Biomedicines

Research

26 pages, 6493 KB

Open AccessArticle

Targeting the AGE-RAGE/NF-κB Pathway: An Integrative Study Decoding the Anti-Colitis Effect of Five-Flavor Sophora Flavescens Enteric-Coated Capsule

by Baihui Hu, Xiaocong Wang, Xiuli Chen, Tong Li, Chuqiao Li, Yapu Zhang, Yingde Wang and Jingwei Mao

Biomedicines 2026, 14(6), 1236; https://doi.org/10.3390/biomedicines14061236 - 29 May 2026

Abstract

Background: The Five-flavor Sophora Flavescens Enteric-coated Capsule (FSEC) is widely used to treat ulcerative colitis (UC), yet its underlying molecular mechanisms remain incompletely understood. This study aimed to systematically elucidate the therapeutic mechanisms and clinical value of FSEC by integrating network pharmacology, experimental [...] Read more.

Background: The Five-flavor Sophora Flavescens Enteric-coated Capsule (FSEC) is widely used to treat ulcerative colitis (UC), yet its underlying molecular mechanisms remain incompletely understood. This study aimed to systematically elucidate the therapeutic mechanisms and clinical value of FSEC by integrating network pharmacology, experimental validation, and clinical data. Methods: A multi-tiered methodological framework was implemented. First, network pharmacology analysis identified potential molecular targets and signaling pathways associated with FSEC in UC. These predictions, including the core targets and the AGE-RAGE/NF-κB signaling pathway, were subsequently validated in a dextran sulfate sodium-induced mouse colitis model in vivo and a lipopolysaccharide-stimulated RAW264.7 macrophage inflammation model in vitro. Finally, a single-center retrospective cohort study of 90 patients evaluated the efficacy and safety of FSEC as monotherapy and in combination with Mesalazine. Results: Network pharmacology identified 12 core targets and predicted the AGE-RAGE/NF-κB pathway as a key mechanism. Experimental validation demonstrated that FSEC inhibits this pathway. Both in vivo and in vitro studies consistently showed that FSEC downregulates RAGE expression and NF-κB p65 phosphorylation, reducing the production of key inflammatory mediators and thereby alleviating intestinal inflammation. Clinically, FSEC monotherapy achieved efficacy comparable to that of Mesalazine, and combination therapy was associated with higher clinical remission and mucosal healing rates, with a favorable safety profile. Conclusion: This comprehensive multi-omics investigation provides integrated evidence that FSEC exerts anti-inflammatory effects, associated with inhibition of the AGE-RAGE/NF-κB pathway. The observed synergy between FSEC and Mesalazine suggests the potential of an integrated therapeutic approach for UC. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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21 pages, 1202 KB

Open AccessArticle

A Cross-Sectional Dual-Site Analysis of the Gastric Antral and Duodenal Mucosa-Associated Microbiome Across Gastroesophageal Reflux Disease Phenotypes

by Selva Rosyta Dewi, Takashi Matsumoto, Titong Sugihartono, Muhammad Miftahussurur and Yoshio Yamaoka

Biomedicines 2026, 14(6), 1221; https://doi.org/10.3390/biomedicines14061221 - 28 May 2026

Abstract

Background/Objectives: Despite increasing GERD prevalence worldwide, the role of gastroduodenal microbiota in GERD phenotypes and symptom severity remains poorly understood. This study profiled mucosa-associated microbiota from the gastric antrum and duodenum across phenotypes and examined site-specific associations with symptom severity. Methods: [...] Read more.

