Showing papers in "Inflammatory Bowel Diseases in 2016"

Current Understanding of Dysbiosis in Disease in Human and Animal Models.

Abstract: Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Although the etiology and pathogenesis of IBD are still largely unknown, dysregulated host/enteric microbial interactions are requisite for the development of IBD. So far, many researchers have tried to identify a precise relationship between IBD and an imbalance of the intestinal microbiota, termed "dysbiosis." Despite extensive efforts, it is still largely unknown about the interplay among microbes, their hosts, and their environments, and whether dysbiosis is a causal factor or an effect of IBD. Recently, deep-sequencing analyses of the microbiota in patients with IBD patients have been instrumental in characterizing the strong association between dysbiosis and IBD development, although it is still unable to identify specific-associated species level changes in most cases. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, including IBD, obesity, and allergic disorders, in both human and animal models. In this review article, the authors have focused on explaining the multiple types of dysbiosis, as well as dysbiosis-related diseases and potential treatments to apply this knowledge to understand a possible cause and potentially find therapeutic strategies for IBD as well as the other dysbiosis-related diseases.

Controversies Revisited : A Systematic Review of the Comorbidity of Depression and Anxiety with Inflammatory Bowel Diseases.

Abstract: BACKGROUND: Although mental health concerns are known to occur commonly for those with inflammatory bowel diseases (IBD), the nature of this comorbid relationship has not been systematically reviewed to date. A review in 2007 identified 5 controversies regarding anxiety/depression rates and various comparators between and within IBD. We aimed to systematically analyze and critique the current evidence regarding this comorbidity, providing an update to the 5 controversies. METHODS: Ebscohost Medline, CINAHL, Embase, and PsychINFO were searched between 2005 and 2014 using systematic review methodology. Controlled quantitative studies examining either symptoms or diagnoses of anxiety and depression in IBD were included in the review, with study quality assessed using a scale developed a priori to evaluate observational research. RESULTS: (1) IBD versus healthy controls (pooled mean proportions) (n = 13 studies): anxiety 19.1% versus 9.6%, depression 21.2% versus 13.4%; (2) IBD inactive versus IBD active disease (n = 26): anxiety 28.2% versus 66.4%, depression 19.9% versus 34.7%; (3) ulcerative colitis versus Crohn's disease (n = 28): anxiety 31% versus 37%, depression 22% versus 24.4%; (4) IBD versus other chronic medical conditions (n = 17): anxiety 41.9% versus 48.2%, depression 14.5% versus 28.4%; (5) onset of anxiety/depression before or after IBD onset (n = 2): adults more likely to develop anxiety/depression before IBD onset, but a substantial proportion develops depression after onset; an increased risk for children of developing anxiety/depression after IBD onset. CONCLUSIONS: The high rates of anxiety and depression for those with IBD, particularly when disease is active, warrant a systemic approach to screening and treatment.

Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study.

Abstract: Background: Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn’s disease (CD) risks. Thus, we investigated associations between diet as a whole, a ...

Increased Intestinal Microbial Diversity Following Fecal Microbiota Transplant for Active Crohn's Disease.

Abstract: BACKGROUND The microbiota in the lumen of patients with Crohn's disease (CD) is characterized by reduced diversity, particularly Firmicutes and Bacteroidetes. It is unknown whether the introduction of the intestinal microbiota from healthy individuals could correct this dysbiosis and reverse mucosal inflammation. We investigated the response to fecal microbial transplantation (FMT) from healthy individuals to subjects with active CD. METHODS We performed a prospective open-label study (uncontrolled) of FMT from healthy donors to subjects with active CD. A single FMT was performed by colonoscopy. Recipients' microbial diversity, mucosal T-cell phenotypes, and clinical and inflammatory parameters were measured over 12 weeks, and safety over 26 weeks. RESULTS Nineteen subjects were treated with FMT and completed the study follow-up. Fifty-eight percent (11/19) demonstrated a clinical response (Harvey-Bradshaw Index decrease >3) following FMT. Fifteen subjects had sufficient pre/postfecal samples for analysis. A significant increase in microbial diversity occurred after FMT (P = 0.02). This was greater in clinical responders than nonresponders. Patients who experienced a clinical response demonstrated a significant shift in fecal microbial composition toward their donor's profile as assessed by the Bray-Curtis index at 4 weeks (P = 0.003). An increase in regulatory T cells (CD4CD25CD127lo) was also noted in recipients' lamina propria following FMT. No serious adverse events were noted over the 26-week study period. CONCLUSIONS In this open-label study, FMT led to an expansion in microbial bacterial diversity in patients with active CD. FMT was overall safe, although the clinical response was variable. Determining donor microbial factors that influence clinical response is needed before randomized clinical trials of FMT in CD.

Fermentable Carbohydrate Restriction (Low FODMAP Diet) in Clinical Practice Improves Functional Gastrointestinal Symptoms in Patients with Inflammatory Bowel Disease.

