Search

Luisa Bertin,1 Martina Crepaldi,1 Miriana Zanconato,1 Greta Lorenzon,1 Daria Maniero,1 Caterina De Barba,1 Erica Bonazzi,1 Sonia Facchin,1 Marco Scarpa,2 Cesare Ruffolo,2 Imerio Angriman,2 Andrea Buda,3 Fabiana Zingone,1 Edoardo Vincenzo Savarino,1 Brigida Barberio1 1Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; 2Chirurgia Generale 3 Unit, Azienda Ospedale Università di Padova, Padua, Italy; 3Gastroenterology Unit, Department of Oncological Gastrointestinal Surgery, Feltre, ItalyCorrespondence: Edoardo Vincenzo Savarino, Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy, Tel +39-049-8217749, Fax +39-049-8760820, Email edoardo.savarino@unipd.itAbstract: Crohn’s disease (CD) is a complex, chronic inflammatory bowel disease characterized by unpredictable flare-ups and periods of remission. Despite advances in treatment, CD remains a significant health burden, leading to substantial direct healthcare costs and out-of-pocket expenses for patients, especially in the first-year post-diagnosis. The impact of CD on patients’ quality of life is profound, with significant reductions in physical, emotional, and social well-being. Despite advancements in therapeutic options, including biologics, immunomodulators, and small molecules, many patients struggle to achieve or maintain remission, leading to a considerable therapeutic ceiling. This has led to an increased focus on novel and emerging treatments. This context underscores the importance of exploring advanced and innovative treatment options for managing refractory CD. By examining the latest approaches, including immunomodulators, combination therapies, stem cell therapies, and emerging treatments like fecal microbiota transplantation and dietary interventions, there is an opportunity to gain a comprehensive understanding of how best to address and manage refractory cases of CD. Keywords: refractory Crohn’s disease, mesenchymal stem cell therapy, medical therapy, combination therapy, fecal microbiota transplantation, biologic drugs, perianal Crohn’s disease, small molecules, hyperbaric oxygen therapy

Pierfrancesco Visaggi,1,* Matteo Ghisa,2,* Edoardo Vespa,3 Alberto Barchi,3 Amir Mari,4 Andrea Pasta,5 Elisa Marabotto,5,6 Nicola de Bortoli,1 Edoardo Vincenzo Savarino2 1Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 2Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; 3Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, 20132, Italy; 4Gastroenterology Unit, Nazareth Hospital EMMS, Azrieli Faculty of Medicine, Bar Ilan University, Ramat Gan, Israel; 5Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; 6IRCCS Policlinico San Martino, Genoa, Italy*These authors contributed equally to this workCorrespondence: Edoardo Vincenzo Savarino, Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, Padua, 35128, Italy, Tel +39-049-8217749, Email edoardo.savarino@unipd.itAbstract: Eosinophilic esophagitis (EoE) is a chronic type 2 inflammation-mediated disease characterized by an eosinophil-predominant inflammation of the esophagus and symptoms of esophageal dysfunction. Relevant treatment outcomes in the setting of EoE include the improvement of histology, symptoms, and endoscopy findings, quality of life (QoL), and the psychological burden of the disease. Established validated tools for the assessment of EoE include questionnaires on dysphagia and QoL (ie, DSQ, EEsAI, and EoE-IQ). More recently, esophageal symptom-specific anxiety and hypervigilance, assessed using the esophageal hypervigilance and anxiety scale (EHAS), have emerged as contributors to disease burden, confirming the importance of psychological aspects in EoE patients. The EoE endoscopic reference score (EREFS) is the only validated endoscopy score in EoE and can quantify mucosal disease burden. However, esophageal panometry using the functional lumen imaging probe (FLIP) and high-resolution manometry (HRM) have shown potential to optimize the assessment of fibrostenotic features of EoE, providing novel insights into the pathophysiology of symptoms. There is a growing number of licenced and off-label therapeutic options in EoE, with various randomized controlled trials demonstrating the efficacy of proton pump inhibitors, topical steroids, food elimination diets, biological drugs, and esophageal dilatation. However, standardized optimal management strategies of EoE are currently lacking. In this review, we provide an overview of established and novel assessment tools in EoE including patient reported outcomes, FLIP panometry, HRM, endoscopy, and histology outcome measures to improve the outcomes of EoE patients. In addition, we summarize available therapeutic options for EoE based on the most recent evidence.Keywords: eosinophilic esophagitis, treatment, monitoring

Introduction: Therapeutic drug monitoring (TDM) has proven to be a valuable strategy for optimizing biologic therapies, among which are anti-tumor necrosis factor (anti-TNF) treatments in inflammatory bowel disease (IBD). In particular, reactive TDM has been shown to manage treatment failures more cost-effectively than empirical dose adjustments for anti-TNF drugs. However, several challenges currently impede the widespread adoption of TDM in clinical practice, particularly addressing the delay between sample collection and result availability. To overcome this limitation, the use of point-of-care technology tests (POCTs) is a potential solution. Point-of-care technology tests are medical diagnostic tests performed at the site of patient care to provide immediate results, allowing for quicker decision-making and treatment. The current standard of care (SOC) for drug level measurement relies on the enzyme-linked immunosorbent assay (ELISA), a method that is time-consuming and requires specialized personnel. This study aims to evaluate a novel, user-friendly, and efficient POCT method (ProciseDx Inc.) and compare its performance with the SOC ELISA in assessing infliximab and adalimumab levels in blood samples from IBD patients. Methods: In this prospective, single-center study, we collected blood samples from IBD patients, both CD and UC, receiving infliximab (87 IBD patients; 50% UC and 50% CD) or adalimumab (60 patients; 14% UC and 48% CD) and we analyzed the blood's drugs levels using both the ProciseDx Analyzer POC and the SOC ELISA. We examined the correlation between the two methods using statistical analyses, including the Deming regression test. Additionally, we assessed the ease of use, turnaround time, and overall practicality of the POCT in a clinical setting. Results: The ProciseDx test demonstrated a strong correlation with the SOC ELISA for measuring both infliximab and adalimumab levels. In particular, the overall correlation between the ProciseDx POCT and the ELISA assessments showed an r coefficient of 0.83 with an R squared value of 0.691 (95% CI 0.717-0.902) for IFX measurements, and an r coefficient of 0.85 with an R squared value of 0.739 (95% CI 0.720-0.930). Conclusions: the ProciseDx POC test offers significantly faster turnaround times and is more straightforward to use, making it a viable alternative for routine clinical monitoring. Despite its promising potential, further refinement and validation of the ProciseDx test are necessary to ensure its effectiveness across diverse patient populations and clinical settings. Future research should focus on optimizing the POC tests' performance and evaluating its long-term impact on IBD management.

Background/Objectives: To develop a deep learning model for esophageal motility disorder diagnosis using high-resolution manometry images with the aid of Gemini. Methods: Gemini assisted in developing this model by aiding in code writing, preprocessing, model optimization, and troubleshooting. Results: The model demonstrated an overall precision of 0.89 on the testing set, with an accuracy of 0.88, a recall of 0.88, and an F1-score of 0.885. It presented better results for multiple categories, particularly in the panesophageal pressurization category, with precision = 0.99 and recall = 0.99, yielding a balanced F1-score of 0.99. Conclusions: This study demonstrates the potential of artificial intelligence, particularly Gemini, in aiding the creation of robust deep learning models for medical image analysis, solving not just simple binary classification problems but more complex, multi-class image classification tasks.

