Ioanna Aggeletopoulou

Fungal esophagitis, predominantly caused by Candida species, remains the leading form of infectious esophagitis worldwide. Although historically linked to human immunodeficiency virus infection, its epidemiology has shifted over recent decades, with a growing incidence among oncology patients receiving immune checkpoint inhibitors, individuals with eosinophilic esophagitis on oral corticosteroids, and solid-organ transplant recipients. Increasing evidence highlights that disease pathogenesis extends beyond simple fungal overgrowth and involves intricate host–pathogen interactions. Pathogenic mechanisms such as adhesion, hyphal transition, and biofilm formation enhance fungal virulence, while mucosal immune dysfunction, particularly impaired T helper 17/interleukin 17 signaling and reduced antimicrobial peptide activity, predisposes to persistent infection. Antifungal resistance represents an emerging challenge, driven by efflux pump overexpression, ERG11 mutations conferring azole resistance, and mutations of FKS genes leading to reduced echinocandin susceptibility. These molecular mechanisms underscore the complexity of treatment and have important implications for antifungal selection and clinical management. While fluconazole remains the first-line agent for most cases, the increasing prevalence of non-albicans Candida species and drug resistance underscore the importance of alternative medications with different molecular targets. Agents such as the recently approved rezafungin as well as compounds such as ibrexafungerp and fosmanogepix, represent promising options for the treatment of refractory disease. This review synthesizes current advances in the molecular pathogenesis of fungal esophagitis, with particular emphasis on host–fungal interactions, antifungal resistance mechanisms, and novel treatment strategies. A deeper understanding of these processes is essential to improve management and to guide the development of innovative immunomodulatory and antifungal therapies.

Refractory celiac disease (RCeD) is a rare but severe complication of celiac disease characterized by persistent or recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, after exclusion of ongoing gluten exposure, alternative enteropathies, and overt lymphoma. RCeD comprises two biologically distinct entities. RCeD-I is associated with phenotypically normal, polyclonal intraepithelial lymphocytes and generally reflects persistent gluten-independent mucosal inflammation with a relatively favorable prognosis. RCeD-II is defined by expansion of aberrant clonal intraepithelial lymphocytes lacking normal surface T-cell markers and is increasingly regarded as a low-grade intraepithelial lymphoma or in situ lymphomatous disorder, with substantial risk of progression to enteropathy-associated T-cell lymphoma (EATL). Mechanistic studies identify epithelial stress, IL-15-driven IEL survival, stromal and innate immune amplification, and cytotoxic epithelial injury as central drivers of refractory mucosal damage. In RCeD-II, aberrant IELs acquire a hybrid T/NK-like phenotype, persist through anti-apoptotic IL-15/JAK–STAT signaling, and induce enterocyte killing, while molecular alterations involving JAK1, STAT3, JAK/STAT regulators, NF-κB signaling, epigenetic regulators, and chromosomal abnormalities support stepwise lymphomagenesis. Recent single-cell multiomic studies further reveal genetically altered intestinal lymphocyte clones and intratumoral heterogeneity across the RCeD-II–EATL continuum. From a nutritional immunology perspective, RCeD illustrates a setting in which removal of the initiating dietary antigen is insufficient to restore mucosal immune homeostasis. This review summarizes the pathogenic processes that distinguish RCeD-I from RCeD-II and link failed mucosal recovery after gluten withdrawal to persistent immune-mediated epithelial injury, aberrant IEL expansion, clonal evolution, and lymphoma progression.

