bluuebunny/crossref_metadata_2025_split huggingface dataset:
A6 EFFECTS OF ELUXADOLINE TREATMENT ON ABDOMINAL AND BOWEL SYMPTOMS IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH DIARRHEA REPORTING INADEQUATE SYMPTOM CONTROL WITH LOPERAMIDE: AGGREGATED RESULTS FROM PHASE 3 AND 4 CLINICAL TRIALS
Authors: Brenner D M , Sayuk G , Saeed M , Janiszewski P , Liu L W 
Published: February 2020

Abstract

Background
The heterogeneous nature of irritable bowel syndrome with diarrhea (IBS-D) presents a complex challenge in the management of a wide range of symptoms. Despite the need for more effective treatments that provide global IBS-D symptom relief, many therapies currently available in Canada only treat individual IBS-D symptoms. Eluxadoline (ELX) is a mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved by Health Canada for the treatment of IBS-D in adults.

Aims
To analyze the efficacy of ELX for managing a constellation of IBS-D symptoms among patients (pts) self-reporting inadequate responses to loperamide (LOP) from Phase 3 and 4 trials of ELX.

Methods
Adults with IBS-D were randomized to placebo (PBO) or ELX (75 or 100 mg) twice daily (BID) for 26 or 52 weeks in two Phase 3 trials (NCT01553591 and NCT01553747); the data from a subset reporting inadequate IBS-D symptom control with prior LOP use were pooled and prospectively analyzed. In the Phase 4 trial (RELIEF: NCT02959983), IBS-D pts with self-reported inadequate symptom control with LOP over the previous 12 months were randomized to PBO or ELX 100 mg BID for 12 weeks. In all trials, pts recorded their daily IBS-D symptoms including worst abdominal pain (0–10 scale), stool consistency (Bristol Stool Form Scale score 1–7), and daily urgency episodes. Results for ELX 100 mg vs. PBO were evaluated after 12 weeks of treatment, which included the generation of radar plots to visualize multiple efficacy endpoints.

Results
Of pts enrolled in the Phase 3 trials with prior LOP use, inadequate control of IBS-D symptoms was reported in 58.9% (n=166) and 58.8% (n=174) of pts in the PBO and ELX groups, respectively; in the Phase 4 trial, 174 and 172 pts were treated with PBO and ELX, respectively. ELX-treated pts had a greater proportion of responders compared to PBO-treated pts for all outcomes, including a significant increase in the proportion of pts achieving both ≥50% and ≥75% urgency-free days in the Phase 3 trials (Figure). Analysis of the global symptoms of pts enrolled in the Phase 4 trial further supported these results. Across Phase 3 and 4 trials, adverse events occurred in similar proportions regardless of treatment, with the most common being nausea.

Conclusions
In pts with inadequate responses to LOP, a greater proportion of ELX-treated pts were responders compared to PBO-treated pts in all Phase 3 and 4 trials for the respective primary composite endpoints, abdominal pain, stool consistency, and urgency after 12 weeks of treatment. These results validate the effectiveness of ELX in alleviating IBS-D symptoms in this population.

Funding Agencies
Writing assistance by Complete HealthVizion, funded by Allergan plc
A9 BACTERIAL BILE SALT HYDROLASE GENE ABUNDANCE IS ASSOCIATED WITH RORC GENE EXPRESSION IN INTESTINAL MUCOSA OF INFLAMMATORY DISEASE PATIENTS
Authors: Hernandez-Rocha C , Borowski K , Turpin W , Smith M , Stempak J , Silverberg M S 
Published: February 2020

Abstract

Background
The role of gut microbes involved in bile acid metabolism and their impact on mucosal immune regulation is beginning to be appreciated. For instance, changes in microbial bile salt hydrolase (BSH) activity which deconjugates bile acids in the gastrointestinal tract of gnotobiotic mice, significantly alters gene expression patterns of immune-related genes in ileum. Moreover, bile acid dysmetabolism may participate in the chronic inflammation loop of Inflammatory bowel disease (IBD).

Aims
We carried out an integrated mucosal microbiome-transcriptome analysis to elucidate associations between microbial bile-acid metabolizing function and host gene expression.

