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Background The burden of Crohn’s disease (CD) and ulcerative colitis (UC) has never been estimated in the Republic of San Marino, the third smallest nation of the world. Aims To assess the occurrence and clinical features of CD and UC in San Marino during the last 35 years. Methods We retrospectively evaluated the prevalence, incidence, and main clinical aspects of CD and UC from 1980 to 2014, crossing data from various sources. Results Prevalence rates (per 100,000) on December 31, were 241 for CD (263 in males and 220 in females) and 311 for UC (370 in males and 255 in females). The specific incidence of UC steadily increased from 4.6 (95% CI: 1.5–10.6) in 1980–1984 to 12.4 (95% CI: 7.6–19.1) in 2010–2014; CD incidence showed a higher proportional increase, from 1.8 (95% CI: 0.2–6.6) in 1980–1984 to 17.9 (95% CI: 12.0–25.7) in 2010–2014. The main clinical features of CD and UC (activity and location at diagnosis, extra-intestinal manifestations, disease progression overtime, therapies, and hospitalizations) were analyzed. Conclusions This study provides the first epidemiological report on CD and UC in San Marino, showing specific traits and overall higher prevalence and incidence rates than previously reported in neighbor Areas.

ObjectivesCOVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear.DesignThis Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death).ResultsBetween 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death.ConclusionsActive IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.

BACKGROUND AND AIMS: Restructuring activities have been necessary during the lockdown phase of the coronavirus disease 2019 (COVID-19) pandemic. Few data are available on the post-lockdown phase in terms of health-care procedures in inflammatory bowel disease (IBD) care, and no data are available specifically from IBD units. We aimed to investigate how IBD management was restructured during the lockdown phase, the impact of the restructuring on standards of care and how Italian IBD units have managed post-lockdown activities. METHODS: A web-based online survey was conducted in two phases (April and June 2020) among the Italian Group for IBD affiliated units within the entire country. We investigated preventive measures, the possibility of continuing scheduled visits/procedures/therapies because of COVID-19 and how units resumed activities in the post-lockdown phase. RESULTS: Forty-two referral centres participated from all over Italy. During the COVID-19 lockdown, 36% of first visits and 7% of follow-up visits were regularly done, while >70% of follow-up scheduled visits and 5% of first visits were done virtually. About 25% of scheduled endoscopies and bowel ultrasound scans were done. More than 80% of biological therapies were done as scheduled. Compared to the pre-lockdown situation, 95% of centres modified management of outpatient activity, 93% of endoscopies, 59% of gastrointestinal ultrasounds and 33% of biological therapies. Resumption of activities after the lockdown phase may take three to six months to normalize. Virtual clinics, implementation of IBD pathways and facilities seem to be the main factors to improve care in the future. CONCLUSION: Italian IBD unit restructuring allowed quality standards of care during the COVID-19 pandemic to be maintained. A return to normal appears to be feasible and achievable relatively quickly. Some approaches, such as virtual clinics and identified IBD pathways, represent a valid starting point to improve IBD care in the post-COVID-19 era.

Aim To explore the influence of Infliximab (IFX) on cancer progression in a murine model of colonic cancer associated to chronic colitis. Methods AOM/DSS model was induced in C57BL/6 mice. Mice were injected with IFX (5 mg/kg) during each DSS cycle while control mice received saline. Body weight, occult blood test and stool consistency were measured to calculate the disease activity index (DAI). Mice were sacrificed at week 10 and colons were analyzed macroscopically and microscopically for number of cancers and degree of inflammation. MTT assay was performed on CT26 to evaluate the potential IFX role on metabolic activity and proliferation. Cells were incubated with TNF-α or IFX or TNF-α plus IFX, and cell vitality was evaluated after 6, 24 and 48 h. The same setting was used after pre-incubation with TNF-α for 24 h. Results IFX significantly reduced DAI and body weight loss in mice compared with controls, preserving also colon length at sacrifice. Histological score was also reduced in treated mice. At macroscopic analysis, IFX treated mice showed a lower number of tumor lesions compared to controls. This was confirmed at microscopic analysis, although differences were not statistically significant. In vitro, IFX treated CT26 maintained similar proliferation ability at MTT test, both when exposed to IFX alone and when associated to TNF-α. Conclusion IFX did not increase colonic cancer risk in AOM-DSS model of cancer on chronic colitis nor influence directly the proliferation of murine colon cancer epithelial cells.

