bluuebunny/crossref_metadata_2025_split huggingface dataset:
A9 DORSAL ROOT GANGLIA NEURONAL RESPONSES AND SUBSTANCE P PRODUCTION ARE HIGHER IN MALE MICE
Authors: Pujo J , De Palma G , Lu J , Collins S M , Bercik P 
Published: March 2021

Abstract

Background
Abdominal pain is a common complaint in patients with chronic gastrointestinal disorders. Accumulating evidence suggests that gut microbiota is an important determinant of gut function, including visceral sensitivity. Germ-free (GF) mice have been shown to display visceral hypersensitivity, which normalizes after colonization. Sex also appears to play a key role in visceral sensitivity, as women report more abdominal pain than men. Thus, both gut bacteria and sex are important in the regulation of gut nociception, but the underlying mechanisms remain poorly understood.

Aims
To investigate the role of gut microbiota and sex in abdominal pain.

Methods
We used primary cultures of sensory neurons from dorsal root ganglia (DRG) of female and male conventionally raised (SPF) or germ-free (GF) mice (7–18 weeks old). To study the visceral afferent activity in vitro, calcium mobilization in DRG sensory neurons was measured by inverted fluorescence microscope using a fluorescent calcium probe Fluo-4 (1mM). Two parameters were considered i) the percentage of responding neurons ii) the intensity of the neuronal response. First, DRG sensory neurons were stimulated by a TRPV1 agonist capsaicin (12.5nM, 125nM and 1.25µM) or by a mixture of G-protein coupled receptors agonist (GPCR: bradykinin, histamine and serotonin; 1µM, 10µM and 100µM). We next measured the neuronal production of substance P and calcitonin gene-related peptide (CGRP), two neuropeptides associated with nociception, in response to capsaicin (1.25µM) or GPCR agonists (100µM) by ELISA and EIA, respectively.

Results
The percentage of neurons responding to capsaicin and GPCR agonists was similar in male and female SPF and GF mice. However, the intensity of the neuronal response was higher in SPF male compared to SPF female in response to capsaicin (125nM: p=0.0336; 1.25µM: p=0.033) but not to GPCR agonists. Neuronal activation was similar in GF and SPF mice of both sexes after administration of capsaicin or GPCR agonists. Furthermore, substance P and CGRP production by sensory neurons induced by capsaicin or GPCR agonists was similar in SPF and GF mice, regardless of sex. However, while the response to capsaicin was similar, the GPCR agonists-induced production of substance P was higher in SPF male mice compared to SPF females (p=0.003). The GPCR agonists-induced production of CGRP was similar in SPF male and female mice.

Conclusions
Our data suggest that at the level of DRG neurons, the absence of gut microbiota does not predispose to visceral hypersensitivity. The intensity of DRG neuronal responses to capsaicin and the GPCR agonists-induced production of substance P are higher in male compared to female mice, in contrast to previously published studies in various models of acute and chronic pain. Further studies are thus needed to investigate the role of sex in visceral sensitivity.

Funding Agencies
CIHR
A14 WIDE VARIATION IN CLINICAL MANAGEMENT OF PAEDIATRIC EOSINOPHILIC ESOPHAGITIS: A CANADIAN EXPERIENCE.
Authors: Bortolin K A , Ashok D , Avinashi V , Barkey J , Burnett D , Critch J , Drouin E , Griffin J , Huynh H , Marcon P , Martinez A , Persad R , Sherlock M , Waterhouse C , Hulst J M 
Published: March 2021

Abstract

Background
Eosinophilic esophagitis (EoE) is a chronic disorder treated by food elimination diet (FED), topical steroids and/or proton-pump inhibitors (PPI). Serial endoscopies and biopsies assess response to therapy. EoE management has evolved as guidelines are updated.

Aims
To identify practice variation among Canadian paediatric gastroenterologists (PG) who care for children with EoE.

Methods
An online survey using REDCap about decision-making in children with EoE was distributed to PG in Canada in November 2020.

Results
62 PG completed the survey (response rate 69%, 62/94). The majority work in academic centres (92%). 3 centers indicated an accrual of &gt;50 new patients per year; 9/16 centres have &gt;100 patients in follow-up. An EoE Clinic is present in 5 centres.
Diagnosis: Familiarity with the 2018 AGREE and 2020 AGA EoE guidelines was found to be 57% and 67% respectively. Criteria required to diagnose EoE according to current guidelines were correctly indicated by 42% of PG. (Figure 1).
Endoscopy: The majority of PG (95%) adhere to guidelines in terms of required number and location of biopsies for the initial diagnosis. Ideal timing of repeat endoscopy after change in therapy in patients who are not in histological remission was 8–12 weeks by 67% of PG, timing in stable patients on maintenance therapy varied (33% only if patient is symptomatic). 25% used the EREFS Score in reporting endoscopic findings.
Therapy: Improvement of symptoms was the highest ranked goal (64%), followed by remission of histologic findings (30%). A treatment algorithm was in place in 4 centers. The majority routinely assess adherence to therapy (73%) and consult a dietitian for FED (77%). Most (87%) do not consult an allergist for initial management. Preferred choices of 1st-line therapy varied among PG (Figure 2). When FED was selected, 32% of PG started with 1 food, 32% started with 2 foods