Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

Environmental Factors Associated with Risk of Crohn's Disease Development in the Crohn's and Colitis Canada - Genetic, Environmental, Microbial Project.

BACKGROUND & AIMS: To date, it is unclear how environmental factors influence Crohn's disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers. METHODS: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing. RESULTS: Over a 5.62-year median follow-up, 86 FDRs developed CD. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased CD risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased CD risk. Furthermore, living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher FCP levels. Large family during participants' first year of life was associated with altered microbiota composition without affecting FCP or LMR. CONCLUSION: This study identifies environmental variables associated with CD risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in CD pathogenesis.

Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis.

OBJECTIVE: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort. DESIGN: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay. RESULTS: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all). CONCLUSION: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction.

Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

BACKGROUND AND AIMS: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development. METHODS: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis. RESULTS: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation. CONCLUSIONS: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.

High prevalence of adenomatous colorectal polyps in young cancer survivors treated with abdominal radiation therapy: results of a prospective trial.

OBJECTIVE: Cancer survivors treated with abdominal/pelvic radiation therapy (ART) have increased the risks of colorectal cancer (CRC), although evidence supporting early CRC screening for these patients is lacking. We sought to determine whether there is an elevated prevalence of adenomatous colorectal polyps in young survivors prior to the age when screening would be routinely recommended. DESIGN: We conducted a prospective study of early colonoscopic screening in cancer survivors aged 35-49 who had received ART ≥10 years previously. The planned sample size was based on prior studies reporting a prevalence of adenomatous polyps of approximately 20% among the average-risk population ≥50 years of age, in contrast to ≤10% among those average-risk people aged 40-50 years, for whom screening is not routinely recommended. RESULTS: Colonoscopy was performed in 54 survivors, at a median age of 45 years (range 36-49) and after median interval from radiation treatment of 19 years (10.6-43.5). Forty-nine polyps were detected in 24 patients, with 15 patients (27.8%; 95% CI 17.6% to 40.9%) having potentially precancerous polyps. Fifty-three per cent of polyps were within or at the edge of the prior ART fields. CONCLUSIONS: Young survivors treated with ART have a polyp prevalence comparable with the average-risk population aged ≥50 years and substantially higher than previously reported for the average-risk population aged 40-50 years. These findings lend support to the early initiation of screening in these survivors. CLINICAL TRIAL REGISTRATION NUMBER: NCT00982059; results.

Progressive learning in endoscopy simulation training improves clinical performance: a blinded randomized trial.

BACKGROUND AND AIMS: A structured comprehensive curriculum (SCC) that uses simulation-based training (SBT) can improve clinical colonoscopy performance. This curriculum may be enhanced through the application of progressive learning, a training strategy centered on incrementally challenging learners. We aimed to determine whether a progressive learning-based curriculum (PLC) would lead to superior clinical performance compared with an SCC. METHODS: This was a single-blinded randomized controlled trial conducted at a single academic center. Thirty-seven novice endoscopists were recruited and randomized to either a PLC (n = 18) or to an SCC (n = 19). The PLC comprised 6 hours of SBT, which progressed in complexity and difficulty. The SCC included 6 hours of SBT, with cases of random order of difficulty. Both groups received expert feedback and 4 hours of didactic teaching. Participants were assessed at baseline, immediately after training, and 4 to 6 weeks after training. The primary outcome was participants' performance during their first 2 clinical colonoscopies, as assessed by using the Joint Advisory Group Direct Observation of Procedural Skills assessment tool (JAG DOPS). Secondary outcomes were differences in endoscopic knowledge, technical and communication skills, and global performance in the simulated setting. RESULTS: The PLC group outperformed the SCC group during first and second clinical colonoscopies, measured by JAG DOPS (P < .001). Additionally, the PLC group had superior technical and communication skills and global performance in the simulated setting (P < .05). There were no differences between groups in endoscopic knowledge (P > .05). CONCLUSIONS: Our findings demonstrate the superiority of a PLC for endoscopic simulation, compared with an SCC. Challenging trainees progressively is a simple, theory-based approach to simulation whereby the performance of clinical colonoscopies can be improved. (Clinical trial registration number: NCT02000180.).