Abstract: BACKGROUND A significant proportion of patients with inflammatory bowel disease (IBD) experience functional-like gastrointestinal symptoms (FGS) even during remission. Research suggests that dietary restriction of fermentable carbohydrates (low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet) can improve FGS, albeit in irritable bowel syndrome. The aim of this study was to investigate the effectiveness of the low FODMAP diet delivered in routine clinical practice in patients with IBD and coexisting FGS. METHODS Gastrointestinal symptom scores were compared in consecutive patients with IBD referred for low FODMAP dietary education for symptom management (n = 88). Symptoms were assessed using the Gastrointestinal Symptoms Rating Scale, and stool output was assessed using the Bristol Stool Form Scale at both baseline and follow-up (minimum of 6 weeks). RESULTS There was a significant and large increase in the numbers of patients reporting satisfactory relief of symptoms between baseline (14/88, 16%) and low FODMAP diet (69/88, 78%; P < 0.001). Following dietary intervention, there was also a significant decrease in severity for most symptoms and a reduction in composite symptom score (baseline mean: 1.2, SD: 0.5 versus low FODMAP diet mean: 0.7, SD: 0.5; P < 0.001). Improvements in stool consistency and frequency were observed, including an increase in "normal" stool form (P = 0.002) and "normal" stool frequency (P < 0.001). CONCLUSIONS The low FODMAP diet delivered in routine clinical practice seems effective in improving satisfaction with, and severity of, FGS in IBD. Randomized controlled trials are warranted to definitively establish effectiveness.

Dietary Practices and Beliefs in Patients with Inflammatory Bowel Disease.

Abstract: Background An epidemiological association implicating diet in IBD risk or protection is widely accepted. Patients with IBD often make links to diet, but there is a dearth of literature exploring dietary perceptions and practices in this population. Our objective was to evaluate dietary beliefs and behaviors in IBD patients. Methods We developed a questionnaire assessing demographics, dietary beliefs and habits in IBD patients. This was prospectively administered to 400 consecutive patients attending our IBD clinics. Results Mean patient age was 48.4 years; 55% were female, 88% white, 39% had Crohn's disease and 51% had ulcerative colitis. Around 48% felt that diet could be the initiating factor in IBD and 57% felt it could trigger a flare. Worsening symptoms with certain foods was reported by 60%. About 66% deprived themselves of their favorite foods in order to prevent relapse. Three-fourth of patients believed that IBD affects appetite, more so during a relapse. Nearly half had never received any formal dietary advice, and two-thirds requested for further dietary advice. After adjusting for other predictors, the IBD subtype and ethnicity of the patients remained as significant factors for influencing beliefs held by patients. Conclusions Our study showed that patients hold beliefs pertaining to the role of diet in IBD, with a high level of consistency around key perceived triggers. Whether all the symptoms reported are due to active inflammation cannot be ascertained, but the potential exists for dietary components triggering active disease and perpetuating gut injury, impacting on quality of life and health care costs.

Ustekinumab for the Treatment of Refractory Crohn's Disease: The Spanish Experience in a Large Multicentre Open-label Cohort.

Abstract: Background Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice. Methods Consecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up. Results One hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5-21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal. Conclusions Subcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.

Fecal Microbiota Transplantation is Safe and Efficacious for Recurrent or Refractory Clostridium difficile Infection in Patients with Inflammatory Bowel Disease.

Abstract: Background New treatments are needed as Clostridium difficile infection (CDI) is becoming increasingly formidable. Fecal microbiota transplantation (FMT) has a 90% success rate in the treatment of recurrent CDI. However, evidence regarding its safety, efficacy, and effect on disease activity in patients with inflammatory bowel disease (IBD) is lacking. Methods This cohort study used data from 8 national and international academic centers. Patients with established IBD who underwent FMT for recurrent CDI were followed for a minimum of 3 months. The primary outcome was CDI recurrence at 3 months after FMT. The secondary outcomes were (1) IBD activity and severity at 3 months based on the judgment of the treating physician, endoscopic findings, and clinical disease activity scores; and (2) safety. Results Sixty-seven patients were included in the analysis. Thirty-five (52%) had Crohn's disease, 31 (46%) ulcerative colitis, and one indeterminate colitis with 43 (64%) patients on an immunosuppressive agent at the time of FMT. The initial FMT was successful in 53 (79%) patients. After the FMT, IBD disease activity was reported as improved in 25 (37%), no change in 20 (30%), and worse in 9 (13%) patients. Serious adverse events included colectomy (1.4%), hospitalization for CDI (2.9%), hospitalization for IBD flare (2.9%), small bowel obstruction (1.4%), CMV colitis (1.4%), and pancreatitis (1.4%). Discussion The overall CDI cure rates were high, with a large percentage of patients experiencing clinical improvement of their IBD after FMT. A minority of patients developed an IBD flare. No severe adverse events directly attributable to FMT were found in this largest reported series of recurrent or refractory CDI patients with concurrent IBD.

Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study.

Abstract: Objectives:Inflammatory bowel disease (IBD) is a chronic inflammatory disorder. Previous studies have suggested that chronic systemic inflammation increases the risk of Parkinson's disease (PD). This study examined the effects of IBD on the development of PD.Methods:In a nationwide population-based

Role of Monocytes and Intestinal Macrophages in Crohn's Disease and Ulcerative Colitis

Abstract: Monocytes and macrophages are part of the body's first line of defence, eliminating pathogens by phagocytosis or by releasing a broad array of inflammatory mediators, such as cytokines, chemokines, and proteases. In humans, 3 subsets of monocytes are described in blood with seemingly different functions, the classical (CD14CD16) monocytes, the intermediate (CD14CD16) monocytes, and the nonclassical (CD14CD16) monocytes. In the intestine, macrophages can be divided into resident and inflammatory macrophages that are distinguished by low and high expression of CD14, respectively. However, the roles and function of the 3 monocyte subsets in health and disease are not fully understood. In this review, we describe what is known about the origin of human intestinal macrophages and their blood monocytic counterparts and many of their numerous distinct mechanisms influencing the intestinal immune system.

Epidemiology and Long-term Outcome of Inflammatory Bowel Disease Diagnosed at Elderly Age-An Increasing Distinct Entity?

Abstract: BACKGROUND Elderly onset (EO) inflammatory bowel disease (IBD) may become a more common entity as a result of population aging and the rising IBD incidence. Its management is challenging, because of multimorbidity, polypharmacy, and frailty. Insight into the long-term outcome is essential for optimal patient counseling and treatment. We studied the incidence and disease outcome of elderly-onset IBD in direct comparison to adult-onset (AO) IBD. METHODS All 2823 cases with IBD from the Dutch population-based IBD South Limburg cohort, diagnosed between 1991 and 2011, were included. Long-term outcome (hospitalization, surgery, and disease phenotype) was compared between AO (<60 years at diagnosis) and EO (≥60 years at diagnosis) disease, for Crohn's disease (CD) and ulcerative colitis (UC) separately. RESULTS In total, 1162 patients with CD (136 EO/1026 AO) and 1661 patients with UC (373 EO/1288 AO) were included. The EO IBD incidence increased from 11.71 per 100,000 persons in 1991 to 23.66 per 100,000 persons in 2010, P < 0.01. Immunomodulators were less often used in EO CD (61.8% versus 77.1%, P = 0.03) and EO UC (22.8% versus 35.4%, P < 0.01), even as biologicals (25.1% versus 55.1%, P = 0.03 and 7.8% versus 18.0%, P < 0.01, respectively). No differences were observed in surgery risk (CD: hazard ratio [HR] 1.19; 95% confidence interval [CI], 0.85-1.67 and UC: HR, 0.88; 95% CI, 0.53-1.46), or in CD phenotype progression (HR, 0.81; 95% CI, 0.52-1.25), but more patients with EO UC required hospitalization (HR, 1.29; 95% CI, 1.01-1.63). CONCLUSIONS EO IBD is rising, warranting physicians' alertness for IBD in elderly patients. The long-term outcome was not different from AO disease, despite a less frequent use of immunomodulators and biologicals.

Bowel Ultrasonography in the Management of Crohn's Disease. A Review with Recommendations of an International Panel of Experts.

Abstract: Background Bowel ultrasonography (US) is considered a useful technique for assessing mural inflammation and complications in Crohn's disease (CD). The aim of this review is to appraise the evidence on the accuracy of bowel US for CD. In addition, we aim to provide recommendations for its optimal use. Methods Publications were identified by literature search from 1992 to 2014 and selected based on predefined criteria: 15 or more patients; bowel US for diagnosing CD, complications, postoperative recurrence, activity; adequate reference standards; prospective study design; data reported to allow calculation of sensitivity, specificity, agreement, or correlation values; articles published in English. Results The search yielded 655 articles, of which 63 were found to be eligible and retrieved as full-text articles for analysis. Bowel US showed 79.7% sensitivity and 96.7% specificity for the diagnosis of suspected CD, and 89% sensitivity and 94.3% specificity for initial assessment in established patients with CD. Bowel US identified ileal CD with 92.7% sensitivity, 88.2% specificity, and colon CD with 81.8% sensitivity, 95.3% specificity, with lower accuracy for detecting proximal lesions. The oral contrast agent improves the sensitivity and specificity in determining CD lesions and in assessing sites and extent. Conclusions Bowel US is a tool for evaluation of CD lesions in terms of complications, postoperative recurrence, and monitoring response to medical therapy; it reliably detects postoperative recurrence and complications, as well as offers the possibility of monitoring disease progression.

Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases.

Abstract: The word "glia" is derived from the Greek word "γλoια," glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the "reactive glial phenotype" is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor-α), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential.

Cytokine Networks and T-Cell Subsets in Inflammatory Bowel Diseases.