Methods
Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) patients were recruited prior to scheduled colonoscopy performed as part of clinical care. Only patients with non-inflamed mucosa defined as a segmental simple endoscopic score 0–2 in CD and a segmental Mayo endoscopic score of 0 in UC/IBDU were included in this analysis to minimize the effect of inflammation on gene expression. Biopsy samples were obtained from terminal ileum, ascending colon and sigmoid colon, and microbial DNA and human RNA was extracted. V4 region of 16S rRNA gene was sequenced and the relative abundance of bile acid-metabolizing genes was inferred using PICRUSt. RNA-seq was used to sequence total human RNA and a supervised transcript reduction analysis focus upon 65 genes previously associated with bile acid metabolism and IBD was utilized. Associations between microbiome clusters of orthologous groups (COGs), transcriptome, diagnosis (CD vs UC/IBDU), and biopsy site were analyzed using linear mixed-effects model with lmer4 function in R. An adjusted-p value after false discovery rate correction &lt; 0.05 was considered significant.

Results
A total of 126 samples from 86 subjects were analyzed corresponding to 35 CD and 51 UC/IBDU. Mean age for the total cohort was 34.7 ± 11 years and 35 (40.6%) were females. There was a significant negative correlation between relative abundance of bacterial bsh genes (COG3049) and human RORC gene (p &lt; 0.03). This association was independent of type of diagnosis and biopsy site. There was no association among other analyzed bacterial COGs and host genes.

Conclusions
Using an integrative microbiome-host transcriptome approach, our data provide new evidence linking microbial bile acid deconjugation (bsh genes) and host gene expression in the mucosal-luminal interface in quiescent IBD-affected tissue. Nuclear receptor RORC is pivotal in the differentiation and function of innate lymphoid cells and T-helper 17 cells. Modulation of this pathway by bile acids or gut bacteria involved in their metabolism could shed light on the immune role of bile acids in IBD patients.

Funding Agencies
CAG, CIHRNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
A11 MICROBIAL AND METABOLOMIC PROFILES IDENTIFY SUBSETS OF DIARRHEA PREDOMINANT IRRITABLE BOWEL SYNDROME
Authors: Bennet S M , De Palma G , Bercik P , Lomax A E , Vanner S , Reed D E 
Published: February 2020

Abstract

Background
Irritable bowel syndrome (IBS) patients are subtyped by predominant bowel habit rather than pathophysiological mechanisms and this may underlie challenges in identifying more effective targets for designing new treatments. Metabolomics and microbial analysis can distinguish IBS patients from healthy controls but it is unknown if they can identify pathophysiological IBS subgroups.

Aims
To phenotype subgroups of IBS patients using metabolomics and microbial analysis and determine if these subgroups have different underlying pain signalling mechanisms.

Methods
Symptom history, stool and urine were collected from 30 diarrhea predominant (IBS-D) and 30 constipation predominant (IBS-C) IBS patients (Rome IV). Liquid Chromatography-Mass Spectrometry quantified 130 metabolites in stool and urine. The GA-map™ Dysbiosis Test targeting ≥300 bacteria on different taxonomic levels was used to identify stool microbial composition. Multivariate OPLS discriminatory analysis assessed metabolomics and microbial profiles. To assess potential effects on pain signalling, the effect of stool supernatant on dissociated dorsal root ganglia (DRG) neuron responses to capsaicin (10nM) was assessed using Ca2+ imaging.

Results
Within both IBS-D and IBS-C, combined stool/urine metabolomic profiles of patients with a dysbiosis-like (DL) IBS (onset following antibiotics, enteric infection, or travel) were distinct from patients with a non-DL IBS onset (IBS-D R2=0.7, Q2=0.5; IBS-C R2=0.5, Q2=0.4); fecal glutamic acid and urinary pyruvic acid were the main metabolites driving separation. However, microbial profiles of DL vs non-DL onset could only be discriminated in IBS-D (R2=0.8, Q2=0.4). In the patients with a DL IBS onset, stool metabolomic profiles of the 7 IBS-C discriminated from the 8 IBS-D patients (R2=0.9, Q2=0.8). Profile differences were not seen between IBS-C and IBS-D with a non-DL onset of IBS. In preliminary studies, incubation of DRG neurons with stool supernatant from 1 DL IBS-D and 1 non-DL IBS-D increased peak [Ca2+]i responses to capsaicin compared to incubation with media (DL: 5.5±0.9 vs 2.3±0.7; non-DL: 6.9±0.7 vs 3.9±0.4% ΔF/F). Similarly, the number of responsive neurons to capsaicin was increased after incubation with IBS stool supernatant vs media (DL: 27% vs 8%; non-DL 19% vs 12%).