Objective: Ulcerative colitis and Crohn's disease are chronic inflammatory diseases and represent the two most important types of inflammatory bowel diseases (IBD), while spondyloarthritis (SpA) comprises a heterogeneous group of systemic inflammatory chronic rheumatic diseases, including peripheral SpA and axial SpA. Joint manifestations are the most commonly observed extraintestinal manifestations, and they can precede or not the diagnosis of IBD. Notably, in women, misdiagnoses of IBD as irritable bowel syndrome and SpA as fibromyalgia are common, leading to delayed diagnoses, increased disease burden, and poorer prognoses. This narrative review emphasizes the critical role of diagnostic tools in facilitating early referrals of IBD patients with suspected SpA and vice versa to rheumatologists and gastroenterologists, respectively. Special attention is given to the multidisciplinary approach for more effective management of these conditions, particularly in female patients., Methods: In this narrative review, we critically evaluated the literature on this topic, focusing on papers written in English that address female issues in IBD and SpA., Results: IBD and SpA are chronic inflammatory disorders often occurring in the same patients. Female patients are often misdiagnosed, and this delay in diagnosis is associated with a higher disease burden and a poorer prognosis., Conclusions: A multidisciplinary approach is needed to enable early referral between gastroenterologists and rheumatologists, as this means a better prognosis for patients with a reduction in the economic and social burden associated with IBD and SpA.

Mild-to-moderate ulcerative colitis (UC) management is centred on 5-aminosalicylic acid (5-ASA) derivatives. Whether supplementing 5-ASA with nutraceuticals can provide real advantages in UC-relevant outcomes is unclear. This retrospective multicentre study compared clinical remission, response rates, and faecal calprotectin levels in a two-arm design, including patients treated with 5-ASA alone and those with additional H. erinaceus -based multi-compound supplementation. In the 5-ASA alone group, clinical response rates were 41% at three months (T 1 ) and 60.2% at six months (T 2 ), while corresponding clinical remission rates were 16.9% and 36.1%. In the nutraceutical supplementation group, clinical response rates were 49.6% (T 1 ) and 70.4% (T 2 ), with clinical remission rates of 30.4% (T 1 ) and 50.9% (T 2 ). No significant differences in clinical response rates between the groups at T 1 ( p = 0.231) and T 2 ( p = 0.143) emerged. Clinical remission rates differed significantly at both time points ( p = 0.029 and p = 0.042, respectively). Faecal calprotectin levels decreased significantly in both groups during the retrospective follow-up ( p < 0.05), and this was more pronounced in nutraceutical supplementation patients at both T 1 ( p = 0.005) and T 2 ( p = 0.01). No adverse events were reported. This multi-component nutraceutical supplementation offers real-world potential in controlling disease activity in patients with mild-to-moderate UC.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the "atopic march" picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. In this comprehensive review, we have focused on the subtle mechanisms of type 2 inflammatory disorders, highlighting the similarities and differences with EoE, taking a deeper look into the evolving field of biologic therapies, already approved or under current investigation.

Background/objectives: Inflammatory bowel disease (IBD) and eosinophilic gastrointestinal diseases (EGIDs) are complex, multifactorial chronic inflammatory disorders affecting the gastrointestinal tract. Their epidemiology, particularly for eosinophilic esophagitis (EoE), is increasing worldwide, with a rise in the co-diagnosis of IBD and EGIDs. Both disorders share common risk factors, such as early exposure to antibiotics or specific dietary habits. Moreover, from a molecular perspective, eosinophilic infiltration is crucial in the diagnosis of eosinophilic disorders, and it also plays a pivotal role in IBD histological diagnosis. Indeed, recent evidence highlights the significant role of eosinophils in the health of the intestinal mucosal barrier and as mediators between innate and acquired immunity, even indicating a potential role in IBD pathogenesis. This narrative review aims to summarize the current evidence regarding the common clinical and molecular aspects of EGIDs and IBD and the current state of knowledge regarding overlap conditions and their pathogenesis., Methods: Pubmed was searched until May 2023 to assess relevant studies describing the epidemiology, pathophysiology, and therapy of EGIDs in IBD., Results: The immune pathways and mechanisms underlying both EGIDs and IBD remain partially known. An improved understanding of the role of eosinophils in overlapping conditions could lead to enhanced diagnostic precision, the development of more effective future therapeutic strategies, and a more accurate prediction of patient response. Consequently, the identification of red flags indicative of an eosinophilic disorder in IBD patients is of paramount importance and must be evaluated on a case-by-case basis.