Background and aims: Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy. Methods: In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4. The primary endpoint was clinical remission, defined as Clinical Activity Index [CAI] ≤4, at Week 12. Secondary endpoints included mucosal healing and symptomatic remission of key patient-reported outcomes [absence of blood in stool and weekly stool frequency

Antibiotics are mainly used in clinical practice for their activity against pathogens, but they also alter the composition of commensal gut microbial community. Rifaximin is a non-absorbable antibiotic with additional effects on the gut microbiota about which very little is known. It is still not clear to what extent rifaximin can be able to modulate gut microbiota composition and diversity in different clinical settings. Studies based on culture-dependent techniques revealed that rifaximin treatment promotes the growth of beneficial bacteria, such as Bifidobacteria and Lactobacilli. Accordingly, our metagenomic analysis carried out on patients with different gastrointestinal and liver diseases highlighted a significant increase in Lactobacilli after rifaximin treatment, persisting in the short time period. This result was independent of the disease background and was not accompanied by a significant alteration of the overall gut microbial ecology. This suggests that rifaximin can exert important eubiotic effects independently of the original disease, producing a favorable gut microbiota perturbation without changing its overall composition and diversity.

A huge number of bacteria are hosted in the gastrointestinal tract, following a gradient increasing towards the colon. Gastric acid secretion and intestinal clearance provide the qualitative and quantitative partitioning of intestinal bacteria; small intestinal bacteria overgrowth (SIBO) occurs when these barrier mechanisms fail. Diagnosis of SIBO is challenging due to the low specificity of symptoms, the frequent association with other diseases of the gastrointestinal tract and the absence of optimal objective diagnostic tests. The therapeutic approach to SIBO is oriented towards resolving predisposing conditions, and is supported by antibiotic treatment to restore the normal small intestinal microflora and by modifications of dietary habits for symptomatic relief. In the near future, metagenomics and metabolomics will help to overcome the uncertainties of SIBO diagnosis and the pitfalls of therapeutic management, allowing the design of a personalized strategy based on the direct insight into the small intestinal microbial community.

The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-α, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past two decades: their use avoid the need for steroids therapy, promote mucosal healing, reduce hospitalizations and surgeries and therefore dramatically improve the quality of life of IBD patients. However, primary non-response to these agents or loss of response over time mainly due to immunogenicity or treatment-related side-effects are a frequent concern in IBD patients. Thus, the identification of predicting factors of efficacy is crucial to allow clinicians to efficiently use these therapies, avoiding them when they are ineffective and eventually shifting towards alternative biological therapies with the end goal of optimizing the cost-effectiveness ratio. In this review, we aim to identify the predictive factors of short- and long-term benefits of anti-TNF-α therapy in IBD patients. In particular, multiple patient-, disease- and treatment-related factors have been evaluated.

Ulcerative colitis (UC) is a chronic inflammatory disease, whose etiology is still unclear. Its pathogenesis involves an interaction between genetic factors, immune response and the "forgotten organ", Gut Microbiota. Several studies have been conducted to assess the role of antibiotics and probiotics as additional or alternative therapies for Ulcerative Colitis. Escherichia coli Nissle (EcN) is a nonpathogenic Gram-negative strain isolated in 1917 by Alfred Nissle and it is the active component of microbial drug Mutaflor(®) (Ardeypharm GmbH, Herdecke, Germany and EcN, Cadigroup, In Italy) used in many gastrointestinal disorder including diarrhea, uncomplicated diverticular disease and UC. It is the only probiotic recommended in ECCO guidelines as effective alternative to mesalazine in maintenance of remission in UC patients. In this review we propose an update on the role of EcN 1917 in maintenance of remission in UC patients, including data about efficacy and safety. Further studies may be helpful for this subject to further the full use of potential of EcN.

The prevalence of cardiometabolic disorders (obesity, type 2 diabetes and cardiovascular disorders) is increasing globally and is a leading cause of mortality worldwide. Both genetics and environmental factors are involved in the pathogenesis of these disorders. Recent studies have shown that a state of dysbiosis may be implicated in body weight control, insulin resistance and cardio-metabolic risk factors, but the underlying mechanisms remain to be fully understood. Here we describe the possible role of the gut microbiota in cardiovascular diseases.

