Molecular Mechanisms Underlying Loss of Vascular and Epithelial Integrity in Irritable Bowel Syndrome.

BACKGROUND AND AIMS: The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and includes epithelial barrier dysfunction, a key element at the interface between the gut lumen and the deeper intestinal layers. Beneath the epithelial barrier there is the vascular one representing the last barrier to avoid luminal antigen dissemination The aims of this study were to correlate morpho-functional aspects of epithelial and vascular barriers with symptom perception in IBS. METHODS: Seventy-eight healthy subjects (controls) and 223 patients with IBS were enrolled in the study and phenotyped according to validated questionnaires. Sugar test was used to evaluate in vivo permeability. Immunohistochemistry, western blot, and electron microscopy were used to characterize the vascular barrier. Vascular permeability was evaluated by assessing the mucosal expression of plasmalemma vesicle-associated protein-1 and vascular endothelial cadherin. Caco-2 or human umbilical vein endothelial cell monolayers were incubated with soluble mediators released by mucosal biopsies to highlight the mechanisms involved in permeability alteration. Correlation analyses have been performed among experimental and clinical data. RESULTS: The intestinal epithelial barrier was compromised in patients with IBS throughout the gastrointestinal tract. IBS-soluble mediators increased Caco-2 permeability via a downregulation of tight junction gene expression. Blood vessel density and vascular permeability were increased in the IBS colonic mucosa. IBS mucosal mediators increased permeability in human umbilical vein endothelial cell monolayers through the activation of protease-activated receptor-2 and histone deacetylase 11, resulting in vascular endothelial cadherin downregulation. Permeability changes correlated with intestinal and behavioral symptoms and health-related quality of life of patients with IBS. CONCLUSIONS: Epithelial and vascular barriers are compromised in patients with IBS and contribute to clinical manifestations.

Sarcopenia evaluated by EASL/AASLD computed tomography-based criteria predicts mortality in patients with cirrhosis: A systematic review and meta-analysis.

Background & Aims: Sarcopenia is associated with increased morbidity and mortality in patients with cirrhosis, but its definition in current literature is very heterogeneous. We performed a systematic review and meta-analysis to assess the association between mortality and sarcopenia evaluated by computed tomography (CT) in patients with cirrhosis, both overall and stratified for the criteria used to define sarcopenia. Methods: Medline, Embase, Scopus, and Cochrane Library were searched up to January 2023. We included studies assessing sarcopenia presence with CT scans and providing data on the risk of mortality. Adjusted hazard ratios (HRs) and 95% CIs were pooled using a random-effects model. Results: Thirty-nine studies comprising 12,827 patients were included in the meta-analysis. The summary prevalence of sarcopenia was 44% (95% CI 38-50%). The presence of sarcopenia (any definition) was an independent predictor of mortality with an adjusted HR of 2.07 (95% CI 1.81-2.36), and the result was consistent in all subgroup analyses. The prognostic role of the EASL/AASLD criteria was confirmed for the first time with an HR of 1.86 (95% CI 1.53-2.26) (n = 14 studies). The cut-offs used to define sarcopenia based on psoas muscle parameters varied among studies, thus, a subgroup analysis was not feasible. There was no substantial heterogeneity for the main estimates and no significant risk of publication bias. Conclusions: Sarcopenia on CT is associated with a 2-fold higher risk of mortality in patients with cirrhosis. The cut-offs proposed by EASL/AASLD are prognostically relevant and should be the recommended criteria used to define sarcopenia in clinical practice. Impact and implications: Sarcopenia assessed by the reference standard (computed tomography scan) is an independent predictor of mortality in patients with cirrhosis, with a 2-fold increase in the risk of death in all sensitivity analyses. This finding is particularly valid in patients from Europe and North America, and in transplant candidates. Stratifying for the parameters and cut-offs used, we confirmed for the first time the prognostic impact of the definition proposed by EASL/AASLD, supporting their use in clinical practice. Psoas muscle assessment is promising, but data are still limited and too heterogeneous to recommend its routine use at present.