Background: The pathophysiological and clinical value of performing High-Resolution Manometry (HRM) after laparoscopic fundoplication (LF) for gastroesophageal reflux disease (GERD) is still unclear and debated., Objective: We sought to establish the HRM parameters indicative of functioning fundoplications, and whether HRM could distinguish them from tight or defective ones., Methods: The study involved patients with GERD who underwent laparoscopic Nissen (LN) or Toupet (LT) fundoplication between 2010 and 2022. HRM and 24-h pH monitoring were performed before and 6 months after surgery. The study population was divided into 5 groups: LN and LT patients with normal 24h-pH findings (LNpH- and LTpH-, respectively); LN and LT patients with pathological 24h-pH findings (LNpH+ and LTpH + groups, respectively); and patients with a postoperative dysphagia intensity score >2 (Dysphagia group). The novel Hiatal Morphology (HM) classification was applied, envisaging 3 different subtypes: HM1 (normal), HM2 (intrathoracic fundoplication), and HM3 (slipped fundoplication)., Results: Among the 132 patients recruited during the study period, 46 were in the LNpH- group, 51 in the LTpH- group, 15 in the LNpH + group, 7 in the LTpH + group, and 5 in the Dysphagia group. In multivariate analysis, postoperative abdominal lower esophageal sphincter length (p = 0.001) and HM2 (p < 0.001) were both independently associated with surgical failure. Integrated relaxation pressure was significantly higher in the Dysphagia group than in the LNpH- group., Conclusion: This study generated reference HRM values for an effective LF, and confirms that using HRM to assess the neo-sphincter and HM improves the clinical assessment in cases of symptom recurrence., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis., Materials and Methods: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed., Results: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis., Conclusions: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed., Methods: This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events., Results: One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q 1 -q 3, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11)., Conclusions: Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background: Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses., Objective: To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice., Methods: Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations., Results: Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8 mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4 mg/day provided no benefit over 2 mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p < 0.001); use of higher doses (OR 4.3, p = 0.03) and lower symptom scores (OR 0.9, p = 0.01) were also determinants of effectiveness., Conclusion: Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Eosinophilic esophagitis (EoE) is recognized as a chronic type 2 inflammatory disease characterized by the eosinophilic infiltration of the esophageal tissue, posing a significant disease burden and highlighting the necessity for novel management strategies to address unmet clinical needs., Objectives: To critically evaluate the existing literature on the epidemiology and management of EoE, identify evidence gaps, and assess the efficacy of current and emerging treatment modalities., Design: An extensive literature review was conducted, focusing on the epidemiological trends, diagnostic challenges, and therapeutic interventions for EoE. This was complemented by a survey among physicians and consultations with a scientific expert panel, including a patient's association (ESEO Italia), to enrich the study findings., Data Sources and Methods: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, scrutinizing epidemiological studies and management research to compile comprehensive insights into the disease's landscape. The physician survey and expert panel discussions aimed to bridge identified evidence gaps., Results: The review included 59 epidemiological and 51 management studies, uncovering variable incidence and prevalence rates of EoE globally, with an estimated diagnosed prevalence of 41 per 100,000 in Italy. Diagnostic challenges were identified, including nonspecific symptoms and the lack of definitive biomarkers, which complicate the use of endoscopy. Treatment options such as elimination diets, proton-pump inhibitors, and swallowed corticosteroids were found to have varying success rates, while Dupilumab, an emerging therapy targeting interleukin (IL)-4 and IL-13, shows promise., Conclusion: Despite advancements in understanding and managing EoE, significant unmet clinical needs remain, particularly in biomarker identification, therapy personalization, and cost-effectiveness evaluation. A comprehensive, multidimensional approach to patient management is required, emphasizing the importance of early symptom recognition, accurate diagnosis, and tailored treatment strategies. Dupilumab offers potential as a novel treatment, underscoring the need for future research to explore the economic and social dimensions of EoE care pathways., Competing Interests: E.S. served as consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, and Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, and Zeta Farmaceutici. G.B. received consulting fees for analysis, conduction, and/or participation in Advisory Boards and/or Conferences from Aboca, AB Biotics, Agave, Alfasigma, AG Pharma, Bayer, Bromatech, Cadigroup, Biocodex, Sanofy, GE Healthcare, Mayoly, Diadema, and Sofar. M.B.B. received fees for lectures from ALK, Astra, Chiesi, GSK, and Sanofi. Nicola De Bortoli received consulting fee from Sofar, Reckitt-Benkiser, Dr. Falk, Malesci, Alfasigma, and Sanofi Genzyme; and for the participation to Advisory Board: Astra Zeneca, Dr. Falk. A.D.S. no conflict of interest to declare. S.O. received consulting fees from Sanofi, Alfasigma, Medtronic, and Bristol Myers Squibb. R.P. received consulting fees from Dr Falk Pharma and Sanofi for analysis conduction, or for the participation in Advisory Boards and/or Conferences. F.R. received consulting fees from Sanofi, Dr. Falk, GSK (Advisory Boards and Conferences). A.T. no conflict of interest to declare. F.R. no conflict of interest to declare. A.C. no conflict of interest to declare., (© The Author(s), 2024.)

Background: Inflammatory bowel diseases (IBDs) have a peak incidence between the second and fourth decades of life and can affect women's reproductive life., Objectives: Our study aimed to assess the impact of IBD on the reproductive life of female patients with this condition., Design: Cross-sectional study., Methods: Women with IBD followed at our IBD Unit and a group of healthy controls were enrolled. Data on reproductive life were collected using a dedicated questionnaire., Results: The study included 457 women, of whom 228 had IBD, and 229 age-matched healthy controls. No differences were found in the use of contraceptives, infertility, and endometriosis. The risk of spontaneous and voluntary abortions was significantly higher in IBD patients than in healthy controls [odds ratio (OR) 2 and 3.62, respectively]. The risk of obstetrical complications in the IBD population was more than six times higher in patients who experienced disease reactivations during pregnancy than in those with persistent remission [OR 6.9, 95% confidence interval (CI) 1.51-31.28]. Finally, we found that the chances of breastfeeding were 66% lower in patients with IBD than in controls (OR 0.44, 95% CI 0.22-0.91)., Conclusion: Our study underlines the negative impact of IBD on women's reproductive life, supporting the need for proactive preconception counseling., Competing Interests: The Associate Editor of Therapeutic Advances in Gastroenterology, Edoardo Vincenzo Savarino, is an author of this paper, therefore, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process. AB (Alessandro Borsato), DM (Daria Maniero), FDL (Francesco della Loggia), GL (Greta Lorenzon), AZ (Annalisa Zanini) and CC (Cristina Canova) have nothing to declare. FZ (Fabiana Zingone) has served as a speaker for EG Stada Group, Fresenius Kabi, Janssen, Pfizer, Takeda, Unifarco, Malesci, Kedrion, Abbvie; has served as a consultant for Galapagos and Takeda BB (Brigida Barberio) has served as speaker for Alfasigma, Janssen, MSD, Procise, Sofar, Takeda; has served as a consultant for Doxapharma, EVS (Edoardo Vincenzo Savarino) has served as speaker for Abbvie, AGPharma, Alfasigma, Dr. Falk, EG Stada Group, Fresenius Kabi, Grifols, Janssen, Innovamedica, Malesci, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Unifarco; EVS has served as a consultant for Alfasigma, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fresenius Kabi, Janssen, Merck & Co, Reckitt Benckiser, Regeneron, Sanofi, Shire, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco; EVS received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco., (© The Author(s), 2024.)

The gastrointestinal tract is home to trillions of diverse microorganisms collectively known as the gut microbiota, which play a pivotal role in breaking down undigested foods, such as dietary fibers. Through the fermentation of these food components, short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are produced, offering numerous health benefits to the host. The production and absorption of these SCFAs occur through various mechanisms within the human intestine, contingent upon the types of dietary fibers reaching the gut and the specific microorganisms engaged in fermentation. Medical literature extensively documents the supplementation of SCFAs, particularly butyrate, in the treatment of gastrointestinal, metabolic, cardiovascular, and gut-brain-related disorders. This review seeks to provide an overview of the dynamics involved in the production and absorption of acetate, propionate, and butyrate within the human gut. Additionally, it will focus on the pivotal roles these SCFAs play in promoting gastrointestinal and metabolic health, as well as their current therapeutic implications.

(1) Background : Inflammatory bowel disease (IBD) is frequently associated to other immune-mediated inflammatory diseases (IMIDs). This study aims at assessing physicians' awareness of the issue and the current status of IMID management. (2) Methods : A web-based survey was distributed to all 567 physicians affiliated to IG-IBD. (3) Results : A total of 249 (43.9%) physicians completed the survey. Over 90% of the responding physicians were gastroenterology specialists, primarily working in public hospitals. About 51.0% of the physicians had access to an integrated outpatient clinic, where gastroenterologists collaborated with rheumatologists and 28.5% with dermatologists. However, for 36.5% of physicians, integrated ambulatory care was not feasible. Designated appointment slots for rheumatologists and dermatologists were accessible to 72.2% and 58.2% of physicians, respectively, while 20.1% had no access to designated slots. About 5.2% of physicians report investigating signs or symptoms of IMIDs only during the initial patient assessment. However, 87.9% inquired about the presence of concomitant IMIDs at the initial assessment and actively investigated any signs or symptoms during subsequent clinical examination. (4) Conclusions : While Italian physicians recognize the importance of IMIDs associated with IBD, organizational challenges impede the attainment of optimal multidisciplinary collaboration. Efforts should be directed toward enhancing practical frameworks to improve the overall management of these complex conditions.