Abstract: Pathogenesis of the inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn's disease (CD), involve proinflammatory changes within the microbiota, chronic immune-mediated inflammatory responses, and epithelial dysfunction. Converging data from genome-wide association studies, mouse models of IBD, and clinical trials indicate that cytokines are key effectors of both normal homeostasis and chronic inflammation in the gut. Yet many questions remain concerning the role of specific cytokines in different IBDs within distinct regions of the gut, and regarding cellular mechanisms of action. In this article, we review current and emerging concepts concerning the role of cytokines in IBD with a focus on immune regulation, T cell subsets, and potential clinical applications.

Emerging Roles for Noncanonical NF-κB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology.

Abstract: Crohn's disease and ulcerative colitis are common and debilitating manifestations of inflammatory bowel disease (IBD). IBD is characterized by a radical imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways in the gut. These pathways are controlled by NF-κB, which is a master regulator of gene transcription. In IBD patients, NF-κB signaling is often dysregulated resulting in overzealous inflammation. NF-κB activation occurs through 2 distinct pathways, defined as either canonical or noncanonical. Canonical NF-κB pathway activation is well studied in IBD and is associated with the rapid, acute production of diverse proinflammatory mediators, such as COX-2, IL-1β, and IL-6. In contrast to the canonical pathway, the noncanonical or "alternative" NF-κB signaling cascade is tightly regulated and is responsible for the production of highly specific chemokines that tend to be associated with less acute, chronic inflammation. There is a relative paucity of literature regarding all aspects of noncanonical NF-ĸB signaling. However, it is clear that this alternative signaling pathway plays a considerable role in maintaining immune system homeostasis and likely contributes significantly to the chronic inflammation underlying IBD. Noncanonical NF-κB signaling may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD. However, significant mechanistic insight is still required to translate the current basic science findings into effective therapeutic strategies.

Fecal Calprotectin Predicts Relapse and Histological Mucosal Healing in Ulcerative Colitis.

Abstract: Background Mucosal healing in ulcerative colitis leads to a decreased need for medication and decreased risk of disease relapse and colectomy. Histological healing seems to improve the disease prognosis even further. An assessment of both endoscopic and histological mucosal healing requires endoscopy, and the need for a reliable noninvasive biomarker to predict disease relapse is obvious. Methods Seventy patients were included and followed up for 12 months. Inclusion criteria were a total Mayo score ≤1 and a Mayo endoscopic score = 0. The patients underwent sigmoidoscopy with rectal biopsies. Fecal calprotectin (FC) was measured 2 to 3 days before the sigmoidoscopy. The tissue samples were evaluated for neutrophilic inflammation. We aimed at testing the predictive performance of FC and histological inflammatory activity on disease relapse. Results A baseline FC level of more than 321 mg/kg predicted disease relapse at both the 6- and 12-month follow-ups. Histological inflammatory activity, C-reactive protein, or length of remission was not predictive of relapse. Of note, 11.8% of all patients had histological inflammatory activity despite endoscopic remission and were found to have a higher level of FC (236.5 versus 56 mg/kg, P = 0.02). A receiver operating characteristic analysis estimated a cutoff level of ≤40.5 mg/kg for FC (area under the curve, 0.755 and confidence interval 95%, 0.5895-0.9208) for predicting a histological inflammatory activity score of 0. Conclusions FC measurements can be used to identify patients with increased risk of relapse after 6 and 12 months and to predict histological mucosal healing. Regular measurement of FC may alter disease monitoring and improve prognosis, and may decrease the need for endoscopy.

A Single Species of Clostridium Subcluster XIVa Decreased in Ulcerative Colitis Patients.

Abstract: Background Imbalance of the intestinal microbiota is associated with gastrointestinal disease and autoimmune disease and metabolic syndrome. Analysis of the intestinal microbiota has recently progressed, and the association with inflammatory bowel disease has been reported at the species level. Such findings suggest that the recovery of homeostasis in the intestinal microbiota could cure inflammatory bowel disease. We aimed to search new probiotic candidates for inflammatory bowel disease through translational research by analysis of ulcerative colitis (UC) patients' intestinal microbiota and clarify the effects of them on inflammation. Here, we focused on Fusicatenibacter saccharivorans, which belongs to Clostridium subcluster XIVa and was successfully isolated and cultured in 2013. We analyzed the association of F. saccharivorans to UC patients' activity and inflammation for the first time. Methods Feces from UC patients and healthy controls were analyzed by 16S ribosomal RNA gene sequences. F. saccharivorans was administered to murine colitis model. Colitic lamina propria mononuclear cells from UC patients and mice were stimulated with F. saccharivorans. Results The whole fecal bacteria in active UC patients were less than that in quiescent UC patients. Furthermore, F. saccharivorans was decreased in active UC patients and increased in quiescent. The administration of F. saccharivorans improved murine colitis. F. saccharivorans induced interleukin 10 production by lamina propria mononuclear cells from not only colitis model mice but also UC patients. Conclusions F. saccharivorans decreased in correlation to UC activity and suppresses intestinal inflammation. These results suggest that F. saccharivorans could lead to a novel UC treatment.