Conclusions
Different metabolomic and bacterial profiles between DL and non-DL onset of IBS-D suggests a novel means to better phenotype clinically defined IBS subgroups. While initial results with stool supernatants from both a DL and non-DL IBS-D patient suggest increased pain signalling in DRG neurons, more studies are needed to determine if there are differences between these two subgroups as well as healthy controls.

Funding Agencies
CIHRSoutheastern Ontario Academic Medical Organization (SEAMO)
A22 ADVERSE EARLY LIFE EVENTS ARE COMMON IN PATIENTS WITH FUNCTIONAL AND ORGANIC GASTROINTESTINAL DISORDERS
Authors: Noejovich C V , Miranda P M , Collins S M , Verdu E , Pinto-Sanchez M I , Bercik P 
Published: February 2020

Abstract

Background
Stressful events in childhood have been associated with the development of functional gastrointestinal (GI) disorders in adulthood, especially irritable bowel syndrome. The influence of early life adverse events in patients with common organic disorders, such as celiac disease and inflammatory bowel disease (IBD), has been poorly investigated.

Aims
To evaluate the frequency of early life adverse events in patients with organic and functional gastrointestinal disorders compared to healthy controls.

Methods
Adult patients with an established diagnosis of IBS (Rome IV criteria), celiac disease and inflammatory bowel disease (IBD) attending a tertiary medical center, as well as healthy volunteers were interviewed by a psychologist. Early life adverse events were assessed during the semi-structured interview using a modified version of the Adverse Childhood Experience (ACE) questionnaire. Number of early life events and the presence of GI and extraintestinal symptoms based on a 10-point Likert scale were quantified. Data are presented as Median (IQR) and n (%). Statistical analysis was performed using Mann-Whitney and Fisher’s exact tests as appropriate.

Results
Sixty-eight patients (18 IBS, 28 celiac, 22 IBD) and 23 healthy controls were enrolled in the study. Patients with IBS, celiac disease and IBD had increased number of early life events compared with healthy controls (6.5 (4.8–8.3), 5.0 (3.0–9.0), 6.0 (4–8.3) vs 2.0 (1.0–4.0) respectively, p&lt;0.0001). Patients reported a higher number of mental disorders in their mothers (IBS p=0.01; celiac disease p=0.01; IBD p=0.001) and increased number of close family member abusing alcohol or drugs during their childhood (IBS p=0.01; celiac p=0.02; IBD p=0.02) compared to healthy controls. History of sexual abuse was higher in patients with IBS (p=0.01), while history of verbal abuse was higher in patients celiac disease and IBD (p=0.003 and p=0.001, respectively) compared to healthy controls. The number of early life adverse events was strongly correlated with number of GI (r= 0.91; p=0.01) and extra-intestinal (r=0.87; p=0.02) symptoms, but not with symptoms severity. Most patients with IBS (83.3%), celiac disease (89.3%) and IBD (85.7%) reported stressful events before the onset of their disease.

Conclusions
Adverse events in childhood are frequent in patients with chronic GI disorders, both of functional and organic origin. Furthermore, stressful events often precede their diagnosis. These data strongly suggest that better psychosocial assessment in patients with chronic GI disorders is needed to improve their overall management.

Funding Agencies
None
A23 NUTRITIONAL DEFICIENCIES ARE FREQUENT IN CELIAC PATIENTS ON A GLUTEN-FREE DIET, REGARDLESS OF THE DURATION AND COMPLIANCE OF THE DIET
Authors: Jivraj A , Connan V , Balart T , Ching E , Marwaha A , Verdu E , Armstrong D , Pinto-Sanchez M I 
Published: February 2020

Abstract

Background
The only available treatment for celiac disease (CD) is adherence to a strict gluten-free diet (GFD). CD is associated with several nutritional deficiencies, which could be explained by malabsorption when the disease is active. However, the magnitude of nutritional deficiencies in treated CD and how this is influenced by the duration and compliance of GFD is less clear.

Aims
We aim to evaluate the presence of nutritional deficiencies in celiac patients on short term (≤2yrs) vs long-term (&gt;2yrs) GFD, and in those with persistent symptoms or asymptomatic in the follow up.

Methods
We included consecutive biopsy-proven CD patients attending the McMaster Adult Celiac Clinic. GFD adherence was assessed by validated Celiac Dietary Adherence Test (CDAT) and by anti-tissue transglutaminase antibody IgA(tTG IgA) levels. Serology, vitamins and minerals were measured in blood samples collected at enrolment. Continuous data was expressed as Median (IQR) and categorical data as proportion%. Mann-U-Whitney and Chi2 were used to compare difference between groups.