Background: Gastroesophageal reflux disease (GERD) is a challenging condition that involves different physicians, such as general practitioners (GPs), gastroenterologists, and ears, nose and throat (ENT) specialists. A common approach consists of proton-pump inhibitors (PPIs) administration. Adjunctive pharmacological treatment may have a role in the management of non-responders to PPIs., Objectives: We aimed to survey GPs and different medical specialists to investigate the medical approaches to patients reporting GERD symptoms. In addition, we examined the use of adjunctive pharmacological treatments in patients with GERD symptoms who do not respond to PPIs., Design: Retrospective observational study., Methods: A survey was conducted among a large sample of gastroenterologists, GPs, and ENT specialists. Symptoms were divided into typical and extraesophageal, and their severity and impact on quality of life were explored with the GERD Impact Scale and with Reflux Symptom Index (RSI). All therapies administered usually for GERD were investigated., Results: A total of 6211 patients were analyzed in this survey. Patients with typical symptoms were 53.5%, while those with extraesophageal symptoms were 46.5%. The latter were more frequently reported by ENT patients (53.6%, p  < 0.0001). The GSI was higher in patients followed by gastroenterologists (9 points) and GPs (9 points) than ENT specialists (8 points), but the RSI was higher in the ENT group (14.3 ± 6.93) than in GPs and gastroenterologist groups (10.36 ± 6.36 and 10.81 ± 7.30, p  < 0.0001). Chest pain had the highest negative impact on quality of life ( p  < 0.0001). Of the 3025 patients who used PPIs, non-responders showed a lower GSI when treated with a combination of adjunctive pharmacological treatments and bioadhesive compounds, than with single-component drugs., Conclusion: Patients with GERD referred to a gastroenterologist had more severe disease and poorer quality of life. The combination of adjunctive pharmacological treatments and bioadhesive compounds seems to be effective in the management of PPI refractory patients., (© The Author(s), 2024.)

Background: Ustekinumab (UST) has demonstrated effectiveness in treating patients with Crohn's disease. Monitoring treatment response can improve disease management and reduce healthcare costs. We investigated whether UST trough levels (TLs), serum IL22, and Oncostatin M (OSM) levels could be early indicators of non-response by analysing their correlation with clinical and biochemical outcomes in CD. Methods: Patients with CD initiating UST treatment from October 2018 to September 2020 were enrolled at six Italian centres for inflammatory bowel disease (IBD). Clinical and biochemical data were collected at four time points: baseline, second subcutaneous (SC) dose, fourth SC dose, and 52 weeks. TLs were measured during maintenance, at the second SC dose, and at the fourth SC dose. IL-22 and OSM serum levels were assessed at baseline and the second SC dose. We analysed whether TLs, IL22 levels, and OSM serum levels were associated with clinical response, clinical remission, biochemical remission, and endoscopic remission using the appropriate statistical tests. Results: Out of eighty-four initially enrolled patients, five were lost to follow-up, and eleven discontinued the drug before 52 weeks. At the 52-week time point, 47% achieved biochemical remission based on faecal calprotectin levels, and 61.8% achieved clinical remission. TLs at the second SC dose significantly correlated with biochemical remission at the same time point ( p = 0.011). However, TLs did not correlate with clinical remission. Baseline OSM levels did not correlate with biochemical or clinical remission or response. IL22 levels notably decreased during UST therapy ( p = 0.000), but its values did not correlate with biochemical or clinical remission. Conclusions: UST is an effective therapy for patients with CD. TLs measured at the second SC dose significantly correlated with biochemical remission, emphasising their potential role in treatment monitoring. Levels of OSM and IL-22, despite a significant decrease in the latter during therapy, did not exhibit correlations with clinical or biochemical outcomes in our study. Further studies are needed to confirm these findings.

Absent contractility (AC), a motility disorder characterized by the absence of esophageal contractions while maintaining normal lower esophageal sphincter relaxation, is recognized as a distinctive major disorder of peristalsis on esophageal high-resolution manometry that warrants comprehensive understanding. This unique motility disorder often co-occurs with connective tissue, rheumatologic or autoimmune diseases, with scleroderma being the classic example. Symptoms of gastroesophageal reflux are common. AC can profoundly impact patients' lives and result in a spectrum of complications, including erosive esophagitis, esophageal candidiasis, Barrett's esophagus, and malnutrition. To address the intricate complexities of AC and its multifaceted complications, a multidisciplinary approach is paramount. This approach considers the distinct clinical presentation and underlying rheumatologic conditions of the individual patient, recognizing the inherent diversity within this disorder. While medical management of gastroesophageal reflux remains the cornerstone of AC treatment, emerging surgical and endoscopic interventions offer additional therapeutic options for those grappling with this challenging condition. This comprehensive review provides an in-depth evaluation of recent advances in our understanding of AC and its management. It endeavors to offer valuable insights into therapeutic strategies for AC and its associated issues., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel syndrome (IBS). However, how the low FODMAP diet works is still not completely understood. These mechanisms encompass not only traditionally known factors such as luminal distension induced by gas and water but also recent evidence on the role of FOMAPs in the modulation of visceral hypersensitivity, increases in intestinal permeability, the induction of microbiota changes, and the production of short-chain fatty acids (SCFAs), as well as metabolomics and alterations in motility. Although most of the supporting evidence is of low quality, recent trials have confirmed its effectiveness, even though the majority of the evidence pertains only to the restriction phase and its effectiveness in relieving abdominal bloating and pain. This review examines potential pathophysiological mechanisms and provides an overview of the existing evidence on the effectiveness of the low FODMAP diet across various IBS subtypes. Key considerations for its use include the challenges and disadvantages associated with its practical implementation, including the need for professional guidance, variations in individual responses, concerns related to microbiota, nutritional deficiencies, the development of constipation, the necessity of excluding an eating disorder before commencing the diet, and the scarcity of long-term data. Despite its recognized efficacy in symptom management, acknowledging these limitations becomes imperative for a nuanced comprehension of the role of a low FODMAP diet in managing IBS. By investigating its potential mechanisms and evidence across IBS subtypes and addressing emerging modulations alongside limitations, this review aims to serve as a valuable resource for healthcare practitioners, researchers, and patients navigating the intricate landscape of IBS.

Pathological obesity is a growing public health concern, and its association with gastroesophageal reflux disease (GERD) poses challenges in selecting the appropriate bariatric procedure. Sleeve gastrectomy (SG) has become a popular choice due to its simplicity and effectiveness in weight loss. However, concerns regarding postoperative GERD have been raised. This study aimed to evaluate the association between preoperative assessment of esophageal function and the risk of developing postoperative GERD in patients undergoing SG. A comprehensive evaluation was conducted, including symptom assessment, upper endoscopy, high-resolution esophageal manometry (HRM), and 24 h esophageal pH impedance monitoring (MII-pH). A total of 500 obese patients were included, and their data were compared with 25 healthy volunteers. This study revealed that patients without GERD symptoms, normal endoscopy, HRM, and MII-pH were suitable candidates for SG, with low risk of developing postoperative GERD. The addition of fundoplication techniques to SG may be considered in patients with mild reflux or those at risk of developing it. This study emphasizes the importance of preoperative evaluation in selecting the appropriate bariatric procedure to minimize the risk of postoperative GERD and expand the indications for SG in obese patients.

