摘要： The exact etiology and pathogenesis of Crohn's disease (CD) remain unknown. Although granulomas assist the diagnosis of CD, they are neither sensitive nor specific.[3] Impaired recognition of bacterial components by the innate immune system may underlie the development of CD as well as the development of granulomas. That study was also the first to describe the prevalence of granulomas in CD in a non-Western population, which was 50%, which was within the range in Caucasians of 13-67%.[10] Finally, the microbial-host interaction in the development of granulomas was tested in pediatric CD. [Extracted from the article]

关键词： Prostasin   TLR4   NF-kappa B   Mucosal permeability  

摘要： Background Prostasin (PRSS8) is a stimulator of epithelial sodium transport. In this study, we evaluated alteration of prostasin expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated the role of prostasin in the gut inflammation. Methods Prostasin expression was evaluated by immunohistochemical staining. Dextran sodium sulfate (DSS)-colitis was induced in mice lacking prostasin specifically in intestinal epithelial cells (PRSS8(Delta IEC) mice). Results In colonic mucosa of healthy individuals, prostasin was strongly expressed at the apical surfaces of epithelial cells, and this was markedly decreased in active mucosa of both ulcerative colitis and Crohn's disease. DSS-colitis was exacerbated in PRSS8(Delta IEC) mice compared to control PRSS8(lox/lox) mice. Toll-like receptor4 (TLR4) expression in colonic epithelial cells was stronger in DSS-treated PRSS8(Delta IEC) mice than in DSS-treated PRSS8 (lox/lox) mice. NF-kappa B activation in colonic epithelial cells was more pronounced in DSS-treated PRSS8(Delta IEC) mice than in DSS-treated PRSS8(lox/lox) mice, and the mRNA expression of inflammatory cytokines was significantly higher in DSS-treated PRSS8(Delta IEC) mice. Broad-spectrum antibiotic treatment completely suppressed the exacerbation of DSS-colitis in PRSS8(Delta IEC) mice. The mRNA expression of tight junction proteins and mucosal permeability assessed using FITC-dextran were comparable between DSS-treated PRSS8(lox/lox) and DSS-treated PRSS8(Delta IEC) mice. Conclusion Prostasin has an anti-inflammatory effect via downregulation of TLR4 expression in colonic epithelial cells. Reduced prostasin expression in IBD mucosa is linked to the deterioration of local anti-inflammatory activity and may contribute to the persistence of mucosal inflammation.

摘要： Background Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis. We investigated two main types of Tregs, the CD4+FOXP3+ and IL-10+ Tr1, in pediatric subjects with inflammatory bowel disease (IBD) both at diagnosis and after the clinical remission. Methods Peripheral blood Tregs were analyzed in 16 children with Crohn's disease (CD), 19 with ulcerative colitis (UC), and 14 healthy controls (HC). Two cocktails of fluoresceinated antibodies were used to discriminate between CD4+FOXP3+ and Tr1. Results We observed in both CD and UC groups a higher frequency of Tr1 at diagnosis compared to controls, which decreased at follow-up compared to diagnosis, in particular in UC. Similarly, in UC patients the percentage of CD4+FOXP3+ Tregs markedly decreased at follow-up compared to the same patients at diagnosis and compared to HC. The expression of CTLA-4 in CD4+FOXP3+ Tregs increased in both groups at clinical remission. Conclusion This study shows that IBD children present at diagnosis an increased frequency of circulating Tregs, probably as a compensative reaction to tissue inflammation. During the clinical remission, the Treg frequency diminishes, and concomitantly, their activation status increases. Notwithstanding, the high Treg density at diagnosis is not sufficient to counteract the inflammation in the childhood IBD.

关键词： Inflammatory bowel disease   Microbiota  

摘要： A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation. Alterations in the gut microbiota and metabolite profiles of patients with IBD have been described. In this Review, Lavelle and Sokol discuss these alterations and their pathophysiological basis, and identify future targets for precision therapeutic modulation.