Results
We enrolled 171 CD patients (80% female; Median age 43 years). 76/171 (44%) of CD patients were following a GFD for over 2 years. Eighty-two percent of the patients (141/171) had persistent symptoms in the follow up and 80.7% had normal tTG IgA levels. The most common nutritional abnormalities were deficiencies in zinc (56%), iron (23%), copper (20%). Chromium was increased in 74% of patients. There were no differences in nutritional deficiencies between group of patients with short and long-term duration of GFD, nor between those strictly compliant with GFD compared to those fairly compliant (p&gt;0.05).

Conclusions
Nutritional deficiencies are frequent in celiac patients on a GFD regardless of the presence of symptoms, dietary compliance or duration. The previous suggest that nutrients deficiencies may be more related to GFD nutritional inadequacy rather than malabsorption.

Funding Agencies
None
A28 RELATIVE RATES OF ULCERATIVE COLITIS TO CROHN’S DISEASE: PARALLEL EPIDEMIOLOGIES IN NEWLY VS. HIGHLY INDUSTRIALIZED COUNTRIES
Authors: Windsor J W , Buie M , Coward S , Gearry R , Hansen T , King J A , Kotze P , Ma C , Ng S , Panaccione N , Panaccione R , Quan J , Seow C , Underwood F , Kaplan G G 
Published: February 2020

Abstract

Background
Inflammatory bowel disease (IBD) first presents in a population as cases of ulcerative colitis (UC) followed by cases of Crohn’s disease (CD). Newly industrialized countries (NIC) show a prallel epidemiology of IBD to highly industrialized countries (HIC) in the previous century; one marker of this is the relative incidence/prevalence rates of UC to CD, which approximates 1 over time.

Aims
Provide evidence for the UC:CD ratio as a proxy for disease penatrance in a population.

Methods
Systematic review of MedLine and Embase for studies reporting incidence or prevalence of UC and CD. Log-linear regression (by region and NIC/HIC [2019 United Nations definitions]) was used to calculate average annual percent change (AAPC) and associated 95% confidence intervals (CI). Data were plotted on an online, interactive map to show trends (link provided).

Results
We extracted data from 218 studies compising population-level data from 69 countries. We found negative AAPCs as the prevalence ratio of UC:CD significantly decreased over time in East Asia, West Asia, North Europe, and South Europe; 6/12 global regions displayed significantly decreasing incidence ratios. No AAPC was found to be significantly increasing (Table 1). When examing HIC/NIC, we found a significant effect of NIC on the UC:CD prevalence ratio after 2000 (AAPC:−3.83;95%CI:−6.28,−1.31) while HIC regions remained stable (AAPC:2.14;95%CI:−1.40,5.82). Looking at all available data, both HICs and NICs show significantly decreasing UC:CD prevalence ratios (HIC:AAPC:−3.72;95% CI:−4.46,−2.97; NIC:AAPC:−2.62;95%CI:−4.13,−1.08).

Conclusions
In some HICs (eg. Canada), the UC:CD incidence ratio was &lt;1 in the earliest available data (1966), explaining the stable AAPC in North America (AAPC:−0.24;95%CI:−1.12,0.65). However, in NICs (eg. Southern Asia), the AAPC is rapidly decreasing (AAPC:−24.68;95%CI:−37.85,−8.71) as areas like Sri Lanka rapidly fall from an incidence ratio of 7.5 (2007) to 2.8 (2012), mimicking trends in IBD epidimeology of HICs in the previous century.

Funding Agencies
None
A31 ALTERED SMALL INTESTINAL EPITHELIAL HOMEOSTASIS AND CELL FATE DECISION UPON LOSS OF TRP53 IN KRT15+ INTESTINAL STEM CELLS
Authors: Dubey A , Giroux V 
Published: February 2020

Abstract

Background
Intestinal homeostasis is mainly maintained by two groups of stem cells: Lgr5+ stem cells and reserve stem cells. Recently, we reported that Krt15+ cells are present in small intestinal and colon epithelia, and harbor self-renewal, multipotent and regenerative capacities. Initiation of sporadic colorectal cancer has been described in Krt15+ stem cells, Lgr5+ stem cells and reserve stem cells following the loss of Apc. While these intestinal stem cell (ISC) populations can act as tumor-initiating cells in sporadic colon cancer, little is known about the cell-of-origin of colitis-associated colon cancer. TP53 alteration is reported as an early event in colitis-associated colon cancer cases. Therefore, we hypothesize that Trp53 loss specifically in Krt15+ stem cells will perturb the epithelial homeostasis and lead to tumor formation

Aims
Identify if Krt15+ cells may act as the cell-of-origin in colitis-associated colorectal cancer.