Background/Objectives: Despite increasing GERD prevalence worldwide, the role of gastroduodenal microbiota in GERD phenotypes and symptom severity remains poorly understood. This study profiled mucosa-associated microbiota from the gastric antrum and duodenum across phenotypes and examined site-specific associations with symptom severity. Methods: In this cross-sectional study, forty individuals, including 26 with erosive reflux disease (ERD), 10 with non-erosive reflux disease (NERD), and 4 participants in the endoscopically normal comparator group, underwent 16S rRNA gene sequencing. Community differences were assessed using Bray–Curtis dissimilarity, differential taxa were explored by linear discriminant analysis effect size (LEfSe), and correlations with validated symptom questionnaires were evaluated. Results: Microbial community structure differed significantly between the antrum and duodenum, with Proteobacteria and Firmicutes predominating at both sites. LEfSe suggested enrichment of Streptococcus, Haemophilus, and Enterobacter in the duodenum, whereas Sphingobium, Acinetobacter, and Aquabacterium were more abundant in the antrum. The genus Helicobacter was relatively enriched in the antrum of ERD samples, whereas Streptococcus-dominant signatures were more prominent in the duodenum. Symptom severity showed stronger associations with duodenal taxa, including Fusobacterium with odynophagia, early satiety, and globus; Aquabacterium with postnatal drip and dyspnea, whereas gastric associations were fewer. Conclusions: In this small exploratory cross-sectional cohort, gastroduodenal microbiota exhibited both site-specific and phenotype-associated differences, with phenotype-related microbial variation being more evident in the duodenum than in the antrum. These hypothesis-generating findings highlight the importance of considering both anatomical context and GERD phenotype in upper gastrointestinal host–microbe interactions, and require confirmation in larger, phenotypically well-characterized cohorts. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

18 pages, 38255 KB

Open AccessArticle

MBNL1 Promotes Intestinal Fibrosis via RAS-MAPK Pathway-Mediated Fibroblast Activation and Proliferation

by Liwen Zhang, Tianqi Liu, Na Yu, Ruijian Zhang, Zhepeng Luo, Xiaoqing Zhang and Jiani Wang

Biomedicines 2026, 14(6), 1207; https://doi.org/10.3390/biomedicines14061207 - 27 May 2026

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Abstract

Background: Intestinal fibrosis is a severe complication of Crohn’s disease (CD) with no effective therapies currently available. Muscleblind-like protein 1 (MBNL1) is an RNA-binding protein that has been implicated in fibrosis across multiple organs, but its role in CD-associated intestinal fibrosis remains unexplored. [...] Read more.

Background: Intestinal fibrosis is a severe complication of Crohn’s disease (CD) with no effective therapies currently available. Muscleblind-like protein 1 (MBNL1) is an RNA-binding protein that has been implicated in fibrosis across multiple organs, but its role in CD-associated intestinal fibrosis remains unexplored. This study aims to investigate the expression, functional role, and underlying mechanism of MBNL1 in intestinal fibrosis. Methods: MBNL1 expression was examined in a TNBS-induced mouse model and in stenotic intestinal tissues from CD patients. In vitro, human colonic fibroblasts (CCD-18Co) were stimulated with transforming growth factor-β1 (TGF-β1) to model fibrosis. MBNL1 was knocked down or overexpressed to assess its effects on fibroblast activation, proliferation (5-ethynyl-2′-deoxyuridine, EdU; Cell Counting Kit-8, CCK-8), and apoptosis (flow cytometry). Potential downstream pathways were predicted using BioGRID and DAVID analyses and validated by Western blot. A rescue experiment with the RAS activator ML-097 was performed to confirm pathway dependency. Results: MBNL1 expression was significantly upregulated in fibrotic tissues from both the mouse model and CD patients, as well as in TGF-β1-stimulated CCD-18Co. MBNL1 knockdown suppressed TGF-β1-induced fibroblast activation and proliferation while promoting apoptosis, whereas MBNL1 overexpression had the opposite effect. Mechanistically, MBNL1 positively regulated the RAS-MAPK signaling pathway. Reactivation of this pathway with ML-097 reversed the inhibitory effects of MBNL1 knockdown on fibroblast activation and proliferation. Conclusions: MBNL1 promotes colonic fibroblast activation and proliferation by activating the RAS-MAPK signaling pathway, establishing it as a potential therapeutic target for intestinal fibrosis in Crohn’s disease. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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10 pages, 215 KB

Open AccessArticle

Long-Term Comparative Outcomes of TNF-α Antagonists vs. Vedolizumab as First-Line Biologic Therapy for Refractory Ulcerative Proctitis: A Propensity-Matched Study

by Ayushi Shah, Azhar Hussain, Ahmad Nawaz, Abdelkader Chaar, Avleen Kaur, Mark M. Aloysius, Bishnu Sapkota, Savio John and Idan Goren

Biomedicines 2026, 14(5), 1135; https://doi.org/10.3390/biomedicines14051135 - 17 May 2026

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Abstract

Background: The optimal first-line biologic therapy for refractory ulcerative proctitis (UP) remains uncertain, largely because patients with UP are frequently excluded from biologic clinical trials, limiting evidence to guide treatment selection. This study evaluated outcomes among patients with UP treated with first-line [...] Read more.