Background: Statins have pleiotropic anti-inflammatory, antifibrotic, and potential antineoplastic effects. Although several studies have linked statin exposure to lower hepatocellular carcinoma (HCC) incidence, their effect on survival after HCC diagnosis remains uncertain. We evaluated whether statin therapy before HCC diagnosis was associated with overall survival in a real-world cohort. Methods: We performed a retrospective single-center cohort study of consecutive patients with HCC managed at a tertiary referral center between January 2000 and January 2025. Demographic, clinical, laboratory, tumor-related, and treatment variables were collected at diagnosis and during follow-up. Patients were classified according to statin use before HCC diagnosis. Overall survival (OS) was assessed using Kaplan–Meier analysis and Cox proportional hazards regression. Results: Overall, 190 patients were included; 172 (90.5%) were male, 136 (71.6%) had cirrhosis, and 42 (22.1%) received statins. Statin users more frequently had diabetes mellitus, elevated body mass index and arterial hypertension, but baseline liver function, alpha-fetoprotein levels, tumor burden, and treatment allocation were broadly comparable between groups. Among 159 patients with available survival data, statin users had longer OS than non-users (mean 82.5 vs. 41.7 months; median 57 vs. 31 months; log-rank p < 0.001). In univariate Cox analysis, statin therapy was associated with reduced mortality risk (HR 0.45, 95% CI 0.28–0.70, p < 0.001). This association remained significant across multivariable models adjusting for baseline liver function, tumor stage, vascular invasion, and diagnostic era. Conclusions: Pre-diagnostic statin therapy was independently associated with improved OS in patients with HCC. These hypothesis-generating findings warrant prospective multicenter validation and careful assessment of confounding by indication.

Irritable bowel syndrome (IBS) is a prevalent disorder of gut–brain interaction, characterized by a substantial symptom burden, impaired quality of life, and increased healthcare use. Despite advances in diagnostic criteria and treatment strategies, many patients feel dismissed, inadequately informed, or uncertain about the nature and meaning of their symptoms; these experiences may undermine trust and reduce engagement with healthcare professionals. The aim of this narrative review is to synthesize clinical and ethical considerations and propose a patient-centered ethical framework for IBS management, positioning communication as a core therapeutic intervention. We highlight how validation, clear and non-stigmatizing explanations, transparency about uncertainty, and recognition of patient values can strengthen the therapeutic alliance, support relational autonomy, and enable shared decision-making. These elements can promote supported self-management and improve adherence to individualized dietary, behavioral, and pharmacologic strategies. In response to the central role of nutrition in IBS care, we further integrate dietary management into the ethical framework, addressing dietary assessment, first-line dietary advice, soluble fiber, the structured low-FODMAP approach, and the risks of excessive or unsupported food restriction. We further discuss how the incorporation of patient-reported outcomes (PROs) can translate patient priorities into measurable outcomes, monitor clinically meaningful changes over time, and reduce discrepancies between clinical assessment and patients’ lived experiences. Finally, we underscore the impact of stigma and uncertainty and provide practical communication approaches to support a stronger therapeutic alliance in IBS care. The integration of ethical communication, PROs, and nutrition-sensitive self-management may improve patient experience, strengthen adherence, and support individualized therapeutic strategies in IBS care.

Alterations in the intestinal microbiota have been implicated in both irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). However, their biological significance and therapeutic implications differ substantially between the two conditions. Although dysbiosis is a common feature, the mechanisms by which alterations in the microbiota contribute to disease pathophysiology and clinical expression are distinct. Some pathways are more prominent in IBS (e.g., the gut–brain axis), whereas others are more prominent in IBD (e.g., reduced microbial diversity). Equally important are pathways that appear to play a role exclusively in IBD [e.g., Adherent-invasive Escherichia coli (AIEC) and Paneth cells], as well as others that seem to be specific to IBS (e.g., mast cell activation). In IBD, microbiota changes are primarily linked to immune dysregulation, mucosal barrier impairment, and inflammation-driven pathways, whereas in IBS, they are mainly associated with functional disturbances mediated by neuroimmune signaling and microbial metabolites. Furthermore, several microbiome-associated biomarkers differ between these two diseases, and some are already assessed by international guidelines. Although the microbiota plays a key role in IBS and IBD pathophysiology, microbiome-based treatments remain limited, especially in IBD. There are clinically available treatments in IBS (e.g., rifaximin, low-FODMAP diet), but in IBD, only the probiotic VSL#3 is guideline-approved in ulcerative colitis pouchitis prophylaxis. Nevertheless, the dynamic nature of the microbiota continues to support the investigation of already studied (e.g., probiotics, fecal microbiota transplantation) and potential novel therapeutic approaches at the research level. The aim of this review is to compare the gut-microbiota-related pathophysiological pathways and biomarkers between IBS and IBD, to summarize the microbiome-related medications that have already been studied in both diseases, and to suggest new potential therapeutic options based on the gut microbiota.