关键词： CD   UC   long-term outcome   disease  

摘要： BACKGROUND & AIMS: Exposure to hormone contraception has been associated with an increased risk of relapse of inflammatory bowel diseases (IBDs). Little is known about the effects of cancer therapies, specifically hormone therapies, on the course of IBD. METHODS: We conducted a retrospective cohort study, collecting data from 5 medical centers, on patients with IBD who received a subsequent diagnosis of breast or prostate cancer from 1997 through 2018. For patients with quiescent IBD at their cancer diagnosis, the primary outcome was relapse of IBD. For patients with active IBD at their cancer diagnosis, the primary outcome was IBD remission. RESULTS: Our analysis included 447 patients with IBD (44% with Crohn's disease, 53% with ulcerative colitis, and 3% with IBD unclassified) who had either breast (78%) or prostate (22%) cancer. At their cancer diagnosis, 400 patients (90%) had inactive IBD, and 47 (10%) had active IBD. Among patients with inactive IBD, 112 (28%) developed active IBD. Previous exposure to steroids, immunomodulators, or biologics was associated with IBD relapse after a cancer diagnosis (hazard ratio [HR] for steroids, 1.79;95% CI, 1.18-2.71;HR for immunomodulators, 2.22;95% CI, 1.38-3.55;HR for biologics, 1.95;95% CI, 1.01-5.36). Hormone monotherapy (HR, 2.00;95% CI, 1.21-3.29) and combination cytotoxic and hormone therapy (HR, 1.86;95% CI, 1.01-3.43) was associated with IBD relapse. Among 34 patients who received only cytotoxic chemotherapy, 75% remained in remission from IBD at 250 months compared with 42% of those who received hormone monotherapy (log rank, 0.02). Among patients with active IBD at their cancer diagnosis, 14 (30%) entered remission from IBD, but there were no significant factors of achieving IBD remission. CONCLUSIONS: In a multicenter retrospective study, we found that patients with IBD and breast or prostate cancer who receive hormone therapy have an increased risk for relapse of IBD and related adverse outcomes.

关键词： Biologics   Child   Efficacy   Inflammatory bowel disease   Safety  

摘要： Background: Biological therapies have modified the disease course of pediatric inflammatory bowel disease (IBD) and are routinely used in clinical practice. Our observational study aims to evaluate effectiveness and safety of biologics in IBD. Method: Clinical benefit and safety data of 93 children with IBD, receiving biologics (Infliximab - IFX, Adalimumab - ADA, Golimumab - GOL) from January 2013 to December 2017, were extracted from the cohort of the Sicilian Network of IBD. Results: Among 87 children aged 7-17 years (63 Crohn's disease [CD], 24 Ulcerative colitis [UC]), 101 out of 108 biologic treatments were considered. Evaluation of 74 biologic treatments in CD patients at 26, 52, 104 weeks showed clinical benefit rates of 84.2%, 93.3%, 66.7% with IFX (n= 38) and 88.9%, 84.4%, 65.2% with ADA (n= 36). Biologic treatments (n=27) evaluated in the UC group at 26, 52, 104 weeks, led to clinical benefit rates of 85.7%, 83.3%, 50% in IFX subgroup (n=21) and 40%, 50%, 33% in the ADA subgroup (n=5), respectively. One patient treated with GOL showed 100% clinical benefit at 26 and 52 weeks. Overall adverse events (AEs) rate was 9.25%. Six younger children, < 6 years, receiving 8 treatments (4 ADA, 4 IFX) presented a clinical remission rate of 75% at 12 weeks and 25% at 52 weeks. AEs rate was 25% in this group. Conclusion: Our data show that biologic therapy in children, even at a younger age, is effective in allowing long-term remission with a good safety profile. (C) 2019 Elsevier Masson SAS. All rights reserved.

关键词： Alvimopan   Ulcerative colitis   Crohn's disease   Gastrointestinal recovery   Bowel surgery   Postoperative ileus  