Eosinophilic esophagitis in adults and adolescents: epidemiology, diagnostic challenges, and management strategies for a type 2 inflammatory disease.

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.

Understanding and improving care for eosinophilic esophagitis: bridging gaps in diagnosis and treatment Eosinophilic esophagitis (EoE) is a chronic inflammatory condition affecting the esophagus. We reviewed studies on how common EoE is and how it's managed. In Italy, about 41 out of 100,000 people may have it. Diagnosis can be tricky due to vague symptoms, and current treatments vary in effectiveness. We found a need for better ways to diagnose and treat EoE, including exploring new therapies. A promising development is a biologic called Dupilumab. Future research should also consider the costs and social aspects of caring for people with EoE.

Unmet needs in treatment of symptomatic uncomplicated diverticular disease and prevention of recurrent acute diverticulitis: a scoping review.

Background: Diverticular disease (DD) represents a common gastrointestinal condition that poses a heavy burden on healthcare systems worldwide. A high degree of uncertainty surrounds the therapeutic approaches for the control of symptoms in patients with symptomatic uncomplicated diverticular disease (SUDD) and primary and secondary prevention of diverticulitis and its consequences. Objectives: To review the current knowledge and discuss the unmet needs regarding the management of SUDD and the prevention of acute diverticulitis. Eligibility criteria: Randomized trials, observational studies, and systematic reviews on lifestyle/dietary interventions and medical treatment (rifaximin, mesalazine, and probiotics) of SUDD or prevention of acute diverticulitis. Sources of evidence: The literature search was performed from inception to April 2023, without language restriction, following the modified Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) reporting guidelines. References of the papers selected were checked to identify additional papers of potential interest. The final list of references was evaluated by a panel of experts, who were asked to check for any lack of relevant studies. Charting methods: Information on patient population, study design, intervention, control group, duration of the observation, and outcomes assessed was collected by two authors independently. Results: The review shows a high degree of uncertainty about therapeutic interventions, both dietary/lifestyle and pharmacological, in patients with SUDD, because of the scarcity and weakness of existing evidence. Available studies are generally of low quality, heterogeneous, and outdated, precluding the possibility to draw robust conclusions. Similarly, acute diverticulitis prevention has been seldom investigated, and there is a substantial lack of evidence supporting the role of dietary/lifestyle or pharmacological approaches to reduce the risk of diverticulitis. Conclusion: The lack of robust evidence regarding therapeutic options for gastrointestinal symptoms in SUDD patients and for primary and secondary prevention of acute diverticulitis remains an important unmet need in the management of DD.

Microbiota modulation in disorders of gut-brain interaction.

Disorders of gut-brain interaction (DGBI) are common chronic conditions characterized by persistent and recurring gastrointestinal symptoms triggered by several pathophysiological factors, including an altered gut microbiota. The most common DGBI are irritable bowel syndrome (IBS), functional constipation (FC) and functional dyspepsia (FD). Recently, a deep understanding of the role of the gut microbiota in these diseases was possible due to multi-omics methods capable to provide a comprehensive assessment. Most of the therapies recommended for these patients, can modulate the gut microbiota such as diet, prebiotics, probiotics and non-absorbable antibiotics, which were shown to be safe and effective. Since patients complain symptoms after food ingestion, diet represents the first line therapeutic approach. Avoiding dietary fat and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, and increasing the number of soluble fibers represent the therapeutic choices for FD, IBS and FC respectively. Probiotics, as a category, have been employed with good results in all the abovementioned DGBI. Rifaximin has been shown to be useful in the context of bowel related disorders, although a recent trial showed positive results for FD. Fecal microbiota transplantation has been tested for IBS and FC with promising results. In this review, we will briefly summarize the current understanding on dysbiosis and discuss microbiota modulation strategies to treat patients with DGBI.

Site and duration of abdominal pain discriminate symptomatic uncomplicated diverticular disease from previous diverticulitis patients.

Abdominal pain in patients with diverticular disease (DD) can be challenging in clinical practice. Patients with symptomatic uncomplicated diverticular disease (SUDD) and patients with a previous acute diverticulitis (PD) may share a similar clinical pattern, difficult to differentiate from irritable bowel syndrome (IBS). We used standardized questionnaires for DD (short and long lasting abdominal pain) and IBS (following Rome III Criteria) to assess clinical features of abdominal pain, in terms of presence, severity and length, in SUDD and PD patients. One hundred and forty-eight SUDD and 118 PD patients completed all questionnaires. Short-lasting pain was more frequent in SUDD than PD patients (p = 0.007). Number of long-lasting pain episodes was higher in SUDD (6.6 ± 11.9) compared to PD patients (3.4 ± 6.9) (p < 0.001). PD patients reported long-lasting pain more frequently in the lower left abdomen (p < 0.001), while in SUDD it was more frequently diffuse (p = 0.002) or localized in the lower right quadrant (p = 0.009). Features associated with long-lasting pain (fever, confinement to bed, consultations, antibiotic therapy, hospitalization) were more often reported in PD patients. IBS criteria were reported in 28.2% of patients and were more frequent in SUDD than PD patients (37.2% vs 17.1%, p < 0.001). SUDD and PD patients presented different pattern of abdominal pain (length, number of long lasting episodes, site and associated features), with a third reporting overlap with IBS. Further observational studies are needed to better characterize abdominal symptoms in DD patients, especially in those not fulfilling IBS criteria.Trial registration: The REMAD Registry is registered as an observational study in ClinicalTrial.gov (ID: NCT03325829).

Italian guidelines for the management of irritable bowel syndrome in children and adolescents : Joint Consensus from the Italian Societies of: Gastroenterology, Hepatology and Pediatric Nutrition (SIGENP), Pediatrics (SIP), Gastroenterology and Endoscopy (SIGE) and Neurogastroenterology and Motility (SINGEM).

The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID), whose prevalence has widely increased in pediatric population during the past two decades. The exact pathophysiological mechanism underlying IBS is still uncertain, thus resulting in challenging diagnosis and management. Experts from 4 Italian Societies participated in a Delphi consensus, searching medical literature and voting process on 22 statements on both diagnosis and management of IBS in children. Recommendations and levels of evidence were evaluated according to the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was reached for all statements. These guidelines suggest a positive diagnostic strategy within a symptom-based approach, comprehensive of psychological comorbidities assessment, alarm signs and symptoms' exclusion, testing for celiac disease and, under specific circumstances, fecal calprotectin and C-reactive protein. Consensus also suggests to rule out constipation in case of therapeutic failure. Conversely, routine stool testing for enteric pathogens, testing for food allergy/intolerance or small intestinal bacterial overgrowth are not recommended. Colonoscopy is recommended only in patients with alarm features. Regarding treatment, the consensus strongly suggests a dietary approach, psychologically directed therapies and, in specific conditions, gut-brain neuromodulators, under specialist supervision. Conditional recommendation was provided for both probiotics and specific fibers supplementation. Polyethylene glycol achieved consensus recommendation for specific subtypes of IBS. Secretagogues and 5-HT4 agonists are not recommended in children with IBS-C. Certain complementary alternative therapies, antispasmodics and, in specific IBS subtypes, loperamide and rifaximin could be considered.

The 1st EoETALY Consensus on the Diagnosis and Management of Eosinophilic Esophagitis-Current Treatment and Monitoring.

The present document constitutes Part 2 of the EoETALY Consensus Statements guideline on the diagnosis and management of eosinophilic esophagitis (EoE) developed by experts in the field of EoE across Italy (i.e., EoETALY Consensus Group). Part 1 was published as a different document, and included three chapters discussing 1) definition, epidemiology, and pathogenesis; 2) clinical presentation and natural history and 3) diagnosis of EoE. The present work provides guidelines on the management of EoE in two final chapters: 4) treatment and 5) monitoring and follow-up, and also includes considerations on knowledge gaps and a proposed research agenda for the coming years. The guideline was developed through a Delphi process, with grading of the strength and quality of the evidence of the recommendations performed according to accepted GRADE criteria.This document has received the endorsement of three Italian national societies including the Italian Society of Gastroenterology (SIGE), the Italian Society of Neurogastroenterology and Motility (SINGEM), and the Italian Society of Allergology, Asthma, and Clinical Immunology (SIAAIC). The guidelines also involved the contribution of members of ESEO Italia, the Italian Association of Families Against EoE.

Palmitoylethanolamide and polydatin in pediatric irritable bowel syndrome: A multicentric randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of co-micronized palmitoylethanolamide (PEA)/polydatin (PD) in the treatment of abdominal pain symptoms in pediatric patients with irritable bowel syndrome (IBS). METHODS: This was a multicenter trial conducted at three Italian pediatric gastroenterology centers, employing a double-blind, placebo-controlled, parallel-arm design. Participants were ages 10 to 17 y and met Rome IV criteria for pediatric IBS. They were randomly allocated to receive either co-micronized PEA/PD or placebo, administered three times daily in a 1:1 ratio, over a 12-wk period. The study assessed baseline severity using the IBS-Severity Scoring System (IBS-SSS) at enrollment and after 4, 8, and 12 wk of treatment. Abdominal pain frequency was assessed on a scale from 1 to 7 d/wk, while stool consistency was classified using the Bristol Stool Scale (BSS) to categorize various IBS subtypes. The primary outcome was the percentage of patients who achieved complete remission, defined as IBS-SSS score <75 points after 12 wk of therapy. RESULTS: The study involved 70 children with IBS. Of the participants, 34 received co-micronized PEA/PD, and 36 received a placebo. As compared with the placebo group, the co-micronized therapy group had significantly more patients achieving complete remission after 12 wk (P = 0.015), with particular benefit in the IBS-diarrhea subtype (P = 0.01). The treatment group also experienced a significant reduction in abdominal pain intensity and frequency compared with the placebo group. No adverse events were recorded during the study period. CONCLUSIONS: Co-micronized PEA/PD is a safe and effective treatment to treat abdominal pain symptoms in pediatric IBS.

The Role of the FODMAP Diet in IBS.

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.

The 1st EoETALY Consensus on the Diagnosis and Management of Eosinophilic Esophagitis - Definition, Clinical Presentation and Diagnosis.

Eosinophilic esophagitis (EoE) is a chronic type 2-mediated inflammatory disease of the esophagus that represents the most common eosinophilic gastrointestinal disease. Experts in the field of EoE across Italy (i.e., EoETALY Consensus Group) including gastroenterologists, endoscopists, allergologists/immunologists, and paediatricians conducted a Delphi process to develop updated consensus statements for the management of patients with EoE and update the previous position paper of the Italian Society of Gastroenterology (SIGE) in light of recent evidence. Grading of the strength and quality of the evidence of the recommendations was performed using accepted GRADE criteria. The guideline is divided in two documents: Part 1 includes three chapters, namely 1) definition, epidemiology, and pathogenesis; 2) clinical presentation and natural history, and 3) diagnosis, while Part 2 includes two chapters: 4) treatment and 5) monitoring and follow-up. This document has received the endorsement of three Italian national societies including the SIGE, the Italian Society of Neurogastroenterology and Motility (SINGEM), and the Italian Society of Allergology, Asthma, and Clinical Immunology (SIAAIC). With regards to patients' involvement, these guidelines involved the contribution of members of ESEO Italia, the Italian Association of Families Against EoE.

