significantly improving the systemic health index without fully restoring the original homeostatic state. Oral IAA exerts pleiotropic effects on both intestinal inflammation and systemic complications. Its food intake-independent anti-cachectic mechanism represents a novel therapeutic paradigm for IBD-associated wasting. These findings position IAA as a promising candidate for microbial metabolite-based therapy aimed at reprogramming, rather than merely restoring, systemic homeostasis in IBD. Full article

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

► Show Figures

Figure 1

17 pages, 1146 KB

Open AccessArticle

Diagnostic Potential of Periostin, Galectin-3 and Tenascin C Serum Measurements in Inflammatory Bowel Disease: Pilot Study

by Aleksandra Górecka, Agnieszka Jura-Półtorak, Anna Szeremeta and Katarzyna Komosinska-Vassev

Int. J. Mol. Sci. 2025, 26(21), 10439; https://doi.org/10.3390/ijms262110439 - 27 Oct 2025

Viewed by 526

Abstract

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are characterized by a complex interplay between chronic inflammatory process and extracellular matrix (ECM) remodeling. This pilot study aims to evaluate the serum levels of three ECM-related proteins—periostin, galectin-3, and tenascin [...] Read more.

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are characterized by a complex interplay between chronic inflammatory process and extracellular matrix (ECM) remodeling. This pilot study aims to evaluate the serum levels of three ECM-related proteins—periostin, galectin-3, and tenascin C—as biomarkers supporting IBD diagnosis. Serum concentration of periostin, galectin-3 and tenascin C were measured using the ELISA method in 49 patients with IBD and 30 healthy individuals. Periostin and galectin-3 levels differed significantly between IBD patients and healthy individuals, whereas tenascin C levels did not show a significant difference. The ROC curve analysis identified periostin as the most promising biomarker for differentiation of both UC and CD from healthy individuals. In UC patients, periostin distinguished them from healthy individuals with excellent accuracy (AUC = 0.922), high sensitivity (100%), and good specificity (77.8%). Similarly, in CD patients, periostin demonstrated excellent diagnostic performance with AUC of 0.943, high sensitivity (100%) and good specificity (77.8%). Galectin-3 also showed potential as a diagnostic marker, which discriminated both UC and CD patients with high accuracy of AUC = 0.745 in UC and AUC = 0.691 in CD groups. Moreover, serum galectin-3 levels correlated with CRP levels (r = 0.603, p < 0.05) in the CD group. After one year of conventional anti-inflammatory treatment in CD patients, levels of periostin (p < 0.001) and galectin-3 (p < 0.05) significantly decreased. In contrast UC patients, receiving anti-TNF-α biological therapy showed a significant increase in galectin-3 (p < 0.05) concentrations. Obtained results indicate that circulating periostin and galectin-3 emerge as promising biomarkers for differentiating both UC and CD patients from healthy individuals. Given the significant correlation between galectin-3 and CRP serum levels, galectin-3 may also serve as a useful marker for monitoring disease activity in CD. Furthermore, galectin-3 may be helpful in monitoring the response to both biological or conventional anti-inflammatory treatment in UC and CD patients. Periostin, in turn, may be particularly valuable for evaluating efficacy of conventional anti-inflammatory therapy in CD. Full article

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

► Show Figures

Figure 1

12 pages, 425 KB

Open AccessArticle

Exploring the Overlap of MASLD and IBD: Insights from a Single-Center Experience

by Ana Stemate, Delia-Ionela Negru-Vodă, Ana Maria Patricia Mazurencu-Pele, Remus-Florin Popescu, Teodora-Iulia Spătaru and Lucian Negreanu

Int. J. Mol. Sci. 2025, 26(21), 10288; https://doi.org/10.3390/ijms262110288 - 22 Oct 2025