Methods
To induce Trp53 loss specifically in Krt15+ cells, we generated Krt15-CrePR1;Trp53fl/fl (Krt15△Trp53) mice, induced Cre recombination by injecting RU486 (PR agonist) and euthanized the mice after 12 months following recombination. Histological analysis was performed on small intestinal tissues.

Results
Results: Trp53 loss in Krt15+ cells severely perturbed small intestinal morphology. Increased crypt (proliferative compartment) length correlated with no proliferation changes surprisingly but higher number of Paneth cells and abnormal presence of goblet cells. Interestingly, we also observed the presence of cells expressing both Paneth and goblet cells markers suggesting a deregulation of secretory cell fate decision. Decreased expression of Hes1 and increased β-catenin nuclear expression in the small intestinal crypt of Krt15△Trp53 mice suggest altered Notch and Wnt signaling. Furthermore, villi (differentiated compartment) were significantly wider and shorter, and showed accumulation of activated fibroblasts. Finally, we observed inflammatory lesions as well as adenomas in the small intestine of Krt15△Trp53 mice which remain to be further characterized

Conclusions
Conclusion: In summary, Trp53 loss specifically in Krt15+ cells impaired cell fate decision, induced inflammation and initiated tumor formation. Overall, these results suggest that Krt15+ cells could act as the cell-of-origin of colitis-associated colon cancer.

Funding Agencies
Cancer Research Society, CRC Tier 2
A39 NOVEL GAIN OF FUNCTION NON-RECEPTOR TYROSINE KINASE MUTATIONS ARE LINKED TO THE PATHOGENESIS OF VEOIBD
Authors: Mehta M , Wang L , Guo C , Warner N , Li Q , Pan J , Boztug K , Uhlig H , Muise A 
Published: February 2020

Abstract

Background
Very early-onset inflammatory bowel disease (VEOIBD) is an emerging global disease, that results in inflammation of the digestive tract. Severe forms of VEOIBD can be caused by mutations in a single gene (monogenic variants) and, can result in death. A candidate gene which codes for a non-receptor tyrosine kinase (nRTK) has recently been implicated as a monogenic cause of IBD (unpublished). Whole exome sequencing was performed in two unrelated children who presented with symptoms of IBD identifying two distinct de novo gain of function mutations (S550Y and P342T). Both mutations are located in the highly conserved region of the nRTK, and were predicted to have similar downstream effects. Furthermore, four other patients with a variety of adult-onset immune disorders have recently been identified with rare variants in the same gene (M450I, R42P, A353T, V433M, S550F) but, their potential gain of function status remains to be determined. Studies show that this nRTK is an essential mediator in inflammation. It is expressed in both intestinal epithelial and immune cells however, its role in infantile IBD is unclear. This protein is first activated by phosphorylation and is linked to activating downstream transcription factors such as ERK and JNK. All these target proteins play a meaningful role in intestinal inflammation in patients with IBD.

Aims
Since we identified P342T and S550Y to be gain of function, we wanted to determine if the new variants exhibit a similar downstream impact on target protein expression levels when compared with S550Y and P342T. We also wanted to identify if all variants can be rescued with a known nRTK inhibitor. It is hypothesized that the new variants are gain of function and that all variants can be rescued with the inhibitor.

Methods
Using western blot analysis, the activation of ERK, JNK and nRTK was compared between wildtype (WT) and mutants. This in vitro method helped identify the degree of activation. For the second part of the study, HEK293T cells were treated with inhibitor to test for a rescue of phenotypes via western blot analysis.

Results
Results show an increased activation of nRTK, ERK and JNK in all variants with S550Y and S550F having the highest activation. Furthermore, pharmacological inhibition using small molecular kinase inhibitors resulted in decreased activation of nRTK, ERK and JNK suggesting a rescue of phenotypes.

Conclusions
Characterizing the downstream functional impact of these nRTK variants is an important first step to determine if gain of function nRTK mutations drive IBD. With a rising prevalence of IBD worldwide, these findings may lead to the development of pharmacological nRTK inhibitors as a novel personalized therapeutic approach for these patients and possibly for the broader IBD population.

Funding Agencies
CIHR