Background Inflammatory bowel disease (IBD) is the results of a chronic inflammatory process deriving from disequilibrium between self-microbiota composition and immune response. Methods New evidence, coming from Clostridium difficile infection, clearly showed that active and powerful modulation of microbiota composition by fecal microbiota composition (FMT) is safe, easy to perform, and efficacious, opening new frontiers in gastrointestinal and extra-intestinal diseases. FMT has been proposed also for IBD as well as other non-gastrointestinal conditions related to intestinal microbiota dysfunctions, with good preliminary data. Results In this setting, ulcerative colitis (UC) represents one of the most robust potential indications for FMT after C difficile colitis. Conclusions In the present review, we focus on FMT and its application on ulcerative colitis, clarifying mechanisms of actions and efficacy data, trough completion of a meta-analysis on available randomized, controlled trial data in UC. Because microbiota is so crucially involved in this topic, a short review of microbial alterations in UC will also be performed.

Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial “fingerprint”, characterized by the reduced ratio of “good” to “potentially pathogenic” bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.

In recent years, CT enterography (CTE) has emerged as an important methodology to study patients with Crohn’s disease (CD). The aim of this study was to evaluate the correlation between clinical response to therapy and CTE findings in CD patients. Forty-five patients with proven CD underwent CTE before and after medical therapy. In CTE we evaluated bowel thickness, longitudinal extension of parietal thickening, presence of target signs and extraintestinal signs. The clinical response to therapy was judged based on clinical global assessment and classified as improved, worsened or stable disease. Radiological judgement was compared to clinical judgement. The Cohen kappa test, t test or Anova analysis and χ 2 test were used for comparisons. Among 45 enrolled patients, 21 (47 %) improved clinically, five (11 %) worsened, 19 (42 %) remained stable. Clinical improvement was significantly correlated to reduced intestinal thickness, reduced longitudinal extension of the disease, increased diameter of pathological bowel and reduced target signs (p

Inflammatory bowel disease (IBD) patients have an increased risk of venous thromboembolism (VTE), which represents a significant cause of morbidity and mortality. The most common sites of VTE in IBD patients are the deep veins of the legs and pulmonary system, followed by the portal and mesenteric veins. However, other sites may also be involved, such as the cerebrovascular and retinal veins. The aetiology of VTE is multifactorial, including both inherited and acquired risk factors that, when simultaneously present, multiply the risk to the patient. VTE prevention involves correcting modifiable risk factors, such as disease activity, vitamin deficiency, dehydration and prolonged immobilisation. The role of mechanical and pharmacological prophylaxis against VTE using anticoagulants is also crucial. However, although guidelines recommend thromboprophylaxis for IBD patients, this method is still poorly implemented because of concerns about its safety and a lack of awareness of the magnitude of thrombotic risk in these patients. Further efforts are required to increase the rate of pharmacological prevention of VTE in IBD patients to avoid preventable morbidity and mortality.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition characterized by an abnormal immune response against food or bacterial antigens in genetically predisposed individuals. Several factors of innate and adaptive immune system take part in the inflammatory process, probably actively contributing in endoscopic and histological healing at molecular level. Although it is difficult to discriminate whether they are primary factors in determining these events or they are secondarily involved, it would be interesting to have a clear map of those factors in order to have a restricted number of potentially “good candidates” for mucosal healing. The present review will present a class of these factors and their modulation in course of therapy, starting from pathogenic studies involving several treatments associated with good clinical outcomes. This approach is meant to help in the difficult task of identifying “good candidates” for healing signatures, which could also be possible new therapeutic targets for clinical management of IBD patients.

Background Infliximab is effective in human and murine IBD, but its pharmacodynamic is still poorly known. The aim of this study was to assess the affinity of infliximab to murine TNF-α, its role in murine colitis when administered intra-rectally and its levels in the blood, gut mucosa and stool of healthy and sick mice. Methods An ELISA kit was built in order to assess the affinity of infliximab to human or murine-TNF-α. Human IgG were used as controls. DSS model of colitis on C57BL/6 mice was used to assess clinical efficacy of infliximab administered intravenously or by enema. Stool, serum and colon samples were collected to assess infliximab levels and histology for Rachmilewitz score. Results Infliximab showed a good affinity both for human-TNF-α and murine-TNF-α. In DSS colitic mice infliximab ameliorated the severity of colitis, regardless of the administration route. In comparison with colitic mice, healthy mice displayed higher serum and mucosal infliximab levels, while detectable levels of infliximab were found in faeces, particularly in colitic mice. Conclusion Our data support murine models to study infliximab pharmacokinetics and dynamics. Measurable levels of infliximab can be found at different concentrations in blood, intestinal mucosa and stool from healthy and sick mice, thus infliximab pharmacokinetics could have a major impact in human IBD.

Inflammatory bowel diseases are chronic diseases affecting the gastrointestinal tract, whose major forms are represented by Crohn’s disease (CD) and ulcerative colitis (UC). Their etiology is still unclear, although several factors have been identified as major determinants for induction or relapses. Among these, the role of the “forgotten organ”, gut microbiota, has become more appreciated in recent years. The delicate symbiotic relationship between the gut microbiota and the host appears to be lost in IBD. In this perspective, several studies have been conducted to assess the role of prebiotics and probiotics in gut microbiota modulation. This is a minireview aimed to address in an easy format (simple questions-simple answers) some common issues about the theme. An update on the role of selected constituents of gut microbiota in the pathogenesis of IBD is presented together with the analysis of the efficacy of gut microbiota modulation by prebiotics and probiotics administration in the management of IBD.

The diagnosis of Crohn’s disease is challenging as it combines clinical and laboratory clues with endoscopic, radiological and histological findings [1, 2]. Consequently, the diagnosis is often delayed or the disease is misdiagnosed, in particular in the case of mainly or exclusively ileal or jejunal involvement [3]. Enteroscopy enables deep intubation, with endoscopic visualization of the small bowel and otherwise complicated or unobtainable tissue sampling. In a secondarytertiary center, based on a strong clinical suspicion of inflammatory bowel disease (IBD) with laboratory findings consistent with Crohn’s disease, radiology could be the first step in making a diagnosis, followed directly by enteroscopy if there are clear signs of jejunal or ileal localization. This is a “top down” strategy in the diagnosis of Crohn’s disease, that might be effective in patients in whom the diagnosis is delayed.

The intestinal barrier serves 2 critical functions for the survival of the individual: first, it allows nutrient absorption and second, it defends the body from dangerous macromolecule penetration. It is a complex multilayer system, consisting of an external "anatomic" barrier and an inner "functional" immunological barrier. The interaction of these 2 barriers enables equilibrated permeability to be maintained. Many factors can alter this balance: gut microflora modifications, mucus layer alterations, and epithelial damage can increase intestinal permeability, allowing the translocation of luminal content to the inner layer of intestinal wall. Several techniques are now available that enable us to study gut permeability: "in vitro" models (Caco-2 and HT29-MTX cells) and "in vivo" not invasive tests (sugar tests and radioisotope scanning tests) are used to estimate permeability and to suggest molecular pathophysiological mechanisms of intestinal permeability in health and diseases. Many medicinal products used in the treatment of gastrointestinal diseases have also found to play an active role in modulate intestinal permeability: corticosteroids, 5-aminosalicylic acid, anti-tumor necrosis factor, probiotics, and mucosal protectors, like gelatin tannate. This review will particularly address the role of the gut barrier in maintaining intestinal permeability (microbiota, mucus, and epithelial cells), the techniques used for estimating intestinal permeability and the therapeutic approaches able to modify it.

BACKGROUND Mucosal healing is one of the biggest issue on the management of IBD. Although clinical use of these drugs in achieving mucosal healing is a reality, the mechanisms of it are still not clear. Aim of our study is to identify the effect of IFX on intestinal epithelial cells in order to induce mucosal healing, by exploring whether IFX is really acting at intestinal mucosal level and whether IFX acts on «wound healing» process of intestinal epithelial cells, using In Vitro and In Vivo approach. METHODS Human intestinal mucosal biopsies from active IBD patients were cultured for 48 h with or without IFX (50 ng/ml), and supernatants were assessed for cytokines content and histology performed. Effect of IFX was explored in C57BL/6 mice exposed for 7 days to 2,5 % of DSS. IFX was administered iv (5 mg/Kg) at day 5 or by daily enema (300 mg/200 ml) for 3 days starting at day 5. At day 9 mice were sacrificed and histology was taken. A scratch assay was performed on CT26 and Caco 2 cell line monolayer. Precice scratches were obtained by seading cells in micro-chamber formed by culture inserts. Cells were exposed for 24 h to IFX (50 ng/ml) and/or TNF-α (100 U/ml), or to supernatants of PBMC or fibroblast treated or not for 24 h with IFX and/ or TNFα. Seriated pictures were taken for 24 h following the stimulation and analized by computer software. RESULTS Human biopsies exposed to IFX showed a decrease in TNFa content, as well as of innate and adaptive immunity cytokines. Furthermore at histology IFX-treated biopsies showed a a decreased immune cells infiltration. In Vivo, IFX iv or given as enema ameliorated the severity of colitis in mice, by lowering the disease activity index (DAI) and the loss of body weight. At day 9 a reduction of intestinal inflammatory infiltrate was observed in treated mice. At scratch assay, TNF-a slightly decreased the healing process, while IFX alone or in combination did not. TNF-a exposed PBMC supernatants decreased epithelial healing; also TNF-a fibroblast supernatants slowed the healing process but adding IFX the healing process was restored. CONCLUSIONS Taken together our preliminary observations suggest that IFX acts locally at mucosa levels, as shown by the decrease in inflammatory infiltrate and cytokines contents in human biopsies and the effect on murine colitis when given intrarectally. The effect of IFX is only partially dependent on direct effect on epithelial cells. IFX ameliorates epithelial cell healing by blocking the detrimental capacity of TNF-a pre-treated fibroblast on intestinal epithelial cells. More data are necessary to unravel molecular pathways of these observations. Understanding mechanisms of action of IFX may clarify mechanisms of loss of responses to it as well as new targets for potential new therapies.

P184 Mucosal healing does not correspond to histological healing in ulcerative colitis L. Laterza1 *, I. Scoleri1, S. Bibbo1, E. Gaetani1, G. Bruno1, L. Larosa2, A. Poscia3, A. Amato4, L.M. Minordi2, L. Bonomo2, G. Cammarota1, A. Gasbarrini1, V. Gerardi1. 1Gastroenterology Division, Catholic University of the Sacred Hearth, Rome, Italy, 2Radiology Department, Catholic University of the Sacred Hearth, Rome, Italy, 3Institute of Hygiene, Catholic University of the Sacred Hearth, Rome, Italy, 4Institute of Anestesiology, Catholic University of the Sacred Hearth, Rome, Italy

Results: Among 887 patients, a subgroup of 439 CD and 173 UC were included with a mean follow-up of 19 and 15 years respectively. One year after the diagnosis 147 CD patients had NS CD. At 5 years and at the maximum follow-up respectively, 83/147 (56%) and 15/147 (10%) patients still had NS CD. Complications were strictures (29%), fistulizing disease (18%), perianal disease (37%). Immunomodulators and antiTNF were required in 79% and 54% of patients respectively. Prognostic factors for persistent NS CD were older age at diagnosis (38 vs 26 years, p = 0.005), no corticosteroid during the first year (p = 0.036). In UC, 142 patients had NS disease one year after the diagnosis. 102/142 (72%) and 62 patients (44%) had NS UC after 5 years and at the maximum follow-up respectively. Surgery occurred in 19 patients (13%) after a mean time a 164 months. Immunomodulators were needed in 66 patients (47%) and anti-TNF in 37 patients (26%). NS UC was associated with absence of hospitalization for active UC over the first 5 years (p = 0.009) and during the total course of UC (p < 0.0001), no intake of corticosteroid during the first year (p = 0.03). Conclusions: In our cohort representing referall centre recruitment, nearly all CD patients and 2/3 of UC with NS disease at diagnosis became severe with time. Old age at diagnosis was associated with NS CD outcome while absence of hospitalisation during the first year was associated with NS UC outcome. Absence of steroid use during the first year was associated with NS outcome in both diseases.