Viewed by 652

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition worldwide, occurring both independently and, more importantly, as the most common extraintestinal complication of inflammatory bowel disease (IBD). The study primarily investigated MASLD prevalence in Crohn’s disease (CD) and ulcerative colitis (UC) [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition worldwide, occurring both independently and, more importantly, as the most common extraintestinal complication of inflammatory bowel disease (IBD). The study primarily investigated MASLD prevalence in Crohn’s disease (CD) and ulcerative colitis (UC) to enhance prevention and early detection, especially given the recent approval of the first treatment for this condition. Secondary objectives included identifying risk factors, exploring the uric acid/high-density lipoprotein cholesterol ratio (UHRatio) as a steatosis marker and evaluating correlations between non-invasive fibrosis scores, Fibrosis-4 (FIB-4), AST-to-Platelet Ratio Index (APRI), and histological fibrosis severity. We conducted a prospective study on 58 patients diagnosed with IBD. The type of IBD was not independently associated with liver steatosis or fibrosis. Disease activity correlated significantly with hepatic steatosis in CD patients and with hepatic fibrosis in UC patients. The UHRatio proved useful in assessing steatosis prevalence, whereas FIB-4 and APRI scores did not correlate significantly with fibrosis severity. This study is, to our knowledge, the first to evaluate UHRatio as a potential predictor of MASLD in patients with IBD, expanding on previous findings reported in the general population. Our results suggest that this non-invasive biomarker, previously used to identify MASLD, may improve early prediction and could serve as a useful screening tool for MASLD in IBD patients. Full article

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

► Show Figures

Figure 1

26 pages, 3332 KB

Open AccessArticle

Distinct B Cell Subsets Changes as Potential Biomarkers of Response to Biologic Therapy in Crohn’s Disease

by Anna Helmin-Basa, Maria Kopoń, Jarosław Koza, Edyta Strzyżewska, Aleksandra Skalska-Bugała, Fabian Leśniewski, Małgorzata Wiese-Szadkowska, Sara Balcerowska, Jacek Michałkiewicz and Maria Kłopocka

Int. J. Mol. Sci. 2025, 26(19), 9539; https://doi.org/10.3390/ijms26199539 - 29 Sep 2025

Viewed by 1564

Abstract

Biological therapies for Crohn’s disease (CD), including infliximab, adalimumab, and vedolizumab, show variable efficacy. While some predictive biomarkers exist, data on regulatory immune cells are limited. This study examined whether baseline levels of circulating T and B cell subsets can predict response to [...] Read more.

Biological therapies for Crohn’s disease (CD), including infliximab, adalimumab, and vedolizumab, show variable efficacy. While some predictive biomarkers exist, data on regulatory immune cells are limited. This study examined whether baseline levels of circulating T and B cell subsets can predict response to these treatments. We recruited 43 adults with conventional treatment-resistant active CD (CDAI > 330) and 16 healthy controls. Blood samples were analysed by flow cytometry at baseline (week 0) and after induction therapy (week 12 or 14, depending on the received drug) to measure T and B cell subsets and correlate them with disease activity. CD patients at baseline showed a significantly reduced frequency of memory B cells, CD5⁺CD1d⁺ B cells, plasmablasts, and transitional B cells. Additionally, significant negative correlations were identified between transitional B cells and calprotectin/platelets, and between CD5⁺CD1d⁺ B cells and calprotectin. All CD patients responded clinically to biologic therapy. In those treated with infliximab or adalimumab, mature naïve B cells decreased, with a trend toward increased CD24^hiCD27⁺ B cells. Adalimumab responders showed a trend toward higher CD161 expression on Tregs, while vedolizumab-treated patients had a slight increase in plasmablasts. Biologic therapies in CD revealed treatment-specific immune correlations: infliximab/adalimumab responses involved B and T cell changes linked to inflammation, while VDZ response correlated with CD4⁺ and CD5⁺CD1d⁺ B cells. Our study suggests that infliximab/adalimumab induction therapy in CD expands circulating CD24^hiCD27⁺ B cells and reduces mature naïve B cells, while vedolizumab increases plasmablasts. These B-cell changes may reflect distinct mechanisms and serve as potential response biomarkers. Full article

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

► Show Figures

Figure 1

15 pages, 1404 KB

Open AccessArticle

Mechanism of Regulation of NaCl Homeostasis in the Distal Colon During Obesity

by Balasubramanian Palaniappan, John Crutchley, Raja Singh Paulraj, Alip Borthakur and Subha Arthur

Int. J. Mol. Sci. 2025, 26(18), 9139; https://doi.org/10.3390/ijms26189139 - 19 Sep 2025

Viewed by 702

Abstract

Obesity is characterized by low-grade chronic inflammation, similar to the pathophysiology of inflammatory bowel disease (IBD) and colon cancer. IBD, which includes Crohn’s disease and ulcerative colitis, is becoming increasingly common in obese individuals. Our previous research documented that both IBD and obesity [...] Read more.