Microbiome Survey of the Inflamed and Noninflamed Gut at Different Compartments Within the Gastrointestinal Tract of Inflammatory Bowel Disease Patients.

Abstract: BACKGROUND We aimed to contrast the mucosal microbiota in Crohn's disease (CD) and ulcerative colitis (UC). METHODS We assessed the concept of localized dysbiosis by comparing the bacterial communities of inflamed and noninflamed mucosa of patients with inflammatory bowel disease (IBD) and by analysis of the microbiota composition at distinct gut compartments (ileum, cecum, mid-colon, and rectum). We performed 16S rDNA sequencing to analyze population structures. Quality control and operational taxonomic unit classification of reads were performed using mothur with statistical analyses executed in the R package, phyloseq. RESULTS There was no variation in any phyla or genera comparing inflamed to noninflamed mucosa within CD (or UC) or when comparing different gut compartments within CD (or UC). There were differences between the inflamed and noninflamed mucosa between CD and UC: analysis of the inflamed IBD gut at the phylum level indicated that Bacteroidetes (P = 0.002) and Fusobacteria (P < 0.05) were detected more frequently in inflamed CD mucosa than in inflamed UC mucosa. Conversely, Proteobacteria and Firmicutes (P < 0.05) were more frequently observed in the inflamed UC mucosa. At the genus level, the abundance of Faecalibacterium (P ≤ 0.05), Bacteroides (P = 0.003), and Pseudomonas (P < 0.001) were significantly different between the inflamed CD and UC and the abundance of 13 genera were significantly different within the noninflamed mucosa. The noninflamed UC mucosa was the most different from non-IBD mucosa. CONCLUSIONS Dramatic shifts of microbial communities were not observed between the noninflamed and inflamed mucosa within CD (or UC) although both the inflamed (and noninflamed) mucosa was different between CD and UC.

Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease.

Abstract: Background Interleukin (IL)-36 (IL-36α, IL-36β, and IL-36γ) is a recently reported member of the IL-1 cytokine family. In this study, we investigated IL-36 expression in the inflamed mucosa of patients with inflammatory bowel disease and characterized the proinflammatory actions of IL-36 cytokines in human colonic epithelial cells. Methods IL-36 mRNA expression was evaluated using real-time PCR. IL-36 protein expression was analyzed using immunoblotting and immunohistochemical technique. Intracellular signaling pathways were evaluated by immunoblotting and by specific siRNA-transfected cells. Results The mRNA expression of IL-36α and IL-36γ, but not of IL-36β, was enhanced in the inflamed mucosa of patients with inflammatory bowel disease, in particular, in ulcerative colitis. Immunohistochemical analysis showed that T cells, monocytes, and plasma cells are the source of IL-36α and IL-36γ in colonic mucosa. DNA microarray analysis indicated that IL-36α induces the mRNA expression of CXC chemokines and acute phase proteins in intestinal epithelial cell line, HT-29 cells. IL-36α and IL-36γ dose-dependently and time-dependently induced the mRNA and protein expression of CXC chemokines (CXCL1, CXCL2, CXCL3 etc.) in HT-29 and Widr cells. Stimulation with IL-36α and IL-36γ assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex and induced the activation of NF-κB and AP-1 and also the phosphorylation of MAPKs. MAPK inhibitors and siRNAs specific for NF-κB and c-Jun AP-1 significantly reduced IL-36-induced CXC chemokine expression. Conclusions IL-36α and IL-36γ may play a proinflammatory role in the pathophysiology of inflammatory bowel disease through induction of CXC chemokines and acute phase proteins.

Gut Microbiota Dysbiosis as Risk and Premorbid Factors of IBD and IBS Along the Childhood–Adulthood Transition

Abstract: Gastrointestinal disorders, although clinically heterogeneous, share pathogenic mechanisms, including genetic susceptibility, impaired gut barrier function, altered microbiota, and environmental triggers (infections, social and behavioral factors, epigenetic control, and diet). Gut microbiota has been studied for inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) in either children or adults, while modifiable gut microbiota features, acting as risk and premorbid factors along the childhood-adulthood transition, have not been thoroughly investigated so far. Indeed, the relationship between variations of the entire host/microbiota/environmental scenario and clinical phenotypes is still not fully understood. In this respect, tracking gut dysbiosis grading may help deciphering host phenotype-genotype associations and microbiota shifts in an integrated top-down omics-based approach within large-scale pediatric and adult case-control cohorts. Large-scale gut microbiota signatures and host inflammation patterns may be integrated with dietary habits, under genetic and epigenetic constraints, providing gut dysbiosis profiles acting as risk predictors of IBD or IBS in preclinical cases. Tracking dysbiosis supports new personalized/stratified IBD and IBS prevention programmes, generating Decision Support System tools. They include (1) high risk or flare-up recurrence -omics-based dysbiosis profiles; (2) microbial and molecular biomarkers of health and disease; (3) -omics-based pipelines for laboratory medicine diagnostics; (4) health apps for self-management of score-based dietary profiles, which can be shared with clinicians for nutritional habit and lifestyle amendment; (5) -omics profiling data warehousing and public repositories for IBD and IBS profile consultation. Dysbiosis-related indexes can represent novel laboratory and clinical medicine tools preventing or postponing the disease, finally interfering with its natural history.

Changes in the Abundance of Faecalibacterium prausnitzii Phylogroups I and II in the Intestinal Mucosa of Inflammatory Bowel Disease and Patients with Colorectal Cancer.

Abstract: BACKGROUND Faecalibacterium prausnitzii comprises 2 phylogroups, whose abundance in healthy and diseased gut and in conjunction with Escherichia coli has not yet been studied. This work aims to determine the contribution of F. prausnitzii phylogroups I and II in intestinal disease and to assess their potential diagnostic usefulness as biomarkers for gut diseases. METHODS Total F. prausnitzii, its phylogroups, and E. coli loads were determined by quantitative polymerase chain reaction targeting the 16S rRNA gene on biopsies from 31 healthy controls (H), 45 patients with Crohn's disease (CD), 25 patients with ulcerative colitis, 10 patients with irritable bowel syndrome, and 20 patients with colorectal cancer. Data were normalized to total bacterial counts and analyzed according to patients' disease location and clinical characteristics. RESULTS Lower levels of both total F. prausnitzii and phylogroup I were found in subjects with CD, ulcerative colitis, and colorectal cancer (P < 0.001) compared with H subjects. Phylogroup I load was a better biomarker than total F. prausnitzii to discriminate subjects with gut disorders from H. Phylogroup II depletion was observed only in patients with CD (P < 0.001) and can be potentially applied to differentiate ulcerative pancolitis from colonic CD. No statistically significant correlation between E. coli and any of the 2 F. prausnitzii phylogroups was found in any group of patients or by inflammatory bowel disease location. Phylogroup I was lower in active patients with CD, whereas those CD with intestinal resection showed a reduction in phylogroup II. Treatments with mesalazine and immunosuppressants did not result in the recovery of F. prausnitzii phylogroups abundance. CONCLUSIONS F. prausnitzii phylogroup I was depleted in CD, ulcerative colitis, and colorectal cancer, whereas phylogroup II was specifically reduced in CD. Quantification of F. prausnitzii phylogroups and E. coli may help to identify gut disorders and to classify inflammatory bowel disease location.

Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn's Disease and Ulcerative Colitis.

Abstract: Background Optimal levels of adalimumab (ADA) have not been defined according to the ultimate goal of inflammatory bowel disease treatment--histologic and/or endoscopic healing. The aim of this study was to assess the relationship between random serum ADA levels and histologic and endoscopic healing in patients with inflammatory bowel disease. Methods This was a cross-sectional study including 66 patients receiving maintenance therapy with ADA for Crohn's disease or ulcerative colitis. ADA levels and anti-adalimumab antibodies (AAA) were measured at the time of colonoscopy. The primary outcome was histologic healing (lack of endoscopic and histologic inflammation) and the secondary outcomes were endoscopic healing and serum levels of C-reactive protein, tumor necrosis factor, ICAM, VCAM, and interleukins 1β, 6, and 8. Results Sixty-six patients (59 with Crohn's disease) were included. Mean random ADA levels were significantly lower in patients with histologic and endoscopic inflammation (9.2 [SD: 8.4] versus 14.1 [6.4] μg/mL, P = 0.03 and 8.5 [SD: 7.8] versus 13.3 [SD: 7.7], P = 0.02, respectively). The ADA level that was best associated with histologic healing was 7.8 μg/mL (receiver operating characteristic: 0.76 [P = 0.04]), whereas the ADA level that was best associated with endoscopic healing was 7.5 μg/mL (receiver operating characteristic: 0.73 [P = 0.02]). The presence of AAA was associated with lower random ADA levels (5.7 versus 12.5 μg/mL, P = 0.002) and higher C-reactive protein levels (30.3 versus 12.0, P = 0.01). Conclusions Achievement of histologic and endoscopic healing may require higher levels of ADA than previously described for endoscopic remission. The measurement of random ADA levels and anti-drug antibodies may guide therapy and edify the course of incomplete responses.

Multi-Center Experience of Vedolizumab Effectiveness in Pediatric Inflammatory Bowel Disease.

Abstract: Background:Though vedolizumab has received regulatory approval for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) in adults, there is increasing off-label use in children.Aims:To describe the experience with vedolizumab in pediatric inflammatory bowel disease (IBD) patients at 3 t

Endoscopic Mucosal Healing Predicts Favorable Clinical Outcomes in Inflammatory Bowel Disease: A Meta-analysis.

