BACKGROUND:Chronic intestinal pseudo-obstruction (CIPO) is a rare, severe disorder of gastrointestinal motility. Although 5-hydroxytryptamine type 4 (5-HT4) receptor agonists stimulate gastrointestinal motility, few trials have assessed their therapeutic effects in patients with CIPO. AIM:To assess the efficacy and safety of velusetrag, a highly selective 5-HT4 receptor agonist, in patients with CIPO. METHODS:This was a phase 2, placebo-controlled, crossover, multiple (n = 1), multicenter, double-blind, proof-of-concept trial. Eligible patients were aged 18-80 years, had CIPO (idiopathic or secondary to neurodegenerative disorders) and received ≥ 30% of their daily caloric intake orally. Over four periods, each of four weeks, patients were randomly assigned to once-daily, oral velusetrag 15 mg (two periods) or placebo (two periods), with a 2-week washout between each treatment period. The primary endpoint was the improvement in the weekly global gastrointestinal symptoms average index score (WGGSAIS) from the start to the end of each treatment period, assessed among patients who were responders or naive to previous 5-HT4 receptor agonist treatment. RESULTS:Overall, 17 patients with idiopathic CIPO received treatment and were included in safety analyses; efficacy was assessed in 15 patients. Mean (standard deviation) changes in WGGSAIS during treatment were -0.42 (0.693) for velusetrag and -0.19 (0.688) for placebo (between-treatment difference: -0.24; 95% confidence interval: -0.553, 0.074; p = 0.1279). No deaths or serious or treatment-related treatment-emergent adverse events were reported. CONCLUSION:Velusetrag treatment was associated with improved symptoms versus placebo, although differences were not statistically significant at this sample size. Velusetrag was generally well tolerated. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05724069; EudraCT number: 2021-000854-24.

BACKGROUND:Chronic intestinal pseudo-obstruction (CIPO) is a severe gastrointestinal motility disorder that may be idiopathic or associated with systemic disease. In idiopathic cases, the pathophysiological mechanisms remain poorly defined. Although mutations in angiogenic factors have been reported in mitochondrial forms of CIPO, their role in non-mitochondrial cases is still unclear. OBJECTIVE:To investigate genetic and molecular contributors to CIPO, with a specific focus on intestinal microvasculature. METHODS:Jejunal samples from patients with CIPO were analysed by whole exome sequencing (WES) and mitochondrial DNA (mtDNA) profiling. Morphometric and immunohistochemical studies assessed collagen remodelling, vascular architecture, neuromuscular integrity and hypoxia. Expression of angiogenic factors, including thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF), was evaluated. RESULTS:WES did not identify known CIPO-causing variants, but rare mutations in collagen-related genes were detected in a subset of patients. Tissue analysis revealed higher fibrosis, vascular remodelling with a predominance of very small vessels, thinning of the longitudinal muscle and neuronal loss. TP and VEGF expression were significantly reduced, whereas hypoxia-inducible factor-1α (HIF-1α) was markedly upregulated. mtDNA integrity and copy number were preserved, whereas haplogroup J was overrepresented. Multivariate analysis linked these alterations to a higher frequency of sub-occlusive episodes. CONCLUSIONS:Vascular dysfunction and collagen abnormalities emerge as key contributors to neuromuscular degeneration in CIPO. These findings provide novel mechanistic insights into disease pathophysiology and support further exploration of vascular-targeted therapeutic strategies.

Chronic intestinal and colonic pseudo-obstruction (CIPO) represent a severe and heterogeneous group of gastrointestinal motility disorders with symptoms of bowel obstruction in the absence of a mechanical cause. Neurological and neuromuscular diseases are among the most important etiological factors, caused by dysfunction of the enteric nervous system, extrinsic autonomic pathways and intestinal smooth muscle. However, intestinal dysmotility in these conditions remains frequently under-recognized leading to delayed diagnosis and substantial morbidity.In this review, we detailed the CIPO-related spectrum of clinical presentations and highlighted features that may suggest an underlying neurogenic or neuromuscular substrate. A structured diagnostic approach is outlined, integrating imaging, physiological testing and targeted investigations to detect enteric neuro-muscular impairment. Also, we examined the main pathophysiological mechanisms linking neurological diseases to intestinal dysmotility, including enteric neuropathies, extrinsic autonomic dysfunction, mitochondrial disorders, visceral myopathies and mixed phenotypes. Particular emphasis was placed on immune-mediated enteric neuropathies, which are of special clinical relevance because they may be affected and potentially reversed via immunomodulatory therapy. Management requires a multidisciplinary approach combining nutritional support, pharmacological/interventional strategies and treatment of complications. Identification of gastrointestinal involvement in neurology-related CIPO is critical to better understand underlying mechanisms and improve management of this challenging condition.

Chronic intestinal pseudo-obstruction (CIPO) is characterized by bowel dilation and obstructive symptoms without any structural blockage. Although the microbiota is known to affect gastrointestinal function, its role in CIPO is poorly understood. We aimed to characterize the CIPO microbiota, investigate its role in disease expression and explore the therapeutic role of fecal microbiota transplantation (FMT). CIPO patients (n = 14) and healthy controls (HC, n = 12) were recruited from Italy and Canada. Microbiota profiles and functions were assessed by 16S rRNA sequencing and PICRUSt. Germ-free NIH Swiss mice were colonized with HC and CIPO microbiota, their intestinal transit and bowel distension were assessed by videofluoroscopy and computed tomography (CT), and the expression of host genes by NanoString®. The CIPO microbiota exhibited reduced microbial diversity with dominance of Proteobacteria and altered metabolic function. Mice with CIPO microbiota developed marked bowel distension and slow intestinal transit associated with altered expression of multiple genes related to immunity, the intestinal barrier and neuromuscular function. FMT from a HC improved the microbiota profile, intestinal transit and bowel distension in both CIPO mice and a selected CIPO patient, in whom a marked clinical improvement was sustained for 8 y. Thus, our findings support the use of microbiota-directed therapies to induce clinical improvement in CIPO patients.

Symptoms that can be attributed to the gastroduodenal area are classified into 5 categories: (1) functional dyspepsia, with 2 subcategories that can overlap: postprandial distress syndrome, with meal-induced symptoms of postprandial fullness or early satiation and epigastric pain syndrome, with epigastric pain or burning that does not occur exclusively postprandially; (2) nausea and vomiting disorders, which include 3 subcategories: chronic nausea vomiting syndrome; cyclic vomiting syndrome; and cannabinoid hyperemesis syndrome; (3) excessive belching disorders, defined as audible escapes of air from the esophagus or the stomach and classified into 2 subcategories depending on the origin of the refluxed gas: gastric or supragastric belching; (4) inability to belch syndrome, a new category defined by the self-reported inability to belch; and (5) rumination syndrome, defined by the repetitive, effortless regurgitation of recently ingested food into the mouth, followed by the reswallowing or expulsion of the food bolus.

BACKGROUND:Visceral myopathy (VSCM) is an ultra-rare life-threatening condition characterized by severe impairment of gastrointestinal (GI), genitourinary, and uterine smooth muscle. This disorder represents a significant clinical challenge due to variable presentation and the lack of standardized diagnostic and therapeutic protocols. METHODS:To discuss advances in the field, scientists and clinicians with a special interest in VSCM met in Arenzano, Genova, Italy in October 2024 for the second International Forum on Visceral Myopathy 2024 (IFVM2024) (https://ifvm2024.ge.ibf.cnr.it/). KEY RESULTS:As in the previous edition of the event (https://poic-e-dintorni.org/efvm-2022/), attendees included clinicians and researchers from around the world who study this disease, representatives from support organizations, patients affected by VSCM and their families, and companies that co-funded the event. The present manuscript aims to summarize knowledge shared during the IFVM2024 conference, thus providing an updated state-of-the-art summary of VSCM biology and disease management. CONCLUSIONS:Here, we pay particular attention to the epidemiology of the disease, histopathology, genetics, novel treatments, advances in molecular and cell biology, experimental models, and the lived experiences and impact of this disorder on families.

Background: Bicarbonate mineral waters have been reported to modulate biliary dynamics. Prior symptom based data with Aqua 3 suggested digestive benefits, but objective confirmation is still lacking. Aims: To evaluate, the effect of Aqua 3 on gallbladder motility in fasting healthy adults, compared with an oligomineral water. Methods: In this randomized, crossover study, twenty healthy volunteers underwent two ultrasound sessions after an overnight fast and the ingestion of 500 mL of either Aqua 3 (bicarbonate mineral water) or oligomineral water. Gallbladder volume was measured at baseline and after 10, 20, 30, and 60 minutes. Primary endpoint was the maximum ejection fraction. Results: Bicarbonate mineral water induced a rapid increase in ejection fraction: peaking at 10 minutes, persisting at 20 minutes and attenuating by 30 minutes. At 60 minutes, gallbladder refilling exceeded baseline. Oligomineral water produced only modest early emptying at 10 minutes, no significant change at 20 minutes, and progressive refilling thereafter. Throughout the observation period, ejection fraction was significantly higher after bicarbonate than oligomineral water. Maximum ejection fraction was significantly greater with bicarbonate than oligomineral water, occurring most frequently at 10 minutes for both waters. Conclusions: A single 500 mL dose of bicarbonate mineral water elicits a rapid and pronounced cholagogue response, with ejection fraction increases evident within 10 minutes that significantly exceed those observed after oligomineral water, providing a mechanistic rationale for the previously reported digestive benefits of bicarbonate mineral water. These findings may be clinically relevant for optimizing early postprandial digestion and mitigating biliary stasis in hypomotile gallbladders.

Irritable bowel syndrome (IBS) is a common disorder of gut–brain interaction, with a multifactorial pathophysiology involving gut–brain axis dysregulation, visceral hypersensitivity, microbiota imbalance, and immune dysfunction. Traditional IBS management emphasizes dietary modifications and pharmacologic therapies. However, increasing attention has been directed toward functional foods, nutraceuticals, and herbal remedies due to their potential to target IBS pathophysiological mechanisms with favorable safety profiles. This clinical review explores the role of these adjunctive therapies, evaluating evidence from preclinical and clinical studies. Functional foods such as kiwifruit, prunes, and rye bread demonstrate benefits in bowel habit regulation through fiber content and microbiota modulation. Nutraceuticals like peppermint oil, palmitoylethanolamide, and herbal mixtures exhibit anti-inflammatory, antispasmodic, and analgesic effects. Prebiotics provide substrate-driven microbiota changes, although dosage is key, as given their fermentative properties, when used at high dosages, they can exacerbate symptoms in some individuals. Probiotics and postbiotics offer microbiota-based interventions with promising symptom relief in IBS subtypes, although factors for personalized treatment still need to be further elucidated. These strategies highlight a paradigm shift in IBS management, integrating diet-based therapies with evolving nutraceutical options to improve patient outcomes. Despite promising findings, challenges in standardizing definitions, mechanisms, and safety profiles still remain. Rigorous, large-scale trials to validate the therapeutic potential of these interventions are needed, to enhance the benefits of these compounds with an individualized treatment approach.

Chronic kidney disease (CKD) may be associated with dysbiosis which may increase the risk of gastrointestinal infections. Patients with kidney failure have a predominance of bacteria responsible for the exacerbation of chronic inflammation through the production of ureases, uricase, and uremic toxins and a reduction of bacteria-producing protective molecules as short-chain fatty acids. Patients with CKD have an increased risk of Clostridioides difficile infection. Currently, besides antibiotic therapy, fecal microbiota transplantation (FMT) is the only effective gut microbiota-targeted therapy for treating this infection. Scant evidence is available on FMT in those receiving peritoneal dialysis (PD). In this case, we report a successful FMT performed by colonoscopy in a patient receiving PD for polycystic kidney disease suffering from recurrent Clostridioides difficile infections. The FMT was repeated to enhance microbiota engraftment. The role of FMT in treating Clostridioides difficile in individuals receiving PD may be an important and promising therapeutic strategy but requires further prospective study.

Bile acid diarrhea (BAD) is a common, under-investigated cause of chronic diarrhea. We aimed to assess the current management of BAD among a group of Italian physicians. A survey was developed by a task force of experts and distributed via the Internet to Italian physicians members of the main Italian gastroenterological associations. Ninety-four physicians accepted to participate, of whom 44% were females. The majority of participants were gastroenterologists (63%) and the mean age was 50.5 years. No differences in the rate of BAD diagnosis among patients with chronic diarrhea were found according to medical specialization. Gastroenterologists reported a higher prevalence of BAD compared with other physicians/general practitioners (1% vs 0.3%). BAD suspicion is mostly raised in the presence of watery stools and > 3 bowel movements/day and the exclusion of organic/drug-related diseases. BAD diagnosis was assessed with 75SeHCAT (67.8% of gastroenterologists and 51.4% of other physicians), followed by a trial of cholestyramine (30.5% of gastroenterologists and 31.4% of other physicians). Therapies most prescribed for BAD were cholestyramine, a low-fat diet, and stool thickeners. BAD is a common condition generally suspected in the presence of chronic watery diarrhea. 75SeHCAT availability influences the awareness of this disease. Therapies currently are often not able to guarantee adequate symptom relief.

Irritable Bowel Syndrome (IBS) is a disorder of gut- brain interaction characterized by recurrent abdominal pain associated with altered bowel habits. The therapeutic options for IBS patients include the use of probiotics. The aim of this study was to assess the effect of a multi-strain probiotic made up by Lactobacillus rhamnosus LR 32, Bifidobacterium lactis BL 04, and Bifidobacterium longum BB 536 (Serobioma, Bromatech s.r.l., Milano, Italy) on an in vitro model of the intestinal epithelial barrier in the presence of mucosal mediators that are released by IBS patients. IBS (n = 28; IBS with predominant diarrhea, IBS-D = 10; IBS with predominant constipation, IBS-C = 9; and IBS with mixed bowel habits, IBS-M = 9) patients, diagnosed according to the Rome IV criteria, and asymptomatic controls (ACs, n = 7) were enrolled. Mucosal mediators that were spontaneously released by colonic biopsies were collected (supernatants). Two doses of Serobioma were tested with/without IBS/AC mediators. RNA was extracted from Caco-2 cells to evaluate the tight junction (TJ) expression. Serobioma (106 CFU/mL) significantly reinforced the Caco-2 monolayer compared to growth medium alone (p < 0.05). IBS supernatants significantly increased Caco-2 paracellular permeability compared to the AC supernatants. The co-incubation of Caco-2 cells with IBS supernatants and Serobioma (106 CFU/mL) avoided the paracellular permeability alterations that were induced by IBS supernatants alone (p < 0.001), and, in particular, IBS-D and IBS-M ones. The co-incubation of Serobioma (106 CFU/mL) and IBS-D supernatants significantly increased ZO-1 expression compared to Caco-2 cells incubated with supernatants alone (p < 0.05), as confirmed via qPCR analyses. Serobioma (106 CFU/mL) counteracts the paracellular permeability changes that are induced by IBS supernatants, in particular IBS-D and IBS-M supernatants, likely modulating ZO-1 expression.

BACKGROUND:Dyspepsia is a common condition with a high prevalence in the general population. Patients in whom traditional diagnostic procedures can detect no identifiable explanation for the symptoms are diagnosed as being affected by functional dyspepsia (FD). To date, no etiological therapy for FD is available, and the current management includes general measures, acid-suppressive drugs, prokinetic agents, fundus-relaxing drugs, antidepressants, and psychological interventions. Recent evidence suggests that microbiota imbalance is involved in the development of FD. As a consequence, the modulation of microbiota through the use of probiotics could represent an effective therapeutic strategy. Moreover, Helicobacter pylori (HP) infection is a frequent cause of dyspepsia, and patients diagnosed with HP-associated dyspepsia are treated with HP eradication. In this regard, probiotics supplementation may also be helpful for HP infection to increase the eradication success rate as well as to reduce gastrointestinal adverse events caused by antibiotics. PURPOSE:This review of the literature aims to summarize and discuss the current evidence on the use of probiotics in the treatment of dyspepsia and as a supplement to HP eradication therapy.

Gastroesophageal reflux disease (GERD) is one of the most common conditions encountered in outpatient general medicine and gastroenterology clinics. However, uncertainties remain, particularly concerning the optimal diagnostic work-up and the most effective management. To address this issue, experts from 5 Italian Societies conducted a Delphi consensus process, which included a review of the current literature and voting process on 27 key statements. Recommendations and quality of evidence were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. Consensus for each statement was defined as ≥ 80 % agreement. Diagnostic Approach: The consensus supports a symptom-based diagnostic strategy for GERD, focusing on the exclusion of alarm symptoms and/or multiple risk factors for Barrett's esophagus or eosinophilic esophagitis (EoE) as well as non-GERD causes in cases of extra-esophageal symptoms. Esophago-gastro-duodenoscopy (EGD) is recommended in patients with alarm features or in patients unresponsive to proton pump inhibitors (PPIs). In addition, the consensus recommends esophageal pH-metry or impedance-pH recording in patients with reflux-like symptoms not responding to medical treatments, in those with extra-oesophageal symptoms, prior to anti-reflux endoscopic or surgical procedures, in patients with belching disorders and to diagnose functional heartburn (FH) and reflux hypersensitivity (RH) in PPI-refractory patients. Treatment Approach: The consensus strongly supports a standard 4-8 weeks course of PPIs for patients with heartburn and regurgitation but without alarm symptoms and an 8 weeks treatment for those with erosive oesophagitis. Twice daily dose PPIs is recommended only if a concomitant Barrett oesophagus is present, in patients with laryngopharyngeal reflux disease (LPRD) or when there is no response or an incomplete response to once daily dose. Bedtime histamine-2 receptor antagonists (H2RAs) as add-on therapy is suggested in patients with persistent nocturnal symptoms and in those with objective evidence of nocturnal acid reflux on pH monitoring despite PPI treatment, while prokinetic agents are advocated as add-on therapy in patients with concomitant symptoms suggestive of delayed gastric emptying. Moreover, the consensus voted for the use of potassium competitive acid blockers (P-CABs), antacids, alginate-containing formulations, neuromodulators in treating visceral hypersensitivity, complementary and alternative medicine and anti-reflux surgery in patients with refractory GERD. Finally, the consensus voted against surgical anti-reflux therapy in patients with extra-esophageal symptoms of GERD, who do not respond to PPI therapy and against the use of ensoscopic procedures [i.e., Medigus ultrasonic surgical endostapler (MUSE), radiofrequency energy application (Stretta), anti-reflux mucosectomy (ARMS)] outside clinical trials.

Irritable bowel syndrome (IBS) is a multifactorial condition with heterogeneous pathophysiology, including intestinal permeability alterations. The aim of the present study was to assess the ability of a probiotic blend (PB) consisting of two Lactiplantibacillus plantarum strains (CECT7484 and CECT7485) and one strain of Pediococcus acidilactici (CECT7483) to recover the permeability increase induced by mediators from IBS mucosal biopsies and to highlight the underlying molecular mechanisms. Twenty-one IBS patients diagnosed according to ROME IV criteria (11 IBS-D and 10 IBS-M) and 7 healthy controls were enrolled. Mucosal mediators spontaneously released by IBS and HC biopsies were collected and incubated with/without the PB (104 and 106 CFU/ml). Paracellular permeability was assessed by evaluating the amount of sulfonic-acid-conjugated to fluorescein passing through the Caco-2 monolayer. RNA was extracted from Caco-2 cells and used to perform qPCR analyses, to evaluate the expression of ZO-1 and β-actin, and RNAseq to evaluate the transcriptomic profile. Untargeted metabolomics was used to characterize metabolites produced by the PB. The PB significantly reduced paracellular permeability after 3 h of incubation. Both doses of the PB significantly recovered the increase in paracellular permeability induced by IBS mediators. qPCR analyses showed that both doses of the PB co-incubated with IBS mediators induced a significant increase in beta-actin expression compared to IBS mediators alone. Concerning IBS subtypes, the high dose of the PB recovered the increase of permeability induced by IBS-D mediators. Transcriptomic analyses, confirmed by qPCR, showed that the high dose of the PB significantly increased CYP1A1 compared to IBS mediators alone. The PB produced a high amount of indole-3-lactic acid. The PB recovers the permeability increase induced by IBS mediators inducing the up-regulation of β-actin. In addition, the PB up-regulates the expression of CYP1A1, known to be involved in the metabolism of xenobiotics, possibly through the production of the indole-3-lactic acid.

BACKGROUND:Exposure to COVID-19 has been shown previously to be associated with a higher risk for irritable bowel syndrome (IBS). This study aimed to better explain this relationship using mediation analysis. METHODS:This post hoc analysis of a multicenter cohort study includes 623 patients with and without COVID-19 infection. All participants completed the ROME IV criteria, gastrointestinal symptom rating scale (GSRS), and hospital anxiety and depression scale (HADS) over 1 year. Mediation analysis utilized the PROCESS macro and Baron and Kenny's method for parametric and nonparametric mediating variables, respectively. KEY RESULTS:The impact of COVID-19 on the development of post-COVID-19 IBS is completely mediated by dyspnea at baseline (adjusted OR = 3.561, p = 0.012), severity of acid regurgitation at 1 month [indirect effect, log-odds metric = 0.090, 95% CI (0.006-0.180)], hunger pains at 1 [indirect effect, log-odds metric = 0.094, 95% CI (0.024-0.178)], and 6 months [indirect effect, log-odds metric = 0.074, 95% CI (0.003-0.150)], depression at 6 [indirect effect, log-odds metric = 0.106, 95% CI (0.009-0.225)] and 12 months [indirect effect, log-odds metric = 0.146, 95% CI (0.016-0.311)] as well as borborygmus [indirect effect, log-odds metric = 0.095, 95% CI (0.009-0.203)], abdominal distention [indirect effect, log-odds metric = 0.162, 95% CI (0.047-0.303)], and increased flatus [indirect effect, log-odds metric = 0.110, 95% CI (0.005-0.234)] at 12 months. CONCLUSIONS AND INFERENCES:Our findings provide evidence for psychological and clinical mediators between COVID-19 and post-COVID-19 IBS, which may be promising targets for interventions tailored for treating or preventing depression. The presence of specific GI symptoms at COVID-19 onset and their persistence should increase awareness of a potential new onset of IBS diagnosis.

BACKGROUND:Functional dyspepsia (FD) and gastroesophageal reflux disease (GERD) frequently coexist. Studies suggest that patients with the Epigastric Pain Syndrome (EPS) subtype of FD have higher esophageal acid exposure and respond better to proton pump inhibitors (PPIs) than those with Postprandial Distress Syndrome (PDS). AIM:To evaluate multichannel intraluminal impedance-pH (MII-pH) monitoring findings in FD patients and assess potential overlap with GERD and esophageal disorders of gut-brain interaction (DGBI). METHODS:Patients fulfilling Rome IV criteria for EPS and PDS, both with and without suspected GERD overlap, underwent MII-pH monitoring. Parameters assessed included esophageal acid exposure time, reflux episodes (acid and non-acid), and symptom association probability. GERD was diagnosed using Lyon 2.0 criteria; esophageal DGBI were evaluated according to Rome IV. RESULTS:A total of 100 patients were included: 40 with FD (20 EPS, 20 PDS), 40 with FD and potential GERD overlap (20 EPS, 20 PDS), and 20 with conclusive GERD. Mean nocturnal baseline impedance (MNBI) declined progressively across groups, from PDS (2637.5 ohms) to GERD (828 ohms) (p < 0.01). Esophageal DGBI were more prevalent in PDS than EPS among patients with GERD symptoms (55 % vs 20 %, p = 0.02). CONCLUSIONS:EPS is more strongly associated with GERD, while PDS more frequently overlaps with esophageal DGBI.

Bile Acid Diarrhea (BAD) is a common cause of chronic diarrhea, often accompanied by urgency, occasional fecal incontinence, abdominal pain, and fatigue. A nationwide survey has shown limited awareness of BAD within the Italian medical community, prompting a panel of experts to develop a Position Paper that outlines the most practical and cost-saving diagnostic investigations and treatments for this frequently overlooked condition. The document provides an overview of the epidemiology, pathophysiology, clinical manifestations, and classification of the different types of Bile Acid Diarrhea (BAD). A key focus is the diagnostic approach to identifying and managing the many undiagnosed BAD patients in both primary care and specialized medical settings. Finally, the paper addresses the optimal therapeutic strategies for BAD, including traditional bile acid sequestrants and newer, promising treatments.