Journal of Clinical Gastroenterology Lectureship Dubai 2022 : Management of Irritable Bowel Syndrome With Diarrhea.

Irritable bowel syndrome (IBS) with diarrhea (IBS-D) affects ~1% of the general population and is characterized by abdominal pain associated with diarrhea. IBS-D symptoms significantly impact the quality of life of patients. Major uncertainties remain regarding the optimal management of these patients. Several therapies have been investigated over the years for the treatment of IBS-D. In the initial management, commonly prescribed approaches with an effect on global IBS symptoms include a low Fermentable Oligo-, Di-, Mono-Saccharides and Polyols diet and probiotics, while antispasmodics are used for targeting abdominal pain and loperamide for diarrhea only. Additional therapeutic options for the relief of global IBS symptoms include rifaximin, 5-HT 3 antagonists, gut-directed psychological therapies, and eluxadoline, while tricyclic antidepressants can target abdominal pain and bile acid sequestrants diarrhea. Promising evidence exists for the use of mesalazine and fecal microbiota transplantation in IBS-D, although further evidence is needed for definitive conclusions regarding their efficacy.

Collinsella aerofaciens as a predictive marker of response to probiotic treatment in non-constipated irritable bowel syndrome.

Probiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We aimed to identify markers for recognizing non-constipated (NC) IBS patients that may show significant clinical improvements upon treatment with the probiotic strain Lacticaseibacillus paracasei DG (LDG). To this purpose, we performed a post-hoc analysis of samples collected during a multicenter, double-blind, parallel-group, placebo-controlled trial in which NC-IBS patients were randomized to receive at least 24 billion CFU LDG or placebo capsules b.i.d. for 12 weeks. The primary clinical endpoint was the composite response based on improved abdominal pain and fecal type. The fecal microbiome and serum markers of intestinal (PV1 and zonulin), liver, and kidney functions were investigated. We found that responders (R) in the probiotic arm (25%) differed from non-responders (NR) based on the abundance of 18 bacterial taxa, including the families Coriobacteriaceae, Dorea spp. and Collinsella aerofaciens, which were overrepresented in R patients. These taxa also distinguished R (but not NR) patients from healthy controls. Probiotic intervention significantly reduced the abundance of these bacteria in R, but not in NR. Analogous results emerged for C. aerofaciens from the analysis of data from a previous trial on IBS with the same probiotic. Finally, C. aerofaciens was positively correlated with the plasmalemmal vesicle associated protein-1 (PV-1) and the markers of liver function. In conclusion, LDG is effective on NC-IBS patients with NC-IBS with a greater abundance of potential pathobionts. Among these, C. aerofaciens has emerged as a potential predictor of probiotic efficacy.

Identification and management of gastrointestinal manifestations of hereditary transthyretin amyloidosis: Recommendations from an Italian group of experts.

Gastrointestinal manifestations are common across all hereditary transthyretin amyloidosis (ATTRv) genotypes. However, they are poorly specific, and their recognition as part of ATTRv is difficult, resulting in misdiagnosis with more common conditions. Moreover, delays in diagnosis occur because of fragmented knowledge, a shortage of centers of excellence and specialists dedicated to ATTRv management, and the scarce involvement of gastroenterologists in multidisciplinary teams. A group of Italian gastroenterologists with experience in the management of ATTRv took part in a project aimed at assessing the awareness of ATTRv among the community of Italian gastroenterologists through an online survey and providing education about practical aspects of ATTRv management. Survey results reported low participation, and very few patients with ATTRv were cared for by gastroenterologists. This highlights the need for greater attention to rare diseases in gastroenterology and emphasizes increasing awareness of ATTRv and diagnostic suspicion. Based on the experts' recommendations, a diagnosis of ATTRv should be suspected when at least one of the 'red flags' is detected. Subsequently, it is suggested to promptly ask for genetic testing and exclude a serum and urinary monoclonal protein, even before the detection of amyloid in biopsy samples, particularly in non-endemic areas.