Reaching the therapeutic ceiling in IBD: Can Advanced Combination Treatment (ACT) offer a solution?

The term Advanced Combination Treatment (ACT) involves the combination of at least two biologics or the use of a biologic with a small molecule drug, each with different mechanisms of action. This narrative review evaluates the current evidence supporting ACT in inflammatory bowel disease (IBD), focusing on preclinical studies, real-world evidence, and randomized controlled trials. A systematic review of randomized controlled trials has concluded that ACT significantly improves clinical outcomes, without significant safety concerns in patient with IBD.

Spatiotemporal analysis of Crohn's disease reveals PECAM2 signaling at the basis of inflammation-to-fibrosis transition.

Background And Aims: Crohn's disease is a chronic inflammatory disease of the bowel, often complicated by fibrotic strictures, for which medical treatment is lacking, and surgery is commonly required. The mechanisms underlying the progression from chronic inflammation to fibrosis are not yet defined. We aim to unravel Crohn's disease pathogenesis using a cutting-edge computational pipeline combining several available tools.

Systemic delivery of cadherin 17-specific CAR T cells allows effective and safe targeting of colorectal cancer liver metastases.

Liver metastases represent the leading cause of death in patients with colorectal cancer (CRC). Chimeric antigen receptor (CAR) T cell therapy holds promise in this context, but any effort to bring it to the bedside requires careful antigen selection and testing in clinically relevant models. Here, we identified cadherin-17 (CDH17) as a candidate antigen for CAR T cell therapy of CRC liver metastases.

Transforming Gastrointestinal Diagnosis with Molecular Endoscopy: Challenges and Opportunities.

Molecular endoscopy represents a transformative advance in the detection, diagnosis, and management of gastrointestinal diseases, addressing the critical limitations of conventional techniques. Current diagnostic standards, such as white light endoscopy (WLE), often fail to detect early-stage lesions, particularly in high-risk populations like Barrett's esophagus or inflammatory bowel disease patients. To overcome these challenges, molecular endoscopy, using fluorescent molecular probes, may offer ultimate precision by targeting disease-specific biomarkers.

Expert recommendations to standardize transcriptomic analysis in inflammatory bowel disease clinical trials.

Background And Aims: Substantial methodological and reporting heterogeneity confounds the interpretation and generalizability of transcriptomic data for inflammatory bowel disease (IBD) studies. We aimed to develop recommendations to standardize transcriptomic research in clinical trials.

Methods: A 2-part study was undertaken.

Microbiota-produced immune regulatory bile acid metabolites control central nervous system autoimmunity.

The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3 regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells.

Artificial intelligence and whole slide imaging, a new tool for the microsatellite instability prediction in colorectal cancer: Friend or foe?

Colorectal cancer (CRC) is the third most common and second most deadly cancer worldwide. Despite advances in screening and treatment, CRC is heterogeneous and the response to therapy varies significantly, limiting personalized treatment options. Certain molecular biomarkers, including microsatellite instability (MSI), are critical in planning personalized treatment, although only a subset of patients may benefit.

Unraveling the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma: the "omics" era.

Barrett's esophagus (BE) represents a pre-cancerous condition that is characterized by the metaplastic conversion of the squamous esophageal epithelium to a columnar intestinal-like phenotype. BE is the consequence of chronic reflux disease and has a potential progression burden to esophageal adenocarcinoma (EAC). The pathogenesis of BE and EAC has been extensively studied but not completely understood, and it is based on two main hypotheses: "transdifferentiation" and "transcommitment".

TL1A Inhibition in Inflammatory Bowel Disease: A Pipeline Review.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), remains challenging to manage, with a substantial proportion of patients not responding to conventional therapies or developing complications. The tumor necrosis factor (TNF) superfamily member TL1A has emerged as an important player in the pathogenesis of IBD, influencing pathways of inflammation and fibrosis. This leading article reviews the role of TL1A in IBD, evaluates the efficacy of anti-TL1A therapies in clinical trials, and discusses future directions for research and treatment.

Clinical, Histologic, and Safety Outcomes With Long-term Maintenance Therapies for Eosinophilic Esophagitis: A Systematic Review and Meta-analysis.

Background & Aims: Our aim was to evaluate the outcomes of maintenance treatments for eosinophilic esophagitis (EoE) among observational studies (OSs) and randomized controlled trials (RCTs).

Materials And Methods: Studies reporting histologic success of maintenance therapy ≥48 weeks were included. The primary outcome was histologic success rate (defined as <15/<6 eosinophils/high-power field).

Artificial intelligence: A new tool in the pathologist's armamentarium for the diagnosis of IBD.

Inflammatory bowel diseases (IBD) are classified into two entities, namely Crohn's disease (CD) and ulcerative colitis (UC), which differ in disease trajectories, genetics, epidemiological, clinical, endoscopic, and histopathological aspects. As no single golden standard modality for diagnosing IBD exists, the differential diagnosis among UC, CD, and non-IBD involves a multidisciplinary approach, considering professional groups that include gastroenterologists, endoscopists, radiologists, and pathologists. In this context, histological examination of endoscopic or surgical specimens plays a fundamental role.