Factors that Influence Health-Related Quality of Life in Patients with Primary Sclerosing Cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an incurable, cholestatic liver disease often coincident with inflammatory bowel disease (IBD). AIMS: To evaluate the impact of liver disease and IBD on health-related quality of life (HRQoL) in PSC. METHODS: A mixed-methods, cross-sectional study was performed at a tertiary center. Short Form-36 (SF-36) scores were compared between PSC, Canadian normative data, and disease controls. Disease-specific instruments scores [PBC-40, Short IBD questionnaire, Liver Disease Quality of Life Questionnaire (LDQOL)] were compared between PSC and disease controls. Multivariable regression identified factors independently associated with final SF-36 component scores. Qualitative evaluation of patient questionnaires was performed using a content analysis framework. RESULTS: One hundred and sixty-two surveys were completed (99 PSC, 26 primary biliary cirrhosis, 16 non-autoimmune cholestatic liver disease, and 21 IBD). PSC patients had significantly lower SF-36 scores than Canadian controls, but similar scores to disease controls. LDQOL most accurately predicted HRQoL. Factors negatively associated with physical HRQoL included shorter IBD duration, liver disease symptoms, and decompensated cirrhosis. Mental HRQoL was influenced by liver disease and IBD symptoms, pruritus, social isolation, and depression. Nearly 75 % expressed existential anxiety regarding disease progression and diminished life expectancy, with 25 % disclosing social isolation. CONCLUSIONS: Patients with PSC have significantly lower HRQoL than healthy controls. Both symptoms of IBD and chronic liver disease impact HRQoL in patients with PSC, which lead to significant psychologic burden that is expressed by existential anxieties and social isolation. A PSC-specific HRQoL tool is critical to adequately quantify the distinct impact of IBD and cholestatic liver disease.

Impact of a simulation training curriculum on technical and nontechnical skills in colonoscopy: a randomized trial.

BACKGROUND: GI endoscopy simulation-based training augments early clinical performance; however, the optimal manner by which to deliver training is unknown. OBJECTIVE: We aimed to validate a simulation-based structured comprehensive curriculum (SCC) designed to teach technical, cognitive, and integrative competencies in colonoscopy. DESIGN: Single-blinded, randomized, controlled trial. SETTING: Endoscopic simulation course at an academic hospital. PARTICIPANTS AND INTERVENTIONS: Thirty-three novice endoscopists were allocated to an SCC group or self-regulated learning (SRL) group. The SCC group received a curriculum consisting of 6 hours of didactic lectures and 8 hours of virtual reality simulation-based training with expert feedback. The SRL group was provided a list of desired objectives and was instructed to practice on the simulator for an equivalent time (8 hours). MAIN OUTCOME MEASUREMENTS: Clinical transfer was assessed during 2 patient colonoscopies using the Joint Advisory Group Direct Observation of Procedural Skills (JAG DOPS) scale. Secondary outcome measures included differences in procedural knowledge, immediate post-training simulation performance, and delayed post-training (4-6 weeks) performance during an integrated scenario test on the JAG DOPS communication and integrated scenario global rating scales. RESULTS: There was no significant difference in baseline or post-training performance on the simulator task. The SCC group performed superiorly during their first and second clinical colonoscopies. Additionally, the SCC group demonstrated significantly better knowledge and colonoscopy-specific performance, communication, and global performance during the integrated scenario. LIMITATIONS: We were unable to measure SRL participants' effort outside of mandatory training. In addition, feedback metrics and number of available simulation cases are limited. CONCLUSIONS: These results support integration of endoscopy simulation into a structured curriculum incorporating instructional feedback and complementary didactic knowledge as a means to augment technical, cognitive, and integrative skills acquisition, as compared with SRL on virtual reality simulators. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01991522.)

The phenotypic expression of inflammatory bowel disease in patients with primary sclerosing cholangitis differs in the distribution of colitis.

BACKGROUND: Inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC) is reported to be mild and prone to right-side predominance with rectal sparing. However, no dedicated studies evaluating patterns of presentation of liver disease with respect to IBD are available. METHODS: We performed a detailed histological examination of the colonic biopsies in the context of PSC, identifying 97 patients [89 with ulcerative colitis and ten with Crohn's disease (CD)] stratified into two groups, based on their initial disease presentation: hepatic/biliary (group 1-PSC-IBD; n=56) versus colonic (group 2-IBD-PSC; n=41). RESULTS: Inflammatory bowel disease that preceded PSC had a tendency to have a "pan-colitis" distribution; this group included all patients with CD. Inflammatory bowel disease diagnosis that followed PSC presentation was more likely to be right-sided, sparing the descending, sigmoid and rectal regions (p=0.002). In both groups, colitis was mild with focal deep plasmacytosis and occasional mild cryptitis. Active cryptitis with crypt abscesses, surface erosion and ulceration were not identified in any of the patients. CONCLUSION: Colitis associated with PSC shows mild disease activity and the colitis pattern is associated with disease presentation, i.e. colitis preceding PSC (IBD-PSC cohort) typically have a pancolitic distribution, while colitis following PSC (PSC-IBD cohort) demonstrates right-sided predominance. Awareness by pathologists and clinicians of these patterns of inflammatory bowel disease is important and of use in directing appropriate investigations for patients.

Validation of a mathematical model for ultrasound assessment of gastric volume by gastroscopic examination.