Background: Intestinal barrier dysfunction is a hallmark of inflammatory bowel disease (IBD), yet the clinical significance of tight junction (TJ) remodeling remains unclear. We investigated whether alterations in the expression and localization of key TJ proteins are associated with disease activity and clinical outcomes in IBD. Methods: This retrospective, single-center study included patients with Crohn’s disease (CD; n = 100), ulcerative colitis (UC; n = 120), and healthy controls (n = 80). Immunohistochemistry was used to assess the expression and subcellular localization of occludin and claudin-1 separately in surface (SE) and crypt epithelium (CR), with staining classified as predominantly membranous (regular) or cytoplasmic (irregular). The primary endpoint was IBD-related hospitalization. Secondary endpoints included surgery, initiation of biologic therapy, and clinical relapse. Logistic and Cox regression models were applied, and longitudinal changes were assessed in paired biopsies. Results: Both occludin and claudin-1 were dysregulated in active disease, showing increased expression and cytoplasmic redistribution compared with remission and controls. TJ alterations were more pronounced in the CR and correlated with clinical, endoscopic, and histological activity. In CD, occludin CR overexpression was independently associated with hospitalization (aOR 1.010; p = 0.05) and surgery (aHR 1.013; p = 0.005), while irregular occludin CR staining was associated with initiation of biologic therapy (aOR 3.48; p = 0.03). In UC, increased occludin CR levels and irregular CR staining were associated with IBD-related hospitalization in multivariable analyses (aOR 1.014; p = 0.035 and aOR 2.78; p = 0.032, respectively). Higher occludin CR levels identified UC patients at increased risk of clinical relapse (aHR 1.012; p = 0.002). In paired biopsies (n = 127), TJ architecture—particularly in the CR—improved over time, with reduced expression and a shift toward membranous localization, most prominently in bio-experienced patients. Conclusions: TJ remodeling, particularly crypt-level occludin dysregulation, is associated with disease activity and clinical outcomes, capturing a clinically relevant dimension of epithelial barrier dysfunction in IBD.

Irritable Bowel Syndrome (IBS) affects 4–15% of the global population, and the limited efficacy of existing pharmacologic therapies has driven growing interest in plant-based therapeutic options among both patients and clinicians. A comprehensive assessment of all plant extracts investigated in IBS is therefore essential, given the limited effectiveness of conventional treatments and the increasing interest in complementary approaches. Evidence from recent systematic reviews and meta-analyses consistently indicates that peppermint oil is the most effective botanical agent, particularly for reducing abdominal pain and overall IBS symptom severity. Iberogast (STW-5 and STW-5 II) has also demonstrated clinical improvements across multiple trials, while curcumin shows mechanistic and preliminary clinical potential by modulating several IBS-related pathways. In contrast, extracts such as Curcuma xanthorrhiza, Fumaria officinalis, and various Ayurvedic formulations have not shown significant clinical benefit. Other agents, including Aloe vera, flavonoids, St John’s wort, and ginger, exhibit mixed or inconsistent results, reflecting heterogeneity in study designs and underlying mechanisms. A review of international guidelines reveals that peppermint oil is the only plant-based therapy consistently acknowledged across adult and pediatric recommendations. The aim of this review is to summarize, compare, and critically evaluate all plant extracts studied for the prevention and treatment of IBS, integrating mechanistic pathways, clinical evidence, and current international guideline recommendations to clarify their therapeutic relevance for clinical practice.