Introduction: Immune-related adverse events (irAEs) constitute a challenge in the clinical management of solid tumors. This study aims to collect real-world data on the occurrence of immune-mediated diarrhea and colitis (IMDC) in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs) and to assess the clinical impact of a multidisciplinary approach (MDA) on IMDC management., Methods: We retrospectively collected data on patients with aNSCLC consecutively treated with ICIs, either as single agent or in combination with chemotherapy, between September 2013 and July 2022. Among patients developing IMDC, we conducted blinded revision of colonic biopsies and evaluated the clinical impact of the introduction of MDA through predefined indicators., Results: Among the 607 patients included, 84 (13.8%) experienced IMDC. Pathological review highlighted a high prevalence of microscopic colitis (28%), with a collagenous pattern linked to longer symptoms duration (P = .01). IMDC occurred more frequently in females (P = .05) and PD-L1 expressors (P = .014) and was correlated with longer progression-free survival (17.0 vs 5.8, P < .001) and overall survival (28.3 vs 9.5, P < .001). The introduction of MDA was associated with increased employment of diagnostical tools such as fecal calprotectin test (P < .001), colonoscopy (P < .001), and gastroenterological evaluation (P = .017) and a significant decrease in both grade 3 conversion rate (P = .046) and recurrence after rechallenge (P = .016). Hospitalization rate dropped from 17.2% to 3.8% (P: ns)., Conclusion: These findings highlight the clinical relevance of IMDC and support the incorporation of a MDA to optimize the clinical management of this irAE to improve patient care. Prospective validation has been planned., (© The Author(s) 2023. Published by Oxford University Press.)

Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist despite apparent compliance with a GFD. This could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on a GFD who experience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This review will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD.

Continuous and significant progress in sequencing technologies and bioinformatics pipelines has revolutionized our comprehension of microbial communities, especially for human microbiomes. However, most studies have focused on studying the taxonomic composition of the microbiomes and we are still not able to characterize dysbiosis and unveil the underlying ecological consequences. This study explores the emergent organization of functional abundances and correlations of gut microbiomes in health and disease. Leveraging metagenomic sequences, taxonomic and functional tables are constructed, enabling comparative analysis. First, we show that emergent taxonomic and functional patterns are not useful to characterize dysbiosis. Then, through differential abundance analyses applied to functions, we reveal distinct functional compositions in healthy versus unhealthy microbiomes. In addition, we inquire into the functional correlation structure, revealing significant differences between the healthy and unhealthy groups, which may significantly contribute to understanding dysbiosis. Our study demonstrates that scrutinizing the functional organization in the microbiome provides novel insights into the underlying state of the microbiome. The shared data structure underlying the functional and taxonomic compositions allows for a comprehensive macroecological examination. Our findings not only shed light on dysbiosis, but also underscore the importance of studying functional interrelationships for a nuanced understanding of the dynamics of the microbial community. This research proposes a novel approach, bridging the gap between microbial ecology and functional analyses, promising a deeper understanding of the intricate world of the gut microbiota and its implications for human health.

The albumin-bilirubin (ALBI) score to assess the risk of decompensation in patients with initially compensated cirrhosis may improve their prognostic evaluation. This letter critically evaluates the research, which utilizes the ALBI score to forecast decompensation in cirrhosis patients over a three-year period. This score was initially developed to assess liver function in hepatocellular carcinoma, its prognostic utility for non-malignant liver diseases has now been explored, recognizing decompensation as a pivotal event that significantly affects patient's survival. Some concerns regarding the methodology of this research may be raised, particularly the exclusive use of radiological diagnosis, potentially including patients without definite cirrhosis and thus skewing the decompensation risk assessment. The reported predominance of variceal bleeding as a decompensating event conflicts with established literature, that often reports ascites as the initial decompensation manifestation. The letter highlights the absence of details on esophageal varices and their management, which could introduce bias in evaluating the ALBI score's predictive power. Furthermore, the letter points out the small sample size of patients with high-risk ALBI grades, potentially compromising the score's validity in this context. We suggest prospective future research to investigate the dynamic changes in the ALBI score over time to reinforce the validity of the ALBI score as a predictor of decompensation in non-malignant liver disease., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Most adverse reactions to food are patient self-reported and not based on validated tests but nevertheless lead to dietary restrictions, with patients believing that these restrictions will improve their symptoms and quality of life. We aimed to clarify the myths and reality of common food intolerances, giving clinicians a guide on diagnosing and treating these cases. We performed a narrative review of the latest evidence on the widespread food intolerances reported by our patients, giving indications on the clinical presentations, possible tests, and dietary suggestions, and underlining the myths and reality. While lactose intolerance and hereditary fructose intolerance are based on well-defined mechanisms and have validated diagnostic tests, non-coeliac gluten sensitivity and fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) intolerance are mainly based on patients' reports. Others, like non-hereditary fructose, sorbitol, and histamine intolerance, still need more evidence and often cause unnecessary dietary restrictions. Finally, the main outcome of the present review is that the medical community should work to reduce the spread of unvalidated tests, the leading cause of the problematic management of our patients.

Gastroesophageal reflux disease (GERD) is a clinical condition with a prevalence of up to 25% in Western countries. Typical GERD symptoms include heartburn and retrosternal regurgitation. Lifestyle modifications, including diet, are considered a first-line therapeutic approach. To evaluate the impact of life habits on GERD in this cross-sectional study, we used data collected through an online survey from 1146 participants. GERD was defined according to the Montreal Consensus. For all participants, clinical and lifestyle characteristics were recorded. Overall, 723 participants (63.1%) consumed a diet including animal food (non-vegans), and 423 participants (36.9%) were vegans. The prevalence of GERD was 11% (CI 95%, 9-14%) in non-vegans and 6% (CI 95%, 4-8%) in vegans. In the multivariate analysis, after adjusting for confounding factors, subjects on a non-vegan diet were associated with a two-fold increase in the prevalence of GERD compared to vegans (OR = 1.96, CI 95%, 1.22-3.17, p = 0.006). BMI and smoking habits were also significantly associated with GERD. This study shows that an animal food-based diet (meat, fish, poultry, dairy, and eggs) is associated with an increased risk of GERD compared to a vegan diet. These findings might inform the lifestyle management of patients with GERD-related symptoms.

The relationship between food and the pathophysiological mechanisms of gastroesophageal reflux disease (GERD) is unclear. There are few data on the impact of dietary habits on GERD symptoms and on the incidence of GERD in subjects undergoing plant-based diets. In this study, we investigated the association between diet and GERD, using data collected through an online survey of the Italian general population. In total, 1077 subjects participated in the study. GERD was defined according to the Montreal Consensus. For all subjects age, gender, body mass index (BMI), marital status, education, occupation, alcohol consumption, and smoking habits were recorded. All participants also completed the SF-36 questionnaire on Quality of Life. A total of 402 subjects (37.3%) were vegans and 675 (62.7%) non-vegans. The prevalence of GERD in the total population was 9%. Subjects with GERD-related symptoms recorded a worse quality of life according to SF-36 analysis ( p < 0.05 for all dimensions). In multivariate analysis, after adjusting for confounders, participants undergoing a vegan diet had a significantly lower risk of GERD (OR = 0.47, 95% CI 0.28-0.81, p = 0.006). These findings should be taken into account to inform the lifestyle management of GERD.

Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intra-epithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a gluten-independent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an in situ aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Scarmozzino, Pizzi, Pelizzaro, Angerilli, Dei Tos, Piazza, Savarino, Zingone and Fassan.)

Eosinophilic gastrointestinal diseases (EGIDs) are an emerging group of pathological entities characterized by an eosinophil-predominant infiltration of different tracts of the gut in the absence of secondary causes of eosinophilia. According to the specific tract of the gut involved, EGIDs can be classified into eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The epidemiology of EGIDs is evolving rapidly. EoE, once considered a rare disease, now has an incidence and prevalence of 7.7 new cases per 100,000 inhabitants per years and 34.4 cases per 100,000 inhabitants per year, respectively. Fewer data are available regarding non-EoE EGIDs, whose prevalence are estimated to range between 2.1 and 17.6 in 100,000 individuals, depending on age, sex, and ethnicity. Diagnosis requires the presence of suggestive symptoms, endoscopic biopsies showing abnormal values of eosinophils infiltrating the gut, and exclusion of secondary causes of eosinophilia. EoE typically presents with dysphagia and episodes of food bolus impactions, while EoG, EoN, and EoC may all present with abdominal pain and diarrhea, with or without other non-specific symptoms. In addition, although different EGIDs are currently classified as different entities, there may be overlap between different diseases in the same patient. Despite EGIDs being relatively novel pathological entities, the research on possible treatments is rapidly growing. In this regard, several randomized controlled trials are currently ongoing to investigate novel molecules, including ad-hoc steroid formulations, immunosuppressants, and mostly monoclonal antibodies that target the specific molecular mediators of EGIDs. This narrative review provides an up-to-date overview of available and investigational drugs for different EGIDs.

The role of type 2 inflammation has been progressively associated with many diseases, including severe asthma, atopic dermatitis, nasal polyposis, eosinophilic granulomatosis with polyangiitis, and, recently, eosinophilic esophagitis. Despite this, the association between asthma and esophagitis is still poorly known, and this is probably because of the low prevalence of each disease and the even lower association between them. Nonetheless, observations in clinical trials and, subsequently, in real life, have allowed researchers to observe how drugs acting on type 2 inflammation, initially developed and marketed for severe asthma, could be effective also in treating eosinophilic esophagitis. For this reason, clinical trials specifically designed for the use of drugs targeted to type 2 inflammation were also developed for eosinophilic esophagitis. The results of clinical trials are presently promising and envisage the use of biologicals that are also likely to be employed in the field of gastroenterology in the near future. This review focuses on the use of biologicals for type 2 inflammation in cases of combined severe asthma and eosinophilic esophagitis.

Introduction: Patients with triple-negative breast cancer (TNBC) achieving a pathological complete response (pCR) after neoadjuvant chemotherapy have a better event-free survival. The role of gut microbiome in early TNBC is underexplored., Methods: Microbiome was analyzed by 16SrRNA sequencing., Results: Twenty-five patients with TNBC treated with neoadjuvant anthracycline/taxane-based chemotherapy were included. Fifty-six percent achieved a pCR. Fecal samples were collected before (t0), at 1 (t1), and 8 weeks (t2) from chemotherapy. Overall, 68/75 samples (90.7%) were suitable for microbiome analysis. At t0, pCR group showed a significantly higher α-diversity as compared with no-pCR, (P = .049). The PERMANOVA test on β-diversity highlighted a significant difference in terms of BMI (P = 0.039). Among patients with available matched samples at t0 and t1, no significant variation in microbiome composition was reported over time., Conclusions: Fecal microbiome analysis in early TNBC is feasible and deserves further investigation in order to unravel its complex correlation with immunity and cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Eosinophilic esophagitis (EoE) is a chronic esophageal disease that needs lifelong management and follow-up. The diagnosis requires an upper endoscopy with at least one esophageal biopsy demonstrating >15 eosinophils/high-power field, and often occurs with a diagnostic delay of up to ten years, partly due to the absence of valid non-invasive screening tools. In addition, serial upper endoscopies with esophageal biopsies are mandatory to assess the efficacy of any ongoing treatment in patients with EoE. These procedures are invasive, costly, and, when performed without sedation, are often poorly tolerated by patients. Therefore, there is the clinical need to identify reliable non-invasive or minimally invasive biomarkers that could be used to assess disease activity in clinical practice as a surrogate of peak eosinophil counts on esophageal biopsies. This review summarizes evidence on investigational non-invasive or minimally invasive biomarkers for the diagnosis and follow-up of EoE to report on the state of the art in the field and support future research. We discussed eosinophil-derived mediators including eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN, also known as eosinophil protein X), eosinophil peroxidase (EPO), and major basic protein (MBP) as well as other promising non-eosinophil-derived biomarkers. Although several studies have shown the utility of most biomarkers collected from the serum, esophageal luminal secretions, and feces of EoE patients, numerous limitations currently hamper the integration of such biomarkers in clinical practice. Future studies should aim at validating the utility of non-invasive and minimally invasive biomarkers using rigorous protocols and updated consensus criteria for EoE.

Mammalian colostrum, known as "liquid gold," is considered a valuable source of essential nutrients, growth factors, probiotics, prebiotics, antibodies, and other bioactive compounds. Precisely for this reason, bovine colostrum (BC) is an emerging ingredient for the feed, food, and pharmaceutical industries, being nowadays commercially available in a variety of forms in several countries. Moreover, quite a large number of functional foods and supplements for athletes, human medicines, pet nutrition plans, and complementary feed for some livestock categories, such as piglets and calves, contain BC. The amount of BC yielded by a cow after calving represents approximately 0.5% of the yearly output in dairy breeds. For its nutritional properties and low availability, BC is characterized by a greater market value and an increasing demand compared with other by-products of the dairy sector. However, information regarding the market size of BC for the food and pharmaceutical industries, as well as future developments and perspectives, is scarcely available in the scientific literature. This lack can be attributed to industrial secrecy as well as to the relatively small scale of the BC business when compared with other dairy products, which makes the BC market limited, specific, and intended for a restricted audience. From a legal perspective, regulations assign BC to the large family of milk-derived powders; thus, collecting specific production data, as well as import-export trend information, is not straightforward and can result in unprecise estimates. Given that the interest in BC is increasing in different fields, it is important to have an overview of the production steps and of pros and cons of this emerging ingredient. The present narrative review discloses why BC has started to be considered a product rather than a by-product of the dairy industry. Moreover, the present document aims to summarize the existing methodologies used to assess BC quality in terms of immunoglobulin concentration, the different applications of BC in the industry, and the BC processing technologies. Finally, a panoramic view of the current international market is provided for the first time for this dairy product., (© 2023, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Inflammatory bowel disease (IBD) is a group of chronic multifactorial inflammatory disorders including two major entities: Crohn's disease (CD) and ulcerative colitis (UC). Preliminary evidence suggests that patients with IBD may be at increased risk of developing intestinal and extraintestinal cancers (EICs). Actually, little is known about the association between IBD and EICs, and there is ever-growing concern regarding the safety of immunomodulators and biological therapy, which may represent a risk factor for carcinogenesis., Aims: The aim of this review is to summarize the evidence regarding the association between IBD and EICs, the safety of immunomodulators and biological therapy and the management of immunomodulators and biologic agents in IBD patients with prior or current EICs., Results: IBD patients have a higher risk of developing different forms of extraintestinal solid organ tumors and hematological malignancies. Immunomodulators and biological therapy may increase the risk of developing some types of EICs and may be consciously used in patients with IBD and current or prior history of malignancy., Conclusions: Decisions regarding the use of immunomodulators or biological therapies should be made on an individual basis, considering a multidisciplinary approach involving oncologists.