INTRODUCTION: Pulmonary aspiration of gastric contents is a serious perioperative complication. Previous models of ultrasound gastric volume assessment are preliminary and have not been validated by an external "gold standard." In the present study we propose a more accurate model based on prospective data obtained from 108 patients undergoing bedside gastric sonography and upper gastrointestinal endoscopy (UGE). METHODS: Patients undergoing elective UGE were randomized to ingest one of 6 predetermined volumes of apple juice after an 8-hour fasting period. A cross-sectional area of the antrum in the right lateral decubitus position (Right lat CSA) was measured by a blinded sonographer following a standardized scanning protocol. Gastric fluid was subsequently suctioned under gastroscopic vision during UGE performed by a blinded gastroenterologist and measured to the nearest milliliter. RESULTS: Data from 108 patients suggest that a previously reported model tends to overestimate gastric volume particularly at low volume states. A new best fit mathematical model to predict gastric fluid volume based on measurements of Right lat CSA is presented. This new model built on a more accurate gold standard can be used to estimate gastric volumes from 0 to 500 mL, in nonpregnant adults with body mass index<40 kg/m2. CONCLUSIONS: We report a new prediction model to assess gastric fluid volume using standard 2-dimentional bedside ultrasound that has several advantages over previously reported models.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

Adult-onset autoimmune-type enteropathy: potential relationship to an adverse drug reaction.

OBJECTIVE: To describe an example of adult-onset autoimmune enteropathy (AIE) that coincided with drug-induced reaction. DESIGN: A 54-year-old patient was presented with Stevens-Johnson syndrome after a course of quinolones. This was followed shortly thereafter by epigastric pain, diarrhoea and weight loss. She also developed an autoimmune neutropenia. RESULTS: Several biopsies were performed from the upper and lower gastrointestinal tract (GIT). The duodenal biopsies showed intraepithelial lymphocytosis; therefore, coeliac disease was considered. However, confirmatory serology was negative and the patient did not respond to a gluten-free/gliadin-free diet. Both upper and lower GIT biopsies consistently showed an absence of goblet cells resembling the changes of an AIE. CONCLUSION: This is an unusual case of autoimmune-pattern enteropathy in an adult that was potentially drug-induced.

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: a randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes.

INTRODUCTION: Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5-10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. METHODS AND ANALYSIS: Children and adults (8-45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. ETHICS AND DISSEMINATION: The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. TRIAL REGISTRATION NUMBER: NCT01566110.

Employment prospects and trends for gastroenterology trainees in Canada: a nationwide survey.

BACKGROUND: Many gastroenterology (GI) trainees face a variety of barriers to stable employment and are finding it increasingly difficult to secure employment in their chosen field. OBJECTIVE: To elucidate factors that contribute to the burden of unemployment and underemployment, and to examine solutions that may remedy this growing problem in the field of GI. METHODS: A nationwide survey of current, incoming and recently graduated individuals of GI training programs in Canada was conducted. Trainees in pediatric GI programs and those enrolled in subspecialty programs within GI were also included. RESULTS: The response rate was 62%, with 93% of respondents enrolled in an adult GI training program. Many (73%) respondents planned to pursue further subspecialty training and the majority (53%) reported concerns regarding job security after graduation as contributory factors. Only 35% of respondents were confident that they would secure employment within six months of completing their training. Regarding barriers to employment, the most cited perceived reasons were lack of funding (both from hospitals and provincial governments) and senior physicians who continue to practice beyond retirement years. Sixty-nine per cent perceived a greater need for career guidance and 49% believed there were too many GI trainees relative to the current job market in their area. Most residents had a contingency plan if they remained unemployed >18 months, which often included moving to another province or to the United States. CONCLUSION: GI trainees throughout Canada reported substantial concerns about securing employment, citing national retirement trends and lack of funding as primary barriers to employment. Although these issues are not easily modifiable, certain problems should be targeted including optimizing training quotas, tailoring career guidance to the needs of the population, and emphasizing credentialing and quality control in endoscopy.

Bone mineral density in Crohn's disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy.

OBJECTIVE: Corticosteroids may contribute to the bone loss associated with Crohn's disease (CD). We investigated the effect on bone mineral density (BMD) of treatment with budesonide, a steroid with low systemic activity, and compared the outcome with prednisone and nonsteroid therapy in patients with CD. METHODS: Prospective annual BMDs of the lumbar spine (LS) and femoral neck (FN) were measured for 2 yr in 138 patients with quiescent CD treated with mean daily doses of 8.5 mg of budesonide (n = 48), 10.5 mg of prednisone (n = 45), or nonsteroid drugs (n = 45). RESULTS: Between baseline and 1 yr, the mean LS BMD decreased 2.36% in the budesonide group (p < 0.001), 0.61% in the prednisone group (ns), and 0.09% in the nonsteroid group (ns). The difference between budesonide and nonsteroid groups was significant (p = 0.003). In the 2nd yr, LS BMD did not change in the three groups. After 2 yr, FN BMD decreased 2.94% in the budesonide group (p < 0.01), 0.36% in the prednisone group (ns), and 1.05% in the nonsteroid group (ns); the differences among groups were not significant. The proportion of patients with bone loss of >2% per annum at the LS and FN was higher in the budesonide group than in the nonsteroid group (p < 0.001) and prednisone group (p < 0.05). CONCLUSIONS: Patients with CD receiving maintenance treatment for 2 yr with prednisone show little change in BMD, whereas treatment with budesonide may be associated with LS and FN bone loss. Budesonide does not confer an advantage over low-dose prednisone for the preservation of BMD.