Background: The optimal first-line biologic therapy for refractory ulcerative proctitis (UP) remains uncertain, largely because patients with UP are frequently excluded from biologic clinical trials, limiting evidence to guide treatment selection. This study evaluated outcomes among patients with UP treated with first-line TNF inhibitors or vedolizumab. Methods: We performed a retrospective cohort study using the TriNetX database between 1995 and 2023. Propensity score matching was applied to balance demographics, laboratory parameters, and baseline medications. Primary outcomes included corticosteroid use, all-cause emergency room (ER) visits and hospitalizations, and colectomy, assessed at 6, 12, and 24 months after initiation of TNF inhibitors or vedolizumab. Secondary outcomes described real-world biologic usage patterns in UP. Results: Among 641 patients with UP receiving advanced therapy, the most commonly used biologics were adalimumab (39%), infliximab (27%), and vedolizumab (26%). Ustekinumab was used in 12% of patients. In matched analyses, TNF inhibitor therapy was associated with reduced ER visits and hospitalizations at 6 and 12 months compared with vedolizumab (6 months: 14.3% vs. 25%, aOR 0.50, p-value 0.03; 12 months: 16.1% vs. 35.2%, aOR 0.35, p-value 0.01). By 24 months, no significant differences were observed. Corticosteroid use and colectomy rates were similar across therapies at all time points. In a subgroup comparison between adalimumab and vedolizumab, results were consistent with the primary analysis, with lower short-term ER visits and/or hospitalizations among patients receiving adalimumab. Conclusions: In this propensity-matched analysis, TNFi therapy was associated with lower short-term healthcare utilization, with no significant differences observed in corticosteroid use. These findings should be interpreted cautiously given nonspecific outcomes and potential residual confounding from unmeasured disease variables such as endoscopic activity. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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19 pages, 12988 KB

Open AccessArticle

Revealing the Potential Associations of Mutation-Related Genes with Lymph Node Metastasis in Gallbladder Cancer Through Transcriptome and Exome Sequencing

by Qi Li, Qingyu Tang, Dong Xue, Hengchao Liu, Zhenqi Tang, Dong Zhang, Chen Chen and Zhimin Geng

Biomedicines 2026, 14(5), 1076; https://doi.org/10.3390/biomedicines14051076 - 10 May 2026

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Abstract

Background/Objectives: Gallbladder cancer (GBC) is an aggressive biliary tract malignancy with poor prognosis. Lymph node metastasis is a major determinant of adverse outcome in patients with GBC. Gene mutations play an essential role in tumorigenesis; however, it remains uncertain whether genetic mutations [...] Read more.

Background/Objectives: Gallbladder cancer (GBC) is an aggressive biliary tract malignancy with poor prognosis. Lymph node metastasis is a major determinant of adverse outcome in patients with GBC. Gene mutations play an essential role in tumorigenesis; however, it remains uncertain whether genetic mutations play a substantial role in lymph node metastasis in GBC. Methods: In this study, transcriptome and whole-exome sequencing (WES) were used to analyze gene mutations and expression in GBC tissues, focusing on lymph node metastasis. Bioinformatics tools identified differentially expressed genes (DEGs) and significantly mutated genes (SMGs), followed by pathway enrichment and survival analyses. Results: In total, 669 DEGs were identified between metastatic and non-metastatic GBC tissues. Through protein–protein interaction (PPI) network analysis of these DEGs, GPT and NR1I2 were identified as candidate genes associated with metabolic reprogramming in lymph node metastasis. Prognostic analysis revealed 22 DEGs associated with patient survival, and significant differences in overall survival, clinicopathological features (e.g., N-stage and positive lymph node count) were observed between cluster 1 and cluster 2. Mutation analysis identified 55 SMGs, primarily related to immune and inflammatory responses. By integrating DEGs and SMGs, PLCL2 was identified as a candidate gene potentially associated with both lymph node metastasis and prognosis. GSEA enrichment analysis suggested that PLCL2 was potentially linked to immunity, inflammation, and cellular processes, which may imply its possible involvement in GBC metastasis pending experimental validation. Conclusions: Based on integrative transcriptomic and exomic analyses, we identified PLCL2 as a candidate gene potentially associated with lymph node metastasis in GBC. These hypothesis-generating findings provide a preliminary basis for future mechanistic validation and biomarker exploration. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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21 pages, 1659 KB