Background: There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation., Aim: To describe the events following AZA cessation., Methods: Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups., Results: A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1 st year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years., Conclusion: AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The gluten-free diet [GFD] has been linked to an increased risk of weight gain and the development of metabolic disorders. Most of the studies have focused on the effect of GFD on the Body Mass Index [BMI]. We aimed to evaluate the nutritional status using specific nutritional parameters in patients with celiac disease [CeD] at diagnosis and on a GFD compared to healthy controls. We recruited subjects at our outpatient clinic at the University of Padua. We collected demographic and clinical data and values obtained with bioelectrical impedance analysis. A total of 24 CeD patients and 28 healthy controls were enrolled. CeD patients at diagnosis had a lower body cell mass index [BCMI, p = 0.006], fat-free mass index [FFMI, p = 0.02], appendicular skeletal muscle index [ASMI, p = 0.02], and phase angle [PA] [ p < 0.001] compared to controls. Their percentage of extracellular water [ECW] was also higher [ p < 0.001]. Considering CeD patients after GFD, nutritional status significantly improved after 6 months of GFD. We did not observe differences in BMI among groups [ p = ns]. CeD patients at diagnosis were found to have a poorer nutritional status than healthy controls, with a positive effect of the GFD on their nutritional status, underlining the inefficacy of evaluating this aspect through only BMI evaluation.

Background: The management of postoperative recurrence (POR) in Crohn's disease (CD) after ileo-colonic resection is a highly debated topic. Prophylactic immunosuppression after surgery is currently recommended in the presence of at least one clinical risk factor., Objective: Our aim was to determine whether early immunosuppression can be avoided and guided by endoscopy in CD patients with only one risk factor., Methods: CD patients with only one risk factor for POR, including previous intestinal resection, extensive small intestine resection (>50 cm), fistulising phenotype, history of perianal disease, and active smoking, were retrospectively included. Two groups were formed based on whether immunosuppression was started immediately after surgery ("prophylaxis group") or guided by endoscopy ("endoscopy-driven group"). Primary endpoints were rates of any endoscopic recurrence (Rutgeerts ≥ i2a) and severe endoscopic recurrence (i4) within 12 months after surgery. Secondary outcomes were clinical recurrence rates at 6, 12 and 24 months after surgery., Results: A total of 195 patients were enroled, of whom 61 (31.3%) received immunoprophylaxis. No differences between immunoprophylaxis and the endoscopy-driven approach were found regarding any endoscopic recurrence (36.1% vs. 45.5%, respectively, p = 0.10) and severe endoscopic recurrence (9.8% vs. 15.7%, respectively, p = 0.15) at the first endoscopic evaluation. Clinical recurrence rates were also not statistically different (p = 0.43, p = 0.09, and p = 0.63 at 6, 12, and 24 months, respectively)., Conclusions: In operated CD patients with only one risk factor for POR, immediate immunoprophylaxis does not decrease the rate of early clinical and endoscopic recurrence. Prospective studies are needed to confirm our results., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background: The effectiveness of anti-TNF or ustekinumab (UST) as a second-line biologic after vedolizumab (VDZ) failure has not yet been described., Aims and Methods: In this retrospective multicenter cohort study, We aim to investigate the effectiveness of anti-TNF and UST as second-line therapy in patients with Crohn's disease (CD) who failed VDZ as a first-line treatment. The primary outcome was clinical response at week 16-22. Secondary outcomes included the rates of clinical remission, steroid-free clinical remission, CRP normalization, and adverse events., Results: Fifty-nine patients who failed on VDZ as a first-line treatment for CD were included; 52.8% patients received anti-TNF and 47.2% UST as a second-line therapy. In initial period (Week 16-22), the clinical response and remission rate was similar between both groups: 61.2% vs. 68%, p = 0.8 and 48.3% vs. 56%, p = 0.8 on anti-TNF and UST therapy, respectively. Furthermore, in the maintenance period the rate was similar: 75% vs. 82.3%, p = 0.8 and 62.5% vs. 70.5%, p = 0.8, respectively. Of the patients, 12 out of the 59 stopped the therapy, without a significant difference between the two groups ( p = 0.6)., Conclusion: Second-line biological therapy after VDZ failure therapy was effective in >60% of the patients with CD. No differences in effectiveness were detected between the use of anti-TNF and UST as a second line.

Background: Eosinophilic esophagitis (EoE) is a chronic immune-mediated rare disease, characterized by esophageal dysfunctions. It is likely to be primarily activated by food antigens and is classified as a chronic disease for most patients. Therefore, a deeper understanding of the pathogenetic mechanisms underlying EoE is needed to implement and improve therapeutic lines of intervention and ameliorate overall patient wellness., Methods: RNA-seq data of 18 different studies on EoE, downloaded from NCBI GEO with faster-qdump ( https://github.com/ncbi/sra-tools ), were batch-corrected and analyzed for transcriptomics and metatranscriptomics profiling as well as biological process functional enrichment. The EoE TaMMA web app was designed with plotly and dash. Tabula Sapiens raw data were downloaded from the UCSC Cell Browser. Esophageal single-cell raw data analysis was performed within the Automated Single-cell Analysis Pipeline. Single-cell data-driven bulk RNA-seq data deconvolution was performed with MuSiC and CIBERSORTx. Multi-omics integration was performed with MOFA., Results: The EoE TaMMA framework pointed out disease-specific molecular signatures, confirming its reliability in reanalyzing transcriptomic data, and providing new EoE-specific molecular markers including CXCL14, distinguishing EoE from gastroesophageal reflux disorder. EoE TaMMA also revealed microbiota dysbiosis as a predominant characteristic of EoE pathogenesis. Finally, the multi-omics analysis highlighted the presence of defined classes of microbial entities in subsets of patients that may participate in inducing the antigen-mediated response typical of EoE pathogenesis., Conclusions: Our study showed that the complex EoE molecular network may be unraveled through advanced bioinformatics, integrating different components of the disease process into an omics-based network approach. This may implement EoE management and treatment in the coming years., (© 2023. The Author(s).)