Abstract: Background Mucosal healing (MH) in inflammatory bowel disease has been associated with improved long-term clinical outcomes. Uncertainty remains as to the magnitude of this effect and to how this association changes with time and degree of healing. Methods PubMed, EMBASE, and Web of Science searches identified 1570 citations. Screening of abstracts identified 155 articles for full-text review, of which 19 met inclusion criteria. For 3 outcomes of interest (surgeries, hospitalizations, remission), weighted random-effects meta-analysis was performed. Results In pooled analysis, MH predicted fewer major abdominal surgeries (relative risk [RR], 0.34; 95% confidence interval [CI], 0.26-0.46), increased remission (RR, 1.84; 95% CI, 1.43-2.36), and fewer hospitalizations (RR, 0.58; 95% CI, 0.42-0.78). Complete MH and partial MH both showed significantly higher rates of favorable outcomes. Separate analyses for Crohn's disease and ulcerative colitis showed identical patterns for surgeries and remission. When subjects with no healing were excluded, and complete versus partial healing was compared, rates of surgery were not significantly different (RR, 0.82; 95% CI, 0.46-1.44). However, complete healing was superior in predicting corticosteroid-free remission (RR, 1.71; 95% CI, 1.24-2.34). Meta-regression found that the predictive power of this complete versus partial healing distinction was strongly associated with the duration of follow-up after endoscopy. Conclusions MH is a strong predictor of fewer surgeries, long-term clinical remission, and fewer hospitalizations. Complete healing is not significantly more favorable than partial healing for predicting surgeries or hospitalizations, but it did predict higher rates of clinical remission. This benefit of complete MH over partial healing increases with follow-up time.

Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies.

Abstract: Background Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention. Methods Literature review. Results Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal inflammatory phenotype influencing the pharmacodynamic (PD) responses to TNF inhibitors also affect treatment outcomes. As an alternative to handling anti-TNF-treated patients by empiric strategies, TDM identifies underlying PK and PD-related reasons for treatment failure and aids decision making to secure optimal clinical and economic outcomes. Although promising, evidence does not the support use of TDM to counteract treatment failure in quiescent disease. Use of TDM is challenged by methodological biases, difficulties related to differentiation between PK and PD problems, and temporal biases due to lack of chronology between changes in PK versus symptomatic and objective disease activity manifestations. Biases can be accommodated by knowledgeable interpretation of results obtained by validated assays with clinically established thresholds, and by repeated assessments over time using complimentary techniques. Conclusions TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.

Epidemiology of Inflammatory Bowel Disease from 1981 to 2014: Results from a Territory-Wide Population-Based Registry in Hong Kong.

Abstract: Background Incidence of inflammatory bowel disease (IBD) is increasing in Asia, but population-based prevalence data are limited. This study examined IBD incidence and prevalence based on results of a territory-wide IBD registry in Hong Kong. Methods We collected data on 2575 patients with IBD (1541 ulcerative colitis [UC], 983 Crohn's disease [CD], 51 IBD unclassified) from 1981 to 2014 using hospital and territory-wide administrative coding system. Prevalence and incidence, disease phenotype, surgery, and mortality were analyzed. Results Adjusted prevalence of IBD, UC, CD, and IBD unclassified per 100,000 individuals in 2014 were 44.0, 24.5, 18.6, and 0.9, respectively. Age-adjusted incidence of IBD per 100,000 individuals increased from 0.10 (95% confidence interval, 0.06-0.16) in 1985 to 3.12 (95% confidence interval, 2.88-3.38) in 2014. UC:CD incidence ratio reduced from 8.9 to 1.0 over 30 years (P Conclusions In a population-based study in Hong Kong, prevalence of IBD is lower than in the west although comparable to that of other East Asian countries. Complicated CD is common. Overall mortality remains low in Asians with IBD.

Gut Microbial Diversity Is Reduced in Smokers with Crohn's Disease.

Abstract: BACKGROUND: Smoking has a negative impact on Crohn's disease (CD), but the mechanisms underlying this association are unclear. We compared the gut microbiota composition of smoking with nonsmoking patients with CD using a metagenomic approach. METHODS: Stool samples and clinical data were collected from current smokers and nonsmokers with CD from France and the Netherlands, matched for country, gender, age, disease activity, and body mass index. Fecal DNA was sequenced on an Illumina HiSeq 2500. On average, 40 million paired-end reads were generated per sample. Gene richness and the Shannon index were computed to assess microbial diversity. Wilcoxon's signed-rank tests for paired samples were performed to detect differences between the 2 groups. RESULTS: In total, 21 smoking and 21 nonsmoking patients with CD were included. Compared with nonsmoking patients, gut microbial gene richness (P = 0.01), genus diversity (P < 0.01), and species diversity (P = 0.01) were decreased in smoking patients. This was accompanied by a reduced relative abundance of the genera Collinsella (P = 0.02), Enterorhabdus (P = 0.02), and Gordonibacter (P = 0.02) in smokers. No statistically significant differences at the species level were observed, although smokers had lower proportions of Faecalibacterium prausnitzii (P = 0.10). CONCLUSIONS: Gut microbial diversity is reduced in smokers with CD compared with nonsmokers with CD. The microbial profile differs between these groups at the genus level. Future studies should evaluate whether intestinal microbes mediate the adverse effects of smoking in CD.