Open AccessArticle

Hepatocellular Carcinoma Treatment with Immune Checkpoint Inhibitors: RECA and CRAFITY Scores Reveal Distinct Clinical Courses and Highlight the Role of Systemic Inflammation in Prognosis

by Xavier Adhoute, Constance Chailloux, Feng Xia, Zhao Huang, Qian Chen, Jing Yan, Qiao Zhang, Victoria Ramdour, Louis Carmarans, Guillaume Pénaranda, Paul Castellani, Albert Tran, Marc Bourlière, René Gerolami and Rodolphe Anty

Biomedicines 2026, 14(5), 1043; https://doi.org/10.3390/biomedicines14051043 - 3 May 2026

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Abstract

Background/Objectives: Systemic treatment of advanced hepatocellular carcinoma (HCC) is based on combinations of immunotherapies (ITs) and lacks predictive markers of efficacy. Objectives: To define the prognostic value of the CRAFITY and RECA biological scores for overall survival (OS) before and during IT, [...] Read more.

Background/Objectives: Systemic treatment of advanced hepatocellular carcinoma (HCC) is based on combinations of immunotherapies (ITs) and lacks predictive markers of efficacy. Objectives: To define the prognostic value of the CRAFITY and RECA biological scores for overall survival (OS) before and during IT, and to evaluate the value of these two models for predicting the therapeutic response. Patients and methods: This was a multicenter retrospective analysis of 229 patients. OS was analyzed using Kaplan–Meier curves, log-rank tests, and Cox models, through which second-line therapy was modeled as a time-dependent covariate to avoid immortal time bias. The predictive capacity was assessed using univariate logistic regression. Validation was performed within two external Chinese cohorts. Results: Sixty-six percent of patients had Barcelona Clinic Liver Cancer (BCLC) stage C HCC (vascular invasion: 36.3%, metastases: 32.6%). After a mean follow-up of 14.9 (12.8) months, the median OS was 17.4 (6.9–38.0) months. The CRAFITY score distinguished only two different prognostic subgroups before treatment, but its prognostic value was confirmed with three different prognostic groups after 3 and 5 cycles and 6 months of treatment. The RECA score was strongly associated with OS before treatment and after 3 and 5 cycles and after 6 months of IT. Conversely, neither score had a discriminatory ability to predict early therapeutic response. The prognostic value of both models for OS was confirmed in the external cohorts. Conclusions: The RECA and CRAFITY scores have strong prognostic value for OS during IT. Beyond the models, the dynamic effects of systemic inflammation on IT reveal distinct clinical outcomes. Neither score has the ability to predict early therapeutic response, further supporting their use during treatment. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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17 pages, 3840 KB

Open AccessArticle

Genome-Wide Dissection of the Neutrophil-to-Lymphocyte Ratio Uncovers Polygenic Determinants Linked to Inflammatory Gastrointestinal Disorder Susceptibility

by Da Miao, Yao Ge, Zhengye Liu, Ziqi Wan, Haotian Chen, Xiaoyin Bai and Jiarui Mi

Biomedicines 2026, 14(4), 814; https://doi.org/10.3390/biomedicines14040814 - 2 Apr 2026

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Abstract

Background: The neutrophil-to-lymphocyte ratio (NLR) is a simple biomarker that reflects the balance between innate immune response and adaptive immunity. Currently, the genetic basis and clinical implications of NLR in relation to inflammatory gastrointestinal diseases have not been extensively explored. Methods: We carried [...] Read more.