Colorectal cancer (CRC) is currently the third most frequent form of malignancy and the second in terms of mortality. Inflammatory bowel diseases (IBDs) are recognized risk factors for this type of cancer. Despite a worldwide increase in the incidence of CRC, the risk of CRC-related death in IBD patients has declined over time, probably because of successful surveillance strategies, the use of more effective drugs in the management of remission and improved indications to colectomy. This notwithstanding, CRC 5-year survival in patients with IBD is poorer than in the general population. This review provides a summary of the epidemiological features, risk factors and various prevention strategies proposed for CRC in IBD patients. Moreover, there is a special focus on reporting and highlighting the various prevention strategies proposed by the most important international scientific societies, both in terms of chemoprevention and endoscopic surveillance. Indeed, in conducting the analysis, we have given attention to the current primary, secondary and tertiary prevention guidelines, attempting to emphasize unresolved research and clinical problems related to this topic in order to improve diagnostic strategies and management.

Background: Data on the role of the microbiome in adult patients with eosinophilic oesophagitis (EoE) are limited., Aims: To prospectively collect and characterise the salivary, oesophageal and gastric microbiome in patients with EoE, further correlating the findings with disease activity., Methods: Adult patients with symptoms of oesophageal dysfunction undergoing upper endoscopy were consecutively enrolled. Patients were classified as EoE patients, in case of more than 15 eosinophils per high-power field, or non-EoE controls, in case of lack of eosinophilic infiltration. Before and during endoscopy, saliva, oesophageal and gastric fundus biopsies were collected. Microbiota assessment was performed by 16 s rRNA analysis. A Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) was implemented to identify biomarkers., Results: Saliva samples were collected from 29 EoE patients and 20 non-EoE controls;, biopsies from 25 EoE and 5 non-EoE controls. In saliva samples, 23 Amplicon Sequence Variants (ASVs) were positively associated with EoE and 27 ASVs with controls, making it possible to discriminate between EoE and non-EoE patients with a classification error (CE) of 24%. In a validation cohort, the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of this model were 78.6%, 80%, 75%, 80% and 60%, respectively. Moreover, the analysis of oesophageal microbiota samples observed a clear microbial pattern able to discriminate between active and inactive EoE (CE = 8%)., Conclusion: Our preliminary data suggest that salivary metabarcoding analysis in combination with machine learning approaches could become a valid, cheap, non-invasive test to segregate between EoE and non-EoE patients., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Chicago classification version 4.0 (CCv4.0) introduced stringent diagnostic criteria for oesophagogastric junction outflow obstruction (EGJOO), in order to increase the clinical relevance of the diagnosis, although this has not yet been demonstrated., Aims: To determine the prevalence of EGJOO using CCv4.0 criteria in patients with CCv3.0-based EGJOO, and to assess if provocative manoeuvres can predict a conclusive CCv4.0 diagnosis of EGJOO., Methods: Clinical presentation, high resolution manometry (HRM) with rapid drink challenge (RDC), and timed barium oesophagogram (TBE) data were extracted for patients diagnosed with EGJOO as per CCv3.0 between 2018 and 2020. Patients were then re-classified according to CCv4.0 criteria, using clinically relevant symptoms (dysphagia and/or chest pain), and abnormal barium emptying at 5 min on TBE. Receiver operating characteristic (ROC) analyses identified HRM predictors of EGJOO., Results: Of 2010 HRM studies, 144 (7.2%) fulfilled CCv3.0 criteria for EGJOO (median age 61 years, 56.9% female). Upon applying CCv4.0 criteria, EGJOO prevalence decreased to 1.2%. On ROC analysis, integrated relaxation pressure during RDC (RDC-IRP) was a significant predictor of a conclusive EGJOO diagnosis by CCv4.0 criteria (area under the curve: 96.1%). The optimal RDC-IRP threshold of 16.7 mm Hg had 87% sensitivity, 97.1% specificity, 95.7% negative predictive value and 91.3% positive predictive value for a conclusive EGJOO diagnosis; lower thresholds (10 mmHg, 12 mmHg) had better sensitivity but lower specificity., Conclusion: CCv4.0 criteria reduced the prevalence of EGJOO by 80%, thereby refining the diagnosis and identifying clinically relevant outflow obstruction. Elevated RDC-IRP can predict conclusive EGJOO per CCv4.0., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: There are several licensed drugs for irritable bowel syndrome (IBS) that have proven efficacy in randomized controlled trials (RCTs), but placebo response rates are high. We conducted a systematic review and meta-analysis of licensed drugs to estimate magnitude of placebo response rate according to Food and Drug Administration (FDA)-recommended endpoints and to assess how this varies with stringency of the endpoint used to define response., Methods: We searched MEDLINE, EMBASE CLASSIC and EMBASE, and the Cochrane central register of controlled trials (through January 2021) to identify RCTs comparing licensed drugs with placebo in adult IBS patients. Studies assessed efficacy according to at least one of composite response, abdominal pain response, or stool response. Data were extracted as intention-to-treat analyses, with dropouts assumed to be treatment failures and pooled using a random-effects model., Results: There were 17 RCTs of licensed drugs versus placebo in IBS with constipation (4603 patients placebo) and 17 trials in IBS with diarrhea (3908 patients placebo). In IBS with constipation, according to FDA criteria, pooled composite, abdominal pain, and stool response rates with placebo over ≥6 of 12 weeks were 18.9%, 34.6%, and 30.1%, respectively. Evaluating response rates over ≥9 of 12 weeks led to placebo response rates of 4.3% for the composite endpoint, 24.5% for abdominal pain, and 7.7% for stool. In IBS with diarrhea, pooled placebo response rates according to FDA criteria were 16.2% for the composite endpoint, 40.2% for abdominal pain, and 16.2% for stool. Increasing the threshold used to define abdominal pain response from ≥30% improvement to ≥40% or ≥50% led to lower placebo response rates of 34.5% and 23.4%., Conclusions: Future RCTs should adhere to current FDA-recommended endpoints for IBS because these lead to lower placebo response rates. However, consideration should be given to further refining some of these to better differentiate between active drug and placebo., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Disorders of gut-brain interaction, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD), frequently overlap, but the impact of this on the natural history is unknown. We examined this issue in a longitudinal follow-up study conducted in a large cohort of individuals., Methods: We collected complete demographic, symptom, mood, and psychological health data from 1374 adults who self-identified as having IBS. We applied the Rome IV criteria to examine what proportion met criteria for IBS and FD, as well as the degree of overlap between them. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health according to degree of overlap between IBS and FD., Results: Overall, 807 individuals met the Rome IV criteria for IBS at baseline and provided complete data. At study entry, overlap of FD occurred in 446 (55.3%) people who met Rome IV criteria for IBS. At 12 months, 451 (55.9%) individuals were successfully followed up. The proportion of individuals consulting their primary care physician (P = .001) or a gastroenterologist (P < .001) because of their IBS was significantly higher in those with overlap of IBS and FD, and the number of new IBS treatments commenced was significantly higher (P = .007). Those with overlap of IBS and FD reported significantly more severe IBS symptoms (P < .001), continuous abdominal pain, and that their IBS symptoms limited normal daily activities ≥50% of the time. Finally, those with overlap were more likely to report abnormal anxiety and depression scores at 12 months compared with those with IBS alone, and to have higher levels of somatization (P < .001 for all analyses)., Conclusions: The natural history of people with IBS with overlap FD defined according to Rome IV criteria is more severe than those with IBS alone. This has important implications for future treatment trials in IBS., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)