Translational characterization of immune pathways in inflammatory bowel disease: insights for targeted treatments.

Introduction: The pathogenesis of inflammatory bowel disease (IBD) involves the dysregulation of multiple inflammatory pathways. The understanding of these mechanisms allows their selective targeting for therapeutic purposes. The discovery of Tumor Necrosis Factor-alpha's (TNF-α) role in mucosal inflammation ushered an exciting new era of drug development which now comprises agents targeting multiple pro-inflammatory signaling pathways, integrins, and leukocyte trafficking regulators.

Inflammatory bowel disease genomics, transcriptomics, proteomics and metagenomics meet artificial intelligence.

Various extrinsic and intrinsic factors such as drug exposures, antibiotic treatments, smoking, lifestyle, genetics, immune responses, and the gut microbiome characterize ulcerative colitis and Crohn's disease, collectively called inflammatory bowel disease (IBD). All these factors contribute to the complexity and heterogeneity of the disease etiology and pathogenesis leading to major challenges for the scientific community in improving management, medical treatments, genetic risk, and exposome impact. Understanding the interaction(s) among these factors and their effects on the immune system in IBD patients has prompted advances in multi-omics research, the development of new tools as part of system biology, and more recently, artificial intelligence (AI) approaches.

The Role of Viruses in the Pathogenesis of Immune-Mediated Gastro-Intestinal Diseases.

Immune-mediated gastrointestinal (GI) diseases, including achalasia, celiac disease, and inflammatory bowel diseases, pose significant challenges in diagnosis and management due to their complex etiology and diverse clinical manifestations. While genetic predispositions and environmental factors have been extensively studied in the context of these conditions, the role of viral infections and virome dysbiosis remains a subject of growing interest. This review aims to elucidate the involvement of viral infections in the pathogenesis of immune-mediated GI diseases, focusing on achalasia and celiac disease, as well as the virome dysbiosis in IBD.

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders-A Comprehensive Review.

Eosinophilic Gastrointestinal Disorders (EGIDs) are a group of conditions characterized by abnormal eosinophil accumulation in the gastrointestinal tract. Among these EGIDs, Eosinophilic Esophagitis (EoE) is the most well documented, while less is known about Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EoC). The role of endoscopy in EGIDs is pivotal, with applications in diagnosis, disease monitoring, and therapeutic intervention.

TL1A inhibition for inflammatory bowel disease treatment: From inflammation to fibrosis.

The pivotal role of TL1A in modulating immune pathways crucial for inflammatory bowel disease (IBD) and intestinal fibrosis offers a promising therapeutic target. Phase 2 trials (TUSCANY and ARTEMIS-UC) evaluating an anti-TL1A antibody show progress in expanding IBD therapeutic options. First-in-human data reveal reduced expression of genes associated with extracellular matrix remodeling and fibrosis post-anti-TL1A treatment.

Microbiota profiling in esophageal diseases: Novel insights into molecular staining and clinical outcomes.

Gut microbiota is recognized nowadays as one of the key players in the development of several gastro-intestinal diseases. The first studies focused mainly on healthy subjects with staining of main bacterial species via culture-based techniques. Subsequently, lots of studies tried to focus on principal esophageal disease enlarged the knowledge on esophageal microbial environment and its role in pathogenesis.

Gut virome in inflammatory bowel disease and beyond.

Objective: The gut virome is a dense community of viruses inhabiting the gastrointestinal tract and an integral part of the microbiota. The virome coexists with the other components of the microbiota and with the host in a dynamic equilibrium, serving as a key contributor to the maintenance of intestinal homeostasis and functions. However, this equilibrium can be interrupted in certain pathological states, including inflammatory bowel disease, causing dysbiosis that may participate in disease pathogenesis.

Gut Dysbiosis in Irritable Bowel Syndrome: A Narrative Review on Correlation with Disease Subtypes and Novel Therapeutic Implications.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. It can be subclassified in different subtypes according to the main clinical manifestation: constipation, diarrhea, mixed, and unclassified. Over the past decade, the role of gut microbiota in IBS has garnered significant attention in the scientific community.

Microbiota in Irritable Bowel Syndrome and Endometriosis: Birds of a Feather Flock Together-A Review.

Endometriosis and irritable bowel syndrome (IBS) are chronic conditions affecting up to 10% of the global population, imposing significant burdens on healthcare systems and patient quality of life. Interestingly, around 20% of endometriosis patients also present with symptoms indicative of IBS. The pathogenesis of both these multifactorial conditions remains to be fully elucidated, but connections to gut microbiota are becoming more apparent.

Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition.

Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the oncoprotein SET is a critical determinant for the levels of histone acetylation within enhancers.

Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes.

Background: In preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations of the GB primarily affect the mucus layer.