Background: The neutrophil-to-lymphocyte ratio (NLR) is a simple biomarker that reflects the balance between innate immune response and adaptive immunity. Currently, the genetic basis and clinical implications of NLR in relation to inflammatory gastrointestinal diseases have not been extensively explored. Methods: We carried out a genome-wide association study (GWAS) on European individuals from the UK Biobank to detect genetic variants related to NLR, followed by post-GWAS analyses including colocalization analysis, transcriptome-wide association studies (TWAS), and LD score regression. Logistic regression, Cox regression, and gene–environment interaction analysis were used to evaluate the impact of NLR polygenic risk scores (PRS) on inflammatory gastrointestinal disease risks. Results: GWAS of 395,442 Europeans identified 306 genomic regions (731 lead SNPs) associated with NLR, mapping to 1542 genes enriched for immune pathways. Colocalization revealed shared genetic signals with TWAS prioritization of 59, 19, 14, 22 and 28 genes in the whole blood, spleen, terminal ileum, transverse colon and sigmoid colon, respectively. LD-score regression showed significant positive genetic correlations with CD (rg = 0.132), coeliac disease (rg = 0.124), peptic ulcer (rg = 0.138) and duodenal ulcer (rg = 0.220). One-SD increase in NLR PRS predicted higher risk of IBD (OR = 1.05, 95% CI 1.03–1.08), Crohn’s disease (OR = 1.06, 1.02–1.10), ulcerative colitis (OR = 1.05, 1.02–1.08) and coeliac disease (OR = 1.07, 1.03–1.11). Restricted cubic splines demonstrated non-linear relationships of NLR PRS for IBD, CD and UC. Gene environment analyses showed smoking and diabetes amplified the risks, while cardioprotective diet, oily fish intake and polyunsaturated fatty acid level attenuated NLR PRS-associated risk in IBD (mainly CD). Conclusions: Our study delineates the polygenic basis of NLR and establishes its genetic correlation with inflammatory gastrointestinal diseases, offering a genetically informed indicator for disease risk stratification with potential utility in population-level prevention strategies. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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20 pages, 7568 KB

Open AccessArticle

Cold Exposure Alleviates Colitis via Parallel Integration of Colonic Mucosal Regeneration and Ileal Antimicrobial Defense

by Yuzhu Di, Jiaxing Deng, Ziyou Hong, Zhirui Liu, Lubo Jin, Wenyuan Zhao and Bo Qu

Biomedicines 2026, 14(3), 609; https://doi.org/10.3390/biomedicines14030609 - 9 Mar 2026

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Abstract

Background: Inflammatory bowel disease (IBD) involves chronic intestinal inflammation, epithelial barrier disruption, and dysbiosis, with environmental factors playing a significant role in its pathogenesis. Previous work revealed that cold exposure alleviates colitis in mice; this study extends that finding by demonstrating that cold [...] Read more.

Background: Inflammatory bowel disease (IBD) involves chronic intestinal inflammation, epithelial barrier disruption, and dysbiosis, with environmental factors playing a significant role in its pathogenesis. Previous work revealed that cold exposure alleviates colitis in mice; this study extends that finding by demonstrating that cold exposure enhances intestinal regeneration even in healthy mice, upregulating proliferation markers (Mki67, PCNA, Cyclin D1). Methods: Applying this pro-regenerative effect to a colitis model, we investigated the underlying mechanisms through multi-omics analysis, transmission electron microscopy (TEM), immunofluorescence, and pathological staining as well as 16S rRNA sequencing. Results: We found that cold exposure activates intestinal epithelial proliferation pathways. Further analysis indicated that cold exposure induces colonic stem cell regeneration, upregulating stem cell markers Lgr5 and Ascl2. Notably, colonic transcriptomic profiling revealed the emergence of a Paneth-like cell phenotype, characterized by altered expression of specific lineage genes. Furthermore, cold exposure simultaneously promoted the accumulation of secretory granules and upregulated the expression of antimicrobial peptide genes (such as Lysozyme and Defa) in ileal Paneth cells. This enhanced ileal antimicrobial defense effectively reshaped the gut microbiota in inflamed intestines. Conclusions: This research elucidates a mechanism whereby cold adaptation promotes mucosal repair by integrating localized colonic epithelial regeneration with enhanced ileal Paneth cell-mediated antimicrobial defense. This offers compelling new perspectives on how environmental factors, such as cold exposure, could influence the pathophysiology of IBD and contribute to intestinal regeneration, which may provide foundational theoretical support for the future diagnosis and treatment of IBD. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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15 pages, 878 KB

Open AccessArticle

Clinical Impact of Stool Polymerase Chain Reaction (PCR) Testing in Hospitalized Patients with Acute Diarrhea: A Retrospective Observational Study

by Crina Fofiu, Daniela Dobru, Adina Andone, Victoria Ancuța Nyulas and Alina Boeriu

Biomedicines 2025, 13(5), 1155; https://doi.org/10.3390/biomedicines13051155 - 9 May 2025

Cited by 1 | Viewed by 3044

Abstract

Background/Objectives: Acute diarrheal illnesses are a major cause of hospital admissions, particularly in immunocompromised patients. Traditional diagnostic methods are slow and often insensitive, delaying treatment. In contrast, PCR panels provide rapid, sensitive detection of multiple pathogens. This study evaluates stool PCR testing [...] Read more.

Background/Objectives: Acute diarrheal illnesses are a major cause of hospital admissions, particularly in immunocompromised patients. Traditional diagnostic methods are slow and often insensitive, delaying treatment. In contrast, PCR panels provide rapid, sensitive detection of multiple pathogens. This study evaluates stool PCR testing in hospitalized adults and its impact on clinical decisions and antimicrobial stewardship. Methods: We conducted a retrospective study at Bistrița County Hospital, Romania (September 2023–September 2024), including 75 adults with acute diarrhea and negative conventional stool tests. PCR testing (VIASURE panels I and II) detected 11 bacteria, 6 viruses, and 5 parasites. Clinical and therapeutic data were analyzed, and logistic regression identified predictors of PCR positivity and adverse outcomes. Results: PCR was positive in 78% of cases, with Campylobacter spp. (57.6%) and Clostridioides difficile (20.3%) being the most common. Bloody diarrhea independently predicted PCR positivity (OR 9.78, p = 0.047). Immunosuppression and end-stage liver disease were linked to worse outcomes. PCR results led to antimicrobial therapy adjustments in 40 patients (p = 0.001), correcting inappropriate antibiotic use in 66% of those receiving empirical treatment. Targeted therapy significantly reduced antimicrobial duration from 7 to 5 days (p = 0.00001). Conclusions: Stool PCR testing enhances pathogen detection, guides targeted therapy, and reduces inappropriate antibiotic use, supporting antimicrobial stewardship and improving outcomes in selected hospitalized patients. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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Review

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27 pages, 1266 KB

Open AccessReview

Opioid-Induced Constipation: Mechanistic Insights, Experimental Models, and Future Perspectives

by Yujia Lin, Panpan Lu, Qiang Ding, Xiang Tao, Qinghai Tan and Mei Liu

Biomedicines 2026, 14(5), 995; https://doi.org/10.3390/biomedicines14050995 - 27 Apr 2026

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Abstract

Opioid-induced constipation (OIC) represents a prevalent adverse effect of opioid analgesics, affecting 60–90% of patients and significantly compromising quality of life. This review delineates the multifactorial pathogenesis of OIC. Peripheral μ-opioid receptor (MOR) activation suppresses enteric neuronal excitability, inhibits intestinal motility and secretion, [...] Read more.

Opioid-induced constipation (OIC) represents a prevalent adverse effect of opioid analgesics, affecting 60–90% of patients and significantly compromising quality of life. This review delineates the multifactorial pathogenesis of OIC. Peripheral μ-opioid receptor (MOR) activation suppresses enteric neuronal excitability, inhibits intestinal motility and secretion, and impairs rectoanal function. Notably, the colon appears to exhibit a distinctive lack of tolerance to opioids. Enteric glial cell activation has been implicated in neuroinflammation, while interstitial cells of Cajal show impaired pacemaker function. Central mechanisms are increasingly recognized to involve the brain–gut axis. Furthermore, opioid-induced barrier disruption, microbiota dysbiosis, and LPS/TLR4-mediated inflammation are proposed to interact and may contribute to a self-reinforcing cycle. Animal models have been instrumental in dissecting these mechanisms. However, they present limitations in reproducibility, clinical phenotype fidelity, and translational validity, particularly regarding microbiome composition and neuroimmune responses. Future research should prioritize the development of standardized, physiologically relevant animal models incorporating multi-omics approaches, and validate mechanism-based therapeutic strategies, including peripherally acting MOR antagonists and microbiota-targeted interventions, for precision management of OIC. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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15 pages, 1042 KB

Open AccessReview

From Conventional Therapy to Precision Medicine in Inflammatory Bowel Disease: A State-of-the-Art Review

by Anwar Almajdi and Mohammad Shehab

Biomedicines 2026, 14(4), 798; https://doi.org/10.3390/biomedicines14040798 - 1 Apr 2026

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Abstract

Background/Objectives: Inflammatory bowel disease (IBD) management has evolved from conventional therapies to advanced biologics and targeted small molecules; however, clinical practice often relies on empirical treatment sequencing rather than individualized approaches. The heterogeneity of IBD phenotypes, variable treatment responses, and expanding therapeutic [...] Read more.

Background/Objectives: Inflammatory bowel disease (IBD) management has evolved from conventional therapies to advanced biologics and targeted small molecules; however, clinical practice often relies on empirical treatment sequencing rather than individualized approaches. The heterogeneity of IBD phenotypes, variable treatment responses, and expanding therapeutic options necessitate a shift toward precision medicine. This review aims to synthesize current evidence on personalizing IBD therapy and provide an implementation framework for clinical practice. Methods: A narrative review was conducted encompassing peer-reviewed literature, recent network meta-analyses, and clinical guidelines. Evidence was gathered on treat-to-target strategies, therapeutic drug monitoring (TDM), clinical decision support systems, artificial intelligence applications, multi-omics platforms (genomics, transcriptomics, microbiome, metabolomics), advanced imaging modalities, and special populations including pediatric patients and pregnant women. Results: Treat-to-target strategies incorporating endoscopic and biochemical endpoints improve long-term outcomes when individualized to patient-disease factors. TDM-guided optimization enhances biologic efficacy and reduces immunogenicity. Emerging AI tools and multi-omics platforms show promise in predicting treatment response and patient stratification. Network meta-analyses provide comparative effectiveness estimates guiding advanced therapy selection in both Crohn’s disease and ulcerative colitis. Implementation of precision medicine frameworks remains constrained by regulatory, economic, and technical barriers. Conclusions: Personalizing IBD therapy through integration of precision medicine tools, patient-specific factors, and comparative effectiveness data represents the future of IBD management. Overcoming implementation barriers through standardized frameworks and multidisciplinary collaboration is essential to translate these advances into routine clinical practice. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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21 pages, 3099 KB

Open AccessReview

The Causal Role of Bile Acids in Cancers of the Digestive System

by Carol Bernstein and Harris Bernstein

Biomedicines 2026, 14(3), 598; https://doi.org/10.3390/biomedicines14030598 - 8 Mar 2026

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Abstract

Bile acids are widely distributed in the human gastrointestinal tract. A literature review indicates that bile acids may have a role in initiating cancers in every organ of the digestive system. The estimated number of new digestive system cancers world-wide in 2022 was [...] Read more.

Bile acids are widely distributed in the human gastrointestinal tract. A literature review indicates that bile acids may have a role in initiating cancers in every organ of the digestive system. The estimated number of new digestive system cancers world-wide in 2022 was about 5 million. In the particular case of colon cancer, secondary bile acids produced in response to a high fat diet disrupt colonic epithelial cell mitochondrial membranes. This disruption leads to the release of oxidative free radicals that damage DNA, potentially leading to carcinogenic mutations. High levels of colonic bile acids may also alter the gut microbiome, with some bacteria causing inflammation and increased reactive oxygen species leading to DNA damage. Also, bile acids taken up by receptors on the surface of gastrointestinal tract cells can activate NF-kB. In turn, NF-kB may activate a super-enhancer at an oncogene. Bile acid reflux also plays a significant role in esophageal adenocarcinoma, stomach cancer and small intestine carcinogenesis. In addition, cancers of the pancreas, liver, and biliary tract can be caused by the constriction of the common bile duct leading to reflux of bile acids back into these organs. Gastroesophageal reflux involving bile acids may also contribute to hypopharyngeal squamous cell carcinogenesis. Thus, bile acids are a likely major contributory cause of cancer throughout the digestive tract. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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19 pages, 1269 KB