Obesity is characterized by low-grade chronic inflammation, similar to the pathophysiology of inflammatory bowel disease (IBD) and colon cancer. IBD, which includes Crohn’s disease and ulcerative colitis, is becoming increasingly common in obese individuals. Our previous research documented that both IBD and obesity involve disrupted NaCl homeostasis in the small intestine. The present study investigated how obesity affects NaCl homeostasis in the distal colon, using the Zucker (Lepr^fa) rat as a genetic model of obesity. The functional and molecular alterations in NaCl homeostasis were evaluated through radioactive uptakes, RT-qPCR, and Western blot studies. We found a significant reduction in Cl absorption via Cl⁻/HCO₃⁻ exchanger, Downregulated in Adenoma (DRA) in the distal colon of obese rats compared to lean controls. This reduction was due to a decrease in the maximum transport capacity (V_max) of DRA, with no change in the affinity of the exchanger for chloride. DRA mRNA and protein levels were also downregulated in obese animals. In contrast, Na absorption via Na⁺/H⁺ exchanger and its expression remained unchanged. These findings are the first to demonstrate that DRA is significantly impaired in the distal colon due to obesity. This suggests that net NaCl absorption in the distal colon is compromised in obesity, potentially increasing the risk for IBD and colon cancer. Full article

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

► Show Figures

Figure 1

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

Cited by 1 | Viewed by 1538

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 [...] Read more.

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)

► Show Figures

Figure 1

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 1388

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 [...] Read more.

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)

► Show Figures

Figure 1

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

Cited by 2 | Viewed by 1044

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 [...] Read more.

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)

► Show Figures

Figure 1

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 2023

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 [...] Read more.

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)

► Show Figures

Figure 1

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 2001

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 [...] Read more.

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)

► Show Figures

Graphical abstract

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 7 | Viewed by 2208

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 [...] Read more.

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)

► Show Figures

Graphical abstract

Review

Jump to: Research

20 pages, 2814 KB

Open AccessReview

From Gut to Lungs: The Hidden Respiratory Impacts of IBD: A Systematic Review of the Literature

by Ionela Preotesoiu, Luana Alexandrescu, Bogdan Cimpineanu, Ioan Tiberiu Tofolean, Ionut Valentin Stanciu, Alexandra Herlo, Eugen Dumitru, Daria Maria Alexandrescu, Elena Dina, Cristina Daniela Aftenie, Andreea Nelson Twakor and Doina Ecaterina Tofolean

Int. J. Mol. Sci. 2025, 26(18), 8912; https://doi.org/10.3390/ijms26188912 - 12 Sep 2025

Viewed by 1150

Abstract

Pulmonary complications are an important yet underappreciated aspect of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC). These conditions often manifest with extraintestinal symptoms that can significantly influence the clinical trajectory of the disease. Pulmonary involvement in IBD [...] Read more.

Pulmonary complications are an important yet underappreciated aspect of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC). These conditions often manifest with extraintestinal symptoms that can significantly influence the clinical trajectory of the disease. Pulmonary involvement in IBD can range from mild symptoms, such as a persistent cough, to severe conditions, including interstitial lung disease or pulmonary embolism. This systematic review aims to assess the prevalence, clinical presentations, and implications of pulmonary involvement in IBD patients. A comprehensive literature search was conducted using PubMed database up to the 1st of May 2024. Inclusion criteria focused on studies involving adult IBD patients with documented pulmonary symptoms, evaluated through clinical, radiological, and histopathological approaches. Of the 463 studies identified, 27 met the inclusion criteria, consisting of 36,264 patients. Pulmonary manifestations were classified into airway diseases and parenchymal involvement. Airway diseases, including bronchiectasis and chronic bronchitis, were the most common, followed by parenchymal conditions such as organizing pneumonia and interstitial lung disease (ILD). Smoking was identified as a significant risk factor for pulmonary involvement. Pulmonary involvement in IBD is diverse and often underdiagnosed. Early recognition and management are crucial to improving patient outcomes. Full article

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

► Show Figures

Figure 1

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

Cited by 3 | Viewed by 2841

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 [...] Read more.

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)

► Show Figures

Figure 1

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 4 | Viewed by 2749

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, [...] Read more.

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)

► Show Figures

Figure 1

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 3 | Viewed by 2147

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 [...] Read more.

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)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Inflammatory Bowel Disease: Molecular Advances in Pathogenesis and Therapies

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (18 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI