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Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable bowel syndrome (IBS) results from disordered brain���gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain���gut interactions underlying IBS.

Background During the peak of the COronaVIrus Disease 2019 (COVID‐19) pandemic, care for patients with gastrointestinal motility and functional disorders was largely suspended. In the recovery phases of the pandemic, non‐urgent medical care is resumed, but there is a lack of guidance for restarting and safely conducting motility and function testing. Breath tests and insertion of manometry and pH monitoring probes carry a risk for SARS‐CoV‐2 spread through droplet formation. Methods A panel of experts from the European Society for Neurogastroenterology and Motility (ESNM) evaluated emerging national and single center recommendations to provide the best current evidence and a pragmatic approach to ensure the safe conduct of motility and function testing for both healthcare professionals and patients. Results At a general level, this involves evaluation of the urgency of the procedure, evaluation of the infectious risk associated with the patient, the investigation and the health care professional(s) involved, provision of the test planning and test units, education and training of staff and use of personnel protection equipment. Additional guidance is provided for specific procedures such as esophageal manometry, pH monitoring and breath tests. Conclusions and Inferences The ESNM guidelines provide pragmatic and appropriate guidance for the safe conduct of motility and function testing in the COVID‐19 pandemic and early recovery phase.

It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.

INTRODUCTION: Gastrointestinal (GI) symptoms in coronavirus-19 disease (COVID-19) have been reported with great variability and without standardization. In hospitalized patients, we aimed to evaluate the prevalence of GI symptoms, factors associated with their occurrence, and variation at 1 month. METHODS: The GI-COVID-19 is a prospective, multicenter, controlled study. Patients with and without COVID-19 diagnosis were recruited at hospital admission and asked for GI symptoms at admission and after 1 month, using the validated Gastrointestinal Symptom Rating Scale questionnaire. RESULTS: The study included 2036 hospitalized patients. A total of 871 patients (575 COVID+ and 296 COVID-) were included for the primary analysis. GI symptoms occurred more frequently in patients with COVID-19 (59.7%; 343/575 patients) than in the control group (43.2%; 128/296 patients) (P < 0.001). Patients with COVID-19 complained of higher presence or intensity of nausea, diarrhea, loose stools, and urgency as compared with controls. At a 1-month follow-up, a reduction in the presence or intensity of GI symptoms was found in COVID-19 patients with GI symptoms at hospital admission. Nausea remained increased over controls. Factors significantly associated with nausea persistence in COVID-19 were female sex, high body mass index, the presence of dyspnea, and increased C-reactive protein levels. DISCUSSION: The prevalence of GI symptoms in hospitalized patients with COVID-19 is higher than previously reported. Systemic and respiratory symptoms are often associated with GI complaints. Nausea may persist after the resolution of COVID-19 infection., Fondazione Cassa di Risparmio in Bologna; Italian Ministry of Education, University and Research; Fondazione del Monte di Bologna e Ravenna [SC1-BHC-01-2019]; European Grant H2020, DISCOvERIE [SC1-BHC-01-2019]; Italian Ministry of Health [Ricerca Finalizzata GR-2018-12367062], G.B. contribution to this research was permitted in part by funding from Fondazione Cassa di Risparmio in Bologna; the ItalianMinistry of Education, University and Research; and Fondazione del Monte di Bologna e Ravenna and European Grant H2020, DISCOvERIE, SC1-BHC-01-2019. M.R.B. is a recipient of a grant from the Italian Ministry of Health (Ricerca Finalizzata GR-2018-12367062). None of the funding organizations have had any role in the design and conduct of the study; in the collection, management, and analysis of the data; or in the preparation, review, and approval of the article.

Background Coronavirus disease 2019 (COVID‐19) is associated with gastrointestinal and hepatic manifestation in up to one fifth of patients. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the etiologic agent of COVID‐19, infects gastrointestinal epithelial cells expressing angiotensin‐converting enzyme 2 (ACE2) receptors triggering a cascade of events leading to mucosal and systemic inflammation. Symptomatic patients display changes in gut microbiota composition and function which may contribute to intestinal barrier dysfunction and immune activation. Evidence suggests that SARS‐CoV‐2 infection and related mucosal inflammation impact on the function of the enteric nervous system and the activation of sensory fibers conveying information to the central nervous system, which, may at least in part, contribute symptom generation such as vomiting and diarrhea described in COVID‐19. Liver and pancreas dysfunctions have also been described as non‐respiratory complications of COVID‐19 and add further emphasis to the common view of SARS‐CoV‐2 infection as a systemic disease with multiorgan involvement. Purpose The aim of this review was to highlight the current knowledge on the pathophysiology of gastrointestinal SARS‐CoV‐2 infection, including the crosstalk with the gut microbiota, the fecal‐oral route of virus transmission, and the potential interaction of the virus with the enteric nervous system. We also review the current available data on gastrointestinal and liver manifestations, management, and outcomes of patients with COVID‐19., SARS‐CoV‐2 infects the gastrointestinal tract leading to a cascade of events including dysbiosis, enterocyte damage and inflammation, immune dysregulation, and enteric nervous system dysfunction possibly involved in GI symptom development.

Background: Clinical features and lifestyle factors associated with diverticulosis compared to diverticular disease (DD), either symptomatic uncomplicated diverticular disease (SUDD) or in patients who have had previous diverticulitis (PD), are unclear. Objective: The objective of this article is to compare cross-sectionally demographic and clinical features and quality of life (QoL) in diverticulosis, SUDD and PD patients. Methods: The REMAD Registry is a prospective, observational, multicentre, cohort study. Patients were categorised according to: diverticulosis; SUDD (recurrent abdominal symptoms attributed to diverticula in absence of overt inflammation) and PD (≥1 previous diverticulitis). Results: A total of 1217 patients (57.9% diverticulosis, 24.7% SUDD and 17.4% PD) were included. Compared to diverticulosis, female gender was associated to SUDD (OR 1.94; 95% CI: 1.43–2.62) and PD (OR 1.79; 95% CI: 1.24–2.56); age ≤ 60 years was associated to PD (OR 2.10; 95% CI: 1.42–3.08 vs diverticulosis, OR 1.57; 95% CI: 1.01–2.45 vs SUDD). PD patients showed an association with past bleeding (OR 29.29; 95% CI: 8.17–104.98 vs diverticulosis, OR 16.84; 95% CI: 3.77–75.25 vs SUDD). Compared to diverticulosis, family history for diverticula was associated to PD (OR 1.88; 95% CI: 1.27–2.78). Patients with diverticulosis showed higher QoL scores, both physical (p = 0.0001 and 0.0257) and mental (p < 0.0001 and 0.0038), in comparison to SUDD and PD. Conclusion: Family history for diverticula and history of bleeding distinguish diverticulosis from DD. These clinical features should be kept in mind in the management of DD.

Background: Effective management of irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, can be challenging for physicians because of the lack of simple diagnostic tests and the wide variety of treatment approaches available. Objective: The objective of this article is to outline a simple algorithm for day-to-day clinical practice to help physicians navigate key stages to reaching a positive IBS diagnosis and guidance on how to prioritise the use of specific management strategies. Methods: This algorithm was based on the opinion of an expert panel evaluating current evidence. Results: The key principles forming the foundation of this evidence-supported algorithm are: confidently naming and explaining an IBS diagnosis for the patient, followed by assessment of key patient characteristics likely to influence the choice of therapy, such as predominant symptoms, and exploring the patient agenda and preferences. Consultation should always include education and reassurance with an explanatory model of IBS tailored to the patient. Individualised lifestyle changes, dietary modifications, pharmacological therapies, psychological strategies or a combination of interventions may be used to optimise treatment for each patient. Conclusion: The simple visual tools developed here navigate the key stages to reaching a positive diagnosis of IBS, and provide a stepwise approach to patient-centred management targeted towards the most bothersome symptoms. Establishing a strong patient-physician relationship is central to all stages of the patient journey from diagnosis to effective management.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca2+ imaging of dorsal root ganglion (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)-positive DRG neurons through a phospholipase C (PLC)- and pertussis toxin-dependent mechanism, suggesting that the effect was mediated by a G protein-coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C. ispartof: SCIENCE SIGNALING vol:11 issue:561 ispartof: location:United States status: published

none 13 no Published Online First: 12 September 2016 OBJECTIVE: The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. DESIGN: Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance. RESULTS: Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. CONCLUSIONS: Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease. Barbara, Giovanni; Scaioli, Eleonora; Barbaro, Maria Raffaella; Biagi, Elena; Laghi, Luca; Cremon, Cesare; Marasco, Giovanni; Colecchia, Antonio; Picone, Gianfranco; Salfi, Nunzio; Capozzi, Francesco; Brigidi, Patrizia; Festi, Davide Barbara, Giovanni; Scaioli, Eleonora; Barbaro, Maria Raffaella; Biagi, Elena; Laghi, Luca; Cremon, Cesare; Marasco, Giovanni; Colecchia, Antonio; Picone, Gianfranco; Salfi, Nunzio; Capozzi, Francesco; Brigidi, Patrizia; Festi, Davide

Background: Colonic diverticulosis is a common condition in industrialized countries. Up to 25% of patients with diverticula develop symptoms, a condition termed symptomatic uncomplicated diverticular disease (SUDD). The aim of the present study was to characterize neuroimmune interactions and nerve fiber plasticity in the colonic mucosa of patients with diverticula. Methods: Controls, patients with diverticulosis and with SUDD were enrolled in the study. Mucosal biopsies were obtained close to diverticula (diverticular region) and in a normal mucosa (distant site), corresponding to sigmoid and descending colon in the controls. Quantitative immunohistochemistry was used to assess mast cells, T cells, macrophages, nerve fibers, and neuronal outgrowth (growth-associated protein 43, GAP43+fibers). Key Results: No difference emerged in mast cells and T cells among the three groups. Macrophages were increased in patients with SUDD and diverticulosis as compared to controls. Nerve fibers were enhanced in patients with SUDD and diverticulosis in comparison with controls in the diverticular region. GAP43+fibers were increased only in patients with SUDD as compared to controls and to patients with diverticulosis in the diverticular region. In patients with SUDD, GAP43 density was increased in the diverticular region compared to distant site. Macrophages close to GAP43+ fibers were increased in the diverticular region of patients with SUDD. Significant correlations were found between GAP43+ fibers and immune cells. Conclusions and Inferences: Patients with diverticula are characterized by increased macrophage counts, while nerve fiber sprouting is increased only in the diverticular region of patients with SUDD suggesting a role in symptom generation.

The dynamic relationship between gut microbiota and its human host is also known as a trophic association that might range from commensalism, where only the microbe enjoys a positive effect from the relationship, to intestinal symbiosis where both host and microbe benefit from their interaction. In the last years, we have started to understand how alterations of the gut microbiota composition leading to the disruption of host-microbial interactions are associated and/or predispose individuals to disease conditions ranging from inflammatory bowel diseases to allergy and functional gastrointestinal disorders, such as irritable bowel syndrome. While we await important insights in this field, the microbiota is already a therapeutic target. Based on the actual definitions, prebiotics are defined as substrates that are selectively utilized by host microorganisms conferring a health benefit, while probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Although their health promoting activities encompasses numerous effects, including immunostimulation, competitive exclusion of pathogens, and gut barrier enhancement, the exact mechanism of action by which these compounds exert their beneficial actions in humans is only partially known. In this review, we highlight the current insights into the clinical applications of prebiotics and probiotics in gastroenterology.

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS. ispartof: GASTROENTEROLOGY vol:155 issue:1 pages:168-179 ispartof: location:United States status: published

The European Commission actively supports research in the health sector, with the ultimate goal of achieving better health for everyone. Between 2007 and 2013, funding was granted under theEU Seventh Framework Programme for Research and Technological Development (FP7, 2007–13) and is currently continued under Horizon 2020(H2020, 2014–20). Projects funded by the European Commissioncover different areas of frontier and collaborative research. The main topics supported, ranked by funding received, have been brain disorders, cancer, cardiovascular diseases, diabetes, obesity, and other chronic diseases. Within FP7, the funding for other chronic diseases focused on non-lethal diseases with a large impact on quality of life at old age, and on translational projects.1 Within H2020, the allocated budget has shifted towards societal challenges and includes broader topics. We aimed to assess research funding for common digestive diseases within FP7 and H2020, and put this into perspective with regard to disease prevalence and the burden of these diseases in terms of total health-care need and quality of life. We examined project abstracts in the European Commission database published between 2007 and 2017, to identify projects relating to gastrointestinal diseases.

Diverticulosis is a common anatomical condition, which appears to be age-dependent. Individuals who develop chronic gastrointestinal symptoms or complications are referred to as having diverticular disease. Although the diagnosis of this condition can be relatively straightforward, randomized controlled trials are scarce and management often follows tradition rather than principles of evidence-based medicine. This report deals with the topics discussed during a symposium held during the United European Gastroenterology Week (Barcelona, October 2017). During the meeting, the role of dysbiosis in the pathogenesis of diverticular disease and its treatment were thoroughly discussed, by examining the efficacy and mechanisms of action of the currently used drugs. Recent studies have shown the presence of dysbiosis in patients with diverticular disease and suggest an imbalance in favor of bacteria with pro-inflammatory and pathogenetic potential. These microbiota changes correlate with mucosal immune activation, mirrored by a marked increase of macrophages in colonic mucosa, both in the diverticular region and at distant sites. The low-grade inflammation, driven by bacteria-induced immune activation, could be involved in the pathophysiology of symptoms. As a consequence, pharmacological approaches targeting enteric bacteria (with poorly absorbed antibiotics, like rifaximin, or probiotics) or intestinal inflammation (with 5-ASA derivatives or rifaximin) have shown capability of controlling symptoms and also preventing complications, albeit more research is needed to establish the optimal regimen (daily dose and duration) of therapy. Well-designed randomized-controlled trials (RCTs), including homogeneous populations of patients, are therefore needed. The future of management of many GI diseases, including symptomatic uncomplicated diverticular disease, will rely on the so-called ‘microbiota-directed therapies’.

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches. Areas covered: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA. Expert opinion: The new 5-HT3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.

BACKGROUND: Gastrointestinal infection is an important risk factor for developing irritable bowel syndrome (IBS). Our aim was to characterise post-infectious IBS (PI-IBS) compared to other IBS patients. METHODS: An internet survey of IBS patients using Rome III diagnostic questionnaire, Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire-12 Somatic Symptom (PHQ12-SS) scale score documenting the mode of onset was conducted. RESULTS: A total of 7811 participants (63.2% female), of whom 1004 (13.3%) met criteria for PI-IBS, were studied. Seventy per cent of PI-IBS patients described sudden onset, 35% onset while travelling, 49.6% vomiting, 49.9% fever and 20.3% bloody diarrhoea. Compared to other IBS individuals, PI-IBS was significantly associated with living in Northern Europe and North America, having a hysterectomy, not having an appendicectomy, higher PHQ12-SS score and having more than one toilet in the family home. PI-IBS patients had more frequent stools. At one year recovery rate in the PI-IBS and non-PI-IBS group was 19.7% and 22.2%, p = 0.15. Recovery rates were lower for females (20.7%) vs males (38.8%), those with somatisation (23.0%) vs those without (33.2%) and those living in North America or Northern Europe (21.1%) vs living elsewhere (33.9%) p ≤ 0.001. CONCLUSION: PI-IBS accounts for around 13% of all IBS in this internet sample, with some distinctive features but a similar prognosis to the remainder. ispartof: UNITED EUROPEAN GASTROENTEROLOGY JOURNAL vol:6 issue:8 pages:1245-1253 ispartof: location:England status: published

none 9 no Objective: To test the hypothesis that allergic proctocolitis, a cause of self-limiting rectal bleeding in infants, can predispose to the development of functional gastrointestinal disorders (FGIDs) later in childhood. Study design: We studied a cohort of 80 consecutive patients diagnosed with allergic proctocolitis. Their sibling or matched children presenting to the same hospital for minor trauma served as controls. Parents of the patients with allergic proctocolitis and controls participated in a telephone interview every 12 months until the child was at least 4 years old. At that time, they were asked to complete the parental Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III version. Results: Sixteen of the 160 subjects (10.0%) included in the study met the Rome III criteria for FGIDs. Among the 80 patients with allergic proctocolitis, 12 (15.0%) reported FGIDs, compared with 4 of 80 (5.0%) controls (P = .035). After adjustment for age and sex, the OR for FGIDs in allergic proctocolitis group was 4.39 (95% CI, 1.03-18.68). FGIDs were significantly associated with iron deficiency anemia, duration of hematochezia, and younger age at presentation. In a multivariate analysis, only the duration of hematochezia was significantly associated with the development of FGIDs (OR, 3.14; 95% CI,1.72-5.74). Conclusions: We have identified allergic proctocolitis as a new risk factor for the development of FGIDs in children. Our data suggest that not only infection, but also a transient early-life allergic inflammatory trigger may induce persistent digestive symptoms, supporting the existence of "postinflammatory" FGIDs. open Di Nardo, Giovanni; Cremon, Cesare; Frediani, Simone; Lucarelli, Sandra; Villa, Maria Pia; Stanghellini, Vincenzo; La Torre, Giuseppe; Martemucci, Luigi; Barbara, Giovanni* Di Nardo, Giovanni; Cremon, Cesare; Frediani, Simone; Lucarelli, Sandra; Villa, Maria Pia; Stanghellini, Vincenzo; La Torre, Giuseppe; Martemucci, Luigi; Barbara, Giovanni*

We have only recently begun to understand how alterations of the intestinal microbial ecosystem lead to the disruption of host-microbial interactions and are associated with diseases, including functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Although we are still far from understanding the human microbiome, gut microbiota is already a therapeutic target. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host and may represent a therapeutic option for diseases characterized by dysbiosis such as IBS. Meta-analyses suggest that probiotics provide a therapeutic gain over placebo on global symptoms with a high safety profile in IBS patients. However, the mechanisms by which they provide benefit in IBS remain virtually unknown. In this issue of Neurogastroenterology and Motility, BIO-25, a multispecies probiotic, did not significantly modify the composition of the fecal microbiota, but interestingly, patients with specific basal features of the intestinal microbial ecosystem improved with treatment. Based on these data, it is tantalizing to speculate that microbiota composition serves as a predictor of the response to probiotic intervention. This mini-review addresses unresolved issues related to mechanisms through which probiotics may exert their beneficial effects, the biological, as well as clinical predictors of favorable outcomes in IBS and finally considers possible new directions for future studies.

Digestive diseases are a broad range of chronic disorders that substantially and negatively impact the patients' quality of life. Here, we review our current understanding on the pathophysiology of hepatic encephalopathy, irritable bowel syndrome, and diverticular disease, with a special focus on the gut microbiota composition associated with these disorders. Furthermore, we review the current clinical practice for their therapeutic treatments, including probiotics, diet change, non-adsorbable disaccharides, and antibiotics. We highlight that broad-spectrum non-adsorbable antibiotics, such as rifaximin, are quite effective and safe for the treatment of all essayed digestive diseases.

Non-celiac gluten sensitivity (NCGS) is a condition characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing foods in the absence of celiac disease and wheat allergy. The diagnosis is cumbersome and currently confirmed only by gluten withdrawal and double-blind placebo challenge protocols. There is great overlap in symptoms between NCGS and other functional gastrointestinal disorders, making a differential diagnosis difficult. The pathophysiology of NCGS is largely unclear, and there are contrasting data on the trigger of this condition. This review will highlight the state-of-the-art knowledge on NCGS and the key open questions.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC). ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:16 issue:10 pages:1673-1676 ispartof: location:United States status: published

ObjectiveIBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS.DesignWe sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population.ResultsCSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (pConclusionsSI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Colonic diverticulosis is a common condition in Western industrialized countries occurring in up to 65% of people over the age of 60 years. Only a minority of these subjects (about 10-25%) experience symptoms, fulfilling Rome III Diagnostic Criteria for irritable bowel syndrome (IBS) diagnosis (IBS-like symptoms) in 10% to 66% of cases. Symptomatic uncomplicated diverticular disease (SUDD) is a syndrome characterized by recurrent abdominal symptoms attributed to diverticula in the absence of macroscopically evident alterations other than the presence of diverticula. Due to the different peak of incidence, the overlap between SUDD and IBS is predominantly present in middle-aged or older patients. In these cases, it is very complex to establish if the symptoms are related to the presence of diverticula or due to an overlapping IBS. In fact, the link between gastrointestinal symptoms and diverticula is unclear, and the mechanism by which diverticula may induce the development of IBS-like symptoms remains to be elucidated. Currently, the etiology and pathophysiology of SUDD, particularly when IBS-like symptoms are present, are not completely understood, and thus these two entities remain a diagnostic challenge not only for the general practitioner but also for the gastroenterologist. Although many issues remain open and unresolved, some minimize the importance of a distinction of these two entities as dietary and pharmacological management may be largely overlapping.

Background & Aims Acute infectious gastroenteritis increases the risk for irritable bowel syndrome (IBS) and functional dyspepsia (FD). Children are particularly vulnerable to gastroenteritis because of the immaturity of their intestinal barrier, enteric nervous system, and immune response to pathogens. We investigated whether acute gastroenteritis in early life increases the risk of IBS and FD throughout adulthood. Methods In 1994, we identified and monitored a single culture-proven foodborne Salmonella enteritidis outbreak that involved 1811 patients (mostly pediatric) in Bologna, Italy. Clinical data were collected and a prospective, controlled, cohort study was designed. Long-term effects were assessed by mailing a questionnaire to 757 subjects 16 years after the outbreak (when all of the children were adults). We randomly selected a cohort of 250 adults exposed to Salmonella as children, all 127 individuals exposed as adults, and a cohort of nonexposed participants matched for number, age, sex, and area of residence (controls). Results Among 198 exposed participants, 64 reported FD (32.3%), compared with 51 of 188 controls (27.1%; P = .268). Among 204 exposed participants, 75 reported having IBS (36.8%) compared with 44 of 189 controls (23.3%; P = .004). The odds ratio for IBS among people exposed to the Salmonella was 1.92 (95% confidence interval: 1.23–2.98). The prevalence of IBS was higher in individuals exposed Salmonella as children than in controls (35.3% vs 20.5%; P = .008), but not in individuals exposed as adults, compared with controls. After multivariate logistic regression, post-infectious IBS was independently associated with anxiety and FD. Conclusions Based on data collected from a single culture-proven foodborne Salmonella enteritidis outbreak in 1994, Salmonella -induced gastroenteritis during childhood (but not adulthood) is a risk factor for IBS.

BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P

Colonic diverticulosis is an increasingly common condition in Western industrialized countries. About 20% of patients develop symptoms, including abdominal pain, bloating, changes in bowel habits, and, eventually, diverticulitis or other complications. The management of symptomatic uncomplicated diverticular disease (SUDD) and the prevention of acute diverticulitis remains a challenge for the clinician. The rationale for the use of aminosalicylates, such as mesalazine, is based on the assumption of low-grade inflammation in SUDD and symptoms generation, whereas an overt inflammation may induce diverticulitis in patients with diverticular disease. Clinical scenarios in which the efficacy and safety of mesalazine have been studied include SUDD, prevention of diverticulitis, and of recurrent diverticulitis. Data from uncontrolled studies suggest a benefit of mesalazine on patients with SUDD, whereas data from randomized controlled trials showed some evidence of improvement of symptoms, although contrasting results are reported. The largest study so far published on the efficacy of mesalamine in the prevention of recurrence of diverticulitis showed that mesalamine was not superior to placebo. At this time, the role of mesalazine in the prevention of acute diverticulitis remains to be defined with many issues open and unresolved.

Objective: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. Design: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. Results: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. Conclusions: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. Trial registration number: ClincialTrials.gov number, NCT00626288.

Ulcerative colitis (UC) is associated with a substantial alteration of specific gut commensals, some of which may be involved in microbiota-mediated protection. In this study, microbiota cataloging of UC patients by 16S rRNA microbial profiling revealed a marked reduction of bifidobacteria, in particular the Bifidobacterium bifidum species, thus suggesting that this taxon plays a biological role in the aetiology of UC. We investigated this further through an in vivo trial by testing the effects of oral treatment with B. bifidum PRL2010 in a wild-type murine colitis model. TNBS-treated mice receiving 10(9) cells of B. bifidum PRL2010 showed a marked reduction of all colitis-associated histological indices as well as maintenance of mucosal integrity as it was shown by the increase in the expression of many tight junction-encoding genes. The protective role of B. bifidum PRL2010, as well as its sortase-dependent pili, appears to be established through the induction of an innate immune response of the host. These results highlight the importance of B. bifidum as a microbial biomarker for UC, revealing its role in protection against experimentally induced colitis.

For decades, interactions between the enteric neuromuscular apparatus and the central nervous system have served as the primary focus of pathophysiological research in the functional gastrointestinal disorders. The accumulation of patient reports, as well as clinical observations, has belatedly led to an interest in the role of various luminal factors and their interactions with each other and the host in functional gastrointestinal disorders. Most prominent among these factors has been the role of food. As a consequence, although not always evidence-based, dietary interventions are enjoying a renaissance in irritable bowel syndrome management. Not surprisingly, given its exploration in many disease states, the gut microbiota has also been studied in functional gastrointestinal disorders; data remain inconclusive. Likewise, there is also a considerable body of experimental and some clinical data to link the pathogenesis of functional gastrointestinal disorders to disturbances in epithelial barrier integrity, abnormal enteroendocrine signaling, and immune activation. These data provide growing evidence supporting the existence of micro-organic changes, particularly in subgroups of patients with functional dyspepsia and irritable bowel syndrome. However, their exact role in the complex pathophysiology and symptom generation of functional gastrointestinal disorders needs to be further studied and elucidated, particularly with longitudinal and interventional studies.

Objectives The purpose of this study was to compare conventional 2-dimensional (2D) B-mode sonography with 3-dimensional (3D) sonography for assessing gallbladder volume and contractility. Methods Gallbladder volume and contractility were evaluated in 32 healthy volunteers after fasting and abstinence from smoking for 8 hours and after a standardized balanced liquid meal. The gallbladder was evaluated with 2D sonography (with the use of the ellipsoid method) and with 3D sonography using a volumetric matrix probe. Both measurements were made by an operator who was skilled in sonography and an unskilled operator. The group of volunteers was subdivided into 2 subgroups including 16 participants, which represented the “2 moments” of acquisition by the techniques, particularly for the unskilled operator. Results The postprandial volumes obtained with 3D sonography were significantly lower in comparison to the volumes obtained with 2D sonography (P= .013), and there was a significant difference between the measurements made by the skilled and unskilled operators only for 2D sonography (P< .001), whereas between the 2 moments of acquisition by the 3D technique, there was no significant difference. The reproducibility of the technique for evaluation of gallbladder volumes was higher for 3D sonography than 2D sonography, particularly for the postprandial evaluation. Conclusions The new 3D sonographic method using a volumetric matrix probe is a simple, reliable, and more reproducible technique than conventional 2D sonography, even if performed by an unskilled operator, and it allows a reliable stimulation test for a gallbladder dynamic study.

Mucosal immune activation and altered serotonin metabolism participate in the pathophysiology of irritable bowel syndrome (IBS). However, the reciprocal interplay between these two systems remains unknown. We evaluated the expression and release of interferon (IFN)-γ from the colonic mucosa of patients with IBS and its impact on serotonin reuptake transporter ( SERT) gene expression in Caco-2 cells. qPCR was used to evaluate IFN-γ gene expression in colonic mucosal biopsies, whereas IFN-γ protein amount was assessed by ELISA. Colonic T box expressed in T cells (T-bet) and phosphorylated signal transducer and activator of transcription 4 protein amount were evaluated by Western blot. The impact of colonic mucosal mediators on SERT gene expression was evaluated in Caco-2 cells using qPCR. IFN-γ receptor was silenced in Caco-2 cells to determine the effect of IFN-γ released by mucosal biopsies. Compared with asymptomatic controls (ACs), the expression of IFN-γ gene and its transcription factor T-bet were markedly increased in the colonic mucosa of patients with IBS. Compared with ACs, IFN-γ protein tissue levels and its release by mucosal biopsies were significantly increased in IBS. The exposure of Caco-2 cells to IBS supernatants induced a significant decrease in SERT gene expression, independently of IBS subtypes, compared with AC mucosal supernatants. In Caco-2 cells, IFN-γ receptor silencing reversed the reduction of SERT expression evoked by IBS supernatants vs. nonsilenced cell lines. IFN-γ gene, its transcription factor T-bet, IFN-γ protein expression, and its release are increased in the colonic mucosa of patients with IBS and downregulate SERT gene expression in vitro. These results suggest that IFN-γ downregulates SERT expression, hence likely playing a role in altered serotonin metabolism of patients with IBS.

Background & Aims In mice, activation of the transient receptor potential cation channels (TRP) TRPV1, TRPV4, and TRPA1 causes visceral hypersensitivity. These receptors and their agonists might be involved in development of irritable bowel syndrome (IBS). We investigated whether polyunsaturated fatty acid (PUFA) metabolites, which activate TRPs, are present in colon tissues from patients with IBS and act as endogenous agonists to induce hypersensitivity. Methods We analyzed colon biopsy samples from 40 patients with IBS (IBS biopsies) and 11 healthy individuals undergoing colorectal cancer screening (controls), collected during colonoscopy at the University of Bologna, Italy. Levels of the PUFA metabolites that activate TRPV1 (12-hydroperoxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, 5-hydroxyeicosatetraenoic acid, and leukotriene B4), TRPV4 (5,6-epoxyeicosatrienoic acid [EET] and 8,9-EET), and TRPA1 (PGA 1 , 8-iso-prostaglandin A 2 , and 15-deoxy-Δ-prostaglandin J 2 ) were measured in biopsies and their supernatants using liquid chromatography and tandem mass spectrometry; we also measured levels of the PUFA metabolites prostaglandin E 2 (PGE 2 ) and resolvins. C57Bl6 mice were given intrathecal injections of small interfering RNAs to reduce levels of TRPV4, or control small interfering RNAs, along with colonic injections of biopsy supernatants; visceral hypersensitivity was measured based on response to colorectal distension. Mouse sensory neurons were cultured and incubated with biopsy supernatants and lipids extracted from biopsies or colons of mice. Immunohistochemistry was used to detect TRPV4 in human dorsal root ganglia samples (from the National Disease Research Interchange). Results Levels of the TRPV4 agonist 5,6-EET, but not levels of TRPV1 or TRPA1 agonists, were increased in IBS biopsies compared with controls; increases correlated with pain and bloating scores. Supernatants from IBS biopsies, but not from controls, induced visceral hypersensitivity in mice. Small interfering RNA knockdown of TRPV4 in mouse primary afferent neurons inhibited the hypersensitivity caused by supernatants from IBS biopsies. Levels of 5,6-EET and 15-HETE were increased in colons of mice with, but not without, visceral hypersensitivity. PUFA metabolites extracted from IBS biopsies or colons of mice with visceral hypersensitivity activated mouse sensory neurons in vitro, by activating TRPV4. Mouse sensory neurons exposed to supernatants from IBS biopsies produced 5,6-EET via a mechanism that involved the proteinase-activated receptor-2 and cytochrome epoxygenase. In human dorsal root ganglia, TPV4 was expressed by 35% of neurons. Conclusions Colon tissues from patients with IBS have increased levels of specific PUFA metabolites. These stimulate sensory neurons from mice and generate visceral hypersensitivity via activation of TRPV4.

Mediators released by the intestinal mucosa of patients with irritable bowel syndrome (IBS) affect the function of enteric and extrinsic sensory nerves, which can contribute to the development of symptoms. Little is known about the effects of mucosal mediators on intestinal neuroplasticity. We investigated how these mediators affect the phenotypes of colonic mucosa nerve fibers, neuron differentiation, and fiber outgrowth.We analyzed mucosal biopsy samples collected from 101 patients with IBS and 23 asymptomatic healthy individuals (controls). We measured levels of neuronal-specific enolase, growth-associated protein 43, nerve growth factor (NGF), and tyrosine kinase receptor A (NTRK1) by immunohistochemistry and enzyme-linked immunosorbent assay. Primary rat enteric neurons and human SH-SY5Y cells were incubated with supernatants from the mucosal biopsies and analyzed by morphometric and polymerase chain reaction analyses.Compared with mucosal tissues of controls, mucosa from patients with IBS had a significant increase in the area of lamina propria occupied by neuronal-specific enolase-positive (57.7% increase) and growth-associated protein 43-positive fibers (56.1% increase) and staining density of NGF (89.3% increase) (P.05 for all). Levels of NGF protein were also increased in tissues from patients with IBS vs controls (18% increase; P = .16) along with levels of NTRK1 (64% increase; P.05). Mucosal supernatants from tissues of patients with IBS induced higher levels of neuritogenesis in primary culture of enteric neurons, compared with controls, and more NGF-dependent neuronal sprouting in SH-SY5Y cells.Nerve fiber density and sprouting, as well as expression of NGF and NTRK1, are significantly increased in mucosal tissues of patients with IBS. Mucosal mediators participate to these neuroplastic changes.

Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinal permeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention. Electronic supplementary material The online version of this article (doi:10.1186/s12876-014-0189-7) contains supplementary material, which is available to authorized users.

While drug development for chronic constipation and IBS with constipation has moved ahead with the marketing of prucalopride and linaclotide in many countries, the development of agents for functional diarrhoea and IBS-D has been more troubled. With the limited availability of the serotonin (5-HT)3 antagonist alosetron, the global market of drugs for diarrhoeal disorders is still led by agents developed 40–60 years ago, including opioid receptor agonists (eg, loperamide), bile acid binders (eg, cholestyramine) and tricyclic antidepressants (eg, amitriptyline). Clearly, the development of new effective and safe drugs for diarrhoeal disorders is greatly needed to provide more options for patients and physicians, higher efficacy and fewer side effects. The problem is of great relevance as diarrhoea is the second leading gastrointestinal symptom after abdominal pain prompting an outpatient clinic visit in the USA. IBS-D affects about 3% of the general population and accounts for approximately 20% of gastroenterology outpatient visits in Europe.1 ,2 The understanding of basic mechanisms underlying IBS-D pathophysiology advanced enormously in recent years. Appreciation of the importance of host–microbiota interactions, epithelial barrier alterations, low-grade immune activation and 5-HT metabolism together with the revival of bile acid malabsorption provides cautious enthusiasm for future drug development for functional diarrhoeal disorders.3 Basic and clinical aspects of the pharmacological modulation of 5-HT receptors continue to generate great interest among scientists and the pharmaceutical industry alike. A meta-analysis of 4440 patients showed the benefit of the 5-HT3 antagonists alosetron and cilansetron in non-constipated IBS, …

Evidence is mounting that molecular mechanisms underlie gut dysfunction and symptom generation in IBS. Although it is still an uphill struggle, this mounting evidence is a good starting point for the discovery of one or more IBS biomarkers.

Management of diverticular disease has significantly improved in the last decade. Antibiotic treatment is used for symptom relief and prevention of complications. In Italy, the non-absorbable antibiotic rifaximin is one of the most frequently used drugs, and it is perceived as the reference drug to treat symptomatic diverticular disease. Its non-systemic absorption and high faecal concentrations have oriented rifaximin use to the gastrointestinal tract, where rifaximin exerts eubiotic effects representing an additional value to its antibiotic activity. This position paper was commissioned by the Italian Society of Gastroenterology governing board for a panel of experts (RC, GB, BA) to highlight the indications for treatment of diverticular disease. There is a lack of rationale for drug use for the primary prevention of diverticulitis in patients with diverticulosis; thus, rifaximin use should be avoided. The cyclic use of rifaximin, in association with high-fibre intake, is safe and useful for the treatment of symptomatic uncomplicated diverticular disease, even if the cost-efficacy of long-term treatment remains to be determined. The use of rifaximin in the prevention of diverticulitis recurrence is promising, but the low therapeutic advantage needs to be verified. No evidence is available on the efficacy of rifaximin treatment on acute uncomplicated diverticulitis.