Open AccessReview

Assessment of IL-6 Pathway Inhibition in Gastrointestinal Behçet’s Disease from Immunological and Clinical Perspectives

by Makoto Naganuma, Mitsuhiro Takeno, Aykut Ferhat Çelik, Robert Moots, Philippe Pinton and Tadakazu Hisamatsu

Biomedicines 2025, 13(1), 247; https://doi.org/10.3390/biomedicines13010247 - 20 Jan 2025

Cited by 3 | Viewed by 4407

Abstract

Behçet’s disease is an autoinflammatory disorder characterized by relapsing and remitting vasculitis that can manifest in various forms, including gastrointestinal Behçet’s disease (GIBD). Its complications (e.g., intestinal perforation) are among the primary causes of morbidity and mortality. GIBD pathogenesis involves the enhanced production [...] Read more.

Behçet’s disease is an autoinflammatory disorder characterized by relapsing and remitting vasculitis that can manifest in various forms, including gastrointestinal Behçet’s disease (GIBD). Its complications (e.g., intestinal perforation) are among the primary causes of morbidity and mortality. GIBD pathogenesis involves the enhanced production of certain cytokines, e.g., tumor necrosis factor α and interleukin-6 (IL-6), which could serve as a target for potential therapies. This review provides an overview of GIBD, including the diagnosis and immunopathogenesis as it is currently understood, and evaluates the emerging role of the inhibition of IL-6 (classic and trans-signaling) as an alternative treatment option for patients with GIBD. Given the current paucity of data, we reflected on the potential of IL-6 inhibitors such as tocilizumab and olamkicept based on immunopathogenic considerations and available clinical data in patients with inflammatory bowel disease (IBD), in whom clinical response or remission was induced. The selective inhibition of IL-6 trans-signaling may bring new impetus to the development of this drug class, particularly regarding safety. Still, the benefits of IL-6 inhibitors for patients with GIBD need to be evaluated in appropriate proof-of-concept studies. The clinical outcomes of IL-6 inhibitors in IBD are promising and may suggest their potential relevance in GIBD. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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Other

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16 pages, 3322 KB

Open AccessSystematic Review

Clinical Evidence Linking the Gut Microbiome and Functional Dyspepsia: A Systematic Review and Meta-Analysis

by Kyungjae Lee, Hojun Kim and Jing-Hua Wang

Biomedicines 2026, 14(2), 457; https://doi.org/10.3390/biomedicines14020457 - 18 Feb 2026

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Abstract

Background/Objectives: Accumulating evidence and clinical observations suggest that the gut microbiome plays a crucial role in functional dyspepsia (FD). However, the precise characterization of this relationship is unclear. This systematic review and meta-analysis aimed to elucidate the potential role of the gut [...] Read more.

Background/Objectives: Accumulating evidence and clinical observations suggest that the gut microbiome plays a crucial role in functional dyspepsia (FD). However, the precise characterization of this relationship is unclear. This systematic review and meta-analysis aimed to elucidate the potential role of the gut microbiome in FD based on evidence from published clinical studies. Methods: A comprehensive search of three databases (PubMed, Google Scholar, and Web of Science) was conducted, and 17 relevant clinical studies, including 8 observational studies and 9 interventional studies, published up to September 2025, were identified. Data on the gut microbiome and FD were extracted and subjected to meta-analysis. Results: Meta-analysis revealed no significant differences in gut microbiota α- or β-diversity between patients with FD and healthy controls (Shannon index: standardized mean difference [SMD] = −0.12, 95% confidence interval [CI] −0.90 to 0.67, I² = 88%). In contrast, effective interventions induced notable shifts in the microbial community structure (pooled SMD = 0.27, 95% CI −0.28 to −0.83, I² = 58%). These shifts were accompanied by increased short-chain fatty acid (SCFA) production and intestinal tight-junction protein levels, which coincided with improved FD symptoms. Conclusions: Although no significant differences in the gut microbiota were detected between patients with FD and healthy controls, interventions in patients with FD induced marked changes in the microbial community. Modulation of gut microbiota-related metabolites, such as SCFAs, may represent a promising therapeutic strategy for the management of FD. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases)

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Advances in Pathogenesis and Therapeutics of Gastrointestinal Diseases

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