Diffusion-weighted Magnetic Resonance Enterography for Evaluating Bowel Inflammation in Crohn's Disease: A Systematic Review and Meta-analysis.

Abstract: BACKGROUND To systematically determine the performance of diffusion-weighted imaging magnetic resonance enterography (DWI-MRE) for evaluating bowel inflammation in Crohn's disease and sources of heterogeneity between reported results. METHODS We identified research studies that investigated DWI-MRE to diagnose bowel inflammation (present versus absent) or to assess bowel inflammatory severity in Crohn's disease by performing a systematic search of PubMed MEDLINE and EMBASE (until March 31, 2015). Study quality was assessed using QUADAS-2. For studies reporting dichotomous diagnosis of bowel inflammation, study heterogeneity and threshold effect were analyzed, summary sensitivity and specificity were estimated, and meta-regression analysis was performed to further explore study heterogeneity. For studies reporting assessment of inflammatory severity, a qualitative summary was performed. RESULTS Of 159 articles screened, we found 12 studies (1515 bowel segments) reporting a diagnosis of bowel inflammation and 6 studies (1066 bowel segments) reporting assessment of inflammatory severity. The summary sensitivity and specificity were 92.9% (95% CI, 85.8%-96.6%; I = 87.9%) and 91% (95% CI, 79.7%-96.3%; I = 95.1%), respectively. Sensitivity and false-positive rate were inversely correlated (r = -0.650; P = 0.022). Lack of blinding to contrast-enhanced MRE when interpreting DWI-MRE (P = 0.01) and use of contrast-enhanced MRE as a reference standard (P < 0.01) in some studies were significant factors for study heterogeneity and likely caused overestimation of DWI-MRE accuracy. There was rather clear correlation between diffusion-related parameters and bowel inflammation severity, although the strengths were heterogeneous (correlation coefficient, 0.39-0.98). CONCLUSIONS DWI-MRE accuracy was very heterogeneous between studies and was likely overestimated in some studies. Despite rather clear correlation between diffusion-related parameters and bowel inflammatory severity, its strength was variable.

Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial.

Abstract: Background In patients with inflammatory bowel disease (IBD) on infliximab, data are limited on immune response to influenza vaccine and the impact of vaccine timing. The study aims were to evaluate immune responses to the influenza vaccine in IBD patients on infliximab and the impact of vaccine timing on immune responses. Methods In this randomized study, 137 subjects with IBD on maintenance infliximab therapy were allocated to receive the 2012/2013 inactivated influenza vaccine at the time of infliximab infusion (n = 69) or midway between infusions (n = 68). Serum was collected before and after vaccination for hemagglutination inhibition titers. Serologic protection was defined by postvaccine titer of ≥1:40. Results Comparing subjects vaccinated at the time of infliximab with those vaccinated midway, serologic protection was achieved in 67% versus 66% to H1N1 (P = 0.8), in 43% versus 49% to H3N2 (P = 0.5), and in 69% versus 79% to influenza B (P = 0.2). Although solicited adverse events were common (60%), no subject experienced a serious adverse event requiring additional medical attention. Only 6% of subjects had a clinically significant increase in disease activity score, not impacted by vaccine timing. Conclusions Serologic protection to influenza vaccine is achieved in only approximately 45% to 80% of IBD patients on maintenance infliximab therapy varying by antigen. Yet, importantly, vaccine timing relative to infliximab infusion does not affect the achievement of serologic protection, and the influenza vaccine is well tolerated. Therefore, influenza vaccination at any point during infliximab scheduling is recommended for patients with IBD and opportunities to broaden the availability and convenience of influenza vaccine to optimize coverage should be explored.

Use of Methotrexate in the Treatment of Inflammatory Bowel Diseases.

Abstract: Low-dose methotrexate (MTX) therapy is a well-recognized therapy for many inflammatory conditions such as rheumatoid arthritis, psoriatic arthritis, and psoriasis. More than 20 years ago, the clinical efficacy of MTX was also established for steroid dependent Crohn's disease, but it was never broadly adapted as a treatment modality. More recently, MTX is being increasingly used in the pediatric population with Crohn's disease, both as a single agent as well as a concomitant therapy with anti-tumor necrosis factor-alpha treatment. This review outlines important pharmacological aspects for the therapeutic application of MTX and the current status of MTX as mono- or combination-therapy in both pediatric and adult patients with inflammatory bowel disease including new results of MTX monotherapy in steroid dependent ulcerative colitis.