Background/Objectives: Vitamin D in its active form, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], plays a critical role in immune regulation, gut barrier function, and systemic inflammation. Its deficiency is frequent in Inflammatory Bowel Disease (IBD), but the clinical implications remain uncertain. The aim of the study is to assess the prevalence of vitamin D deficiency in a well-characterized IBD cohort in Western Greece, and explore its associations with clinical features, laboratory biomarkers, and treatment intensity. Methods: In this cross-sectional study, 184 consecutive, well-characterized IBD outpatients followed at a tertiary referral center in Western Greece underwent clinical evaluation and laboratory testing between January 2023 and December 2024. Vitamin D is determined by measuring 25-hydroxyvitamin D [25(OH)D], which reflects the body’s vitamin D stores due to its longer half-life compared with the biologically active form. Deficiency was defined as serum 25(OH)D < 20 ng/mL. Associations with disease type, clinical and laboratory biomarkers, severity indices, and treatment were analyzed using multivariate logistic regression. Results: Vitamin D deficiency was identified in 67 patients (36.4%). Although unrelated to disease type, hospitalization, surgery, or disease activity indices, deficiency correlated with systemic inflammation, nutrition/metabolic markers, and treatment intensity. More specifically, vitamin D-deficient patients exhibited higher platelet counts (p = 0.005) and erythrocyte sedimentation rate (ESR) (p = 0.014), lower hemoglobin (p = 0.005), albumin (p = 0.011), and serum glutamic-oxaloacetic transaminase (SGOT) (p = 0.009) levels and more frequent use of biologic therapy (p = 0.009). In multivariate analysis, vitamin D deficiency remained independently associated with biologic therapy (aOR = 0.374; 95% CI: 0.148–0.946), platelet count (aOR = 0.996, 95% CI: 0.992–0.999), and SGOT (aOR = 1.05, 95% CI: 1.00–1.10), indicating consistent links between vitamin D deficiency and treatment intensity, systemic inflammation, and nutritional or metabolic status. Conclusions: Vitamin D deficiency is common among IBD patients and independently associates with systemic inflammation, metabolic impairment, and intensified treatment requirement, supporting its potential role as a marker of disease burden.

Irritable Bowel Syndrome (IBS) is a prevalent and heterogeneous functional gastrointestinal disorder with a complex and multifactorial pathophysiology. Traditional treatment approaches have focused on symptom relief, often overlooking the underlying biological mechanisms driving the disease. Τhis review summarizes the current evidence linking core pathophysiological pathways of IBS with mechanism- and diet- based therapeutic strategies to guide personalized treatment. Serotonergic signaling, microbial dysbiosis, immune activation, epithelial barrier dysfunction, and bile acid malabsorption interact to shape the diverse phenotypes of IBS, contributing to altered motility, visceral hypersensitivity, and gut-brain axis dysregulation. Increasing evidence supports that targeted dietary and biological interventions including low-FODMAP and Mediterranean low-FODMAP diets, targeted use of probiotics and psychobiotics, and vitamin D supplementation can modulate microbial composition, reduce luminal irritants, support barrier integrity, and attenuate immune system activation. Similarly, pharmacologic therapies including serotonergic receptor modulators, bile acid sequestrants and neuroimmune agents act on specific mechanistic pathways, reflecting a shift from symptom-based to mechanism-driven management. Collectively, these findings highlight that integrating dietary, microbial, neuroimmune, and serotonergic modulation within a unified therapeutic framework can support a more rational and individualized approach to IBS management and long term symptom control.

Irritable Bowel Syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting about 11% of the global population and exerting a substantial burden on quality of life and healthcare systems. Despite the emerging interest in this disease, its pathophysiology remains elusive, reflecting the interplay between the brain–gut axis, neuroendocrine dysregulation, immune activation, barrier dysfunction, microbial imbalance, and environmental triggers. Disruptions in the hypothalamic–pituitary–adrenal axis, impaired serotonin signaling, bile acid malabsorption, and altered intestinal permeability collectively result in the emergence of abnormal motility, visceral hypersensitivity, and chronic inflammation. The gut microbiome further modulates these processes by influencing neurotransmitter metabolism, immune responses, and epithelial integrity, positioning it as both a driver of symptoms and a promising therapeutic target. The aim of this review is to synthesize current mechanistic insights into IBS, highlighting the interconnected roles of the brain–gut axis, immune modulation, and microbial dynamics, and to explore how these pathways may be translated into precision medicine approaches. This review integrates molecular, microbial, and neuroimmune perspectives to propose a systems-level understanding of IBS pathophysiology and its implications for precision medicine. By integrating host–microbe interactions, dietary influences, and genetic predispositions, we highlight the mechanistic complexity underlying IBS and the potential for translating these insights into personalized strategies for symptom control and improved quality of life.