摘要： Background Postoperative ileus (POI) is a temporary delay of coordinated intestinal peristalsis. Alvimopan, an oral peripherally acting mu-opioid receptor antagonist approved for accelerating gastrointestinal recovery, has never been studied specifically in patients with inflammatory bowel disease (IBD). Aim To investigate the efficacy of alvimopan in preventing POI among IBD patients. Methods A retrospective chart review was conducted on 246 IBD patients undergoing bowel surgery between 2012 and 2017. Data collected included demographics, IBD subtype, length of stay (LOS), postoperative gastrointestinal symptoms, and administration of alvimopan. The primary outcome was POI;secondary gastrointestinal recovery outcomes were: time to first flatus, time to first bowel movement, time to tolerating a liquid diet, time to tolerating solid food, and LOS. Results When compared with the control group, patients in the alvimopan group had shorter times to tolerating liquids and solids, first flatus, and first bowel movements (p < 0.01). LOS was shorter in the alvimopan group when compared with controls (p < 0.01). The overall incidence of POI was higher in controls than in the alvimopan group (p = 0.07). For laparoscopic surgeries, the incidence of POI was also higher in controls than in the alvimopan group (p < 0.01). On multivariable analysis, alvimopan significantly decreased time to all gastrointestinal recovery endpoints when compared to controls (p < 0.01). Conclusions Alvimopan is effective in accelerating time to gastrointestinal recovery and reducing POI in IBD patients. While the benefits of alvimopan have been demonstrated previously, this is the first study of the efficacy of alvimopan in IBD patients.

关键词： Crohn’s disease   Inflammatory bowel disease   endoscopic remission   endoscopic scoring   mucosal healing   treat to target   ulcerative colitis  

摘要： Endoscopic assessment is currently the criterion standard for the diagnosis and assessment of mucosal disease activity, prognosis and monitoring for dysplasia, and assessment of response to therapy. Wider appreciation of the potential disconnect between symptoms and objective measures of disease activity and evidence that uncontrolled inflammation may lead to progressive intestinal injury and irreversible bowel damage with adverse events has led to the concept of treating to target. Treating to target is defined as treating patients with high risk for disease progression early to prevent or limit intestinal injury or disability. Endoscopic remission (mucosal healing) has emerged as a key goal of therapy. Although there are no currently validated definitions of endoscopic mucosal remission, the use of endoscopic scoring systems add uniformity and objectivity and aid standardization with reporting of mucosal appearance, augmenting clinical decision making. A plethora of scoring systems exist to define activity, response, and remission in both Crohn's disease and ulcerative colitis. In this review, we discuss the most commonly used endoscopic scoring systems and proposed definitions of response and remission, and how they can be integrated into a treat-to-target approach to optimize patient outcomes.

关键词： Inflammation   Gastrointestinal Microbiome   Metabolic Disorder   Glucose Homeostasis   Corticosteroids  

摘要： BACKGROUND & AIMS: The intestine regulates glucose homeostasis, but it is not clear whether chronic intestinal inflammation affects risk for type 2 diabetes. We investigated the long-term risk of type 2 diabetes in patients with inflammatory bowel diseases (IBD) in a nationwide cohort study in Denmark. METHODS: In a nationwide population-based cohort of 6,028,844 persons in Denmark, we compared data from individuals with a diagnosis of IBD (Crohn's disease [CD] or ulcerative colitis UC]) with data from individuals from the general population from 1977 through 2014. Persons with type 2 diabetes were identified in the National Patient Register. Risk is presented as standardized incidence ratios (SIR) with 95% CIs. RESULTS: During 736,072 person-years of follow-up, 3436 patients with IBD developed type 2 diabetes vs 2224 expected (SIR, 1.54;95% CI, 1.49-1.60). The risk was significantly increased in patients with UC (SIR, 1.54;95% CI, 1.48-1.60), in patients with CD (SIR, 1.57;95% CI, 1.47-1.67), in women (SIR, 1.51;95% CI, 1.44-1.59), and in men (SIR, 1.57;95% CI, 1.50-1.65). The risk was highest the first year after a diagnosis of IBD (SIR, 4.48;95% CI, 4.16-4.83), but remained increased for 20 or more years following the diagnosis (SIR, 1.26;95% CI, 1.16-1.38). The increased risk could not be accounted for by frequency of health care contacts or corticosteroid exposure. Patients who received a diagnosis of IBD from 2003 through 2014 (SIR, 1.79;95% CI, 1.67-1.91) had a significantly higher risk of type 2 diabetes than patients who received a diagnosis of IBD from 1977 through 1988 (SIR, 1.47;95% CI, 1.39-1.56) or 1989 through 2002 (SIR, 1.48;95% CI, 1.41-1.56) (P <.001). CONCLUSIONS: In a population-based cohort study, we found an increased risk of type 2 diabetes in patients with UC or CD, with highest risk estimates from 2003 through 2014, compared with earlier years. Studies are needed to determine the effects of IBD treatment on risk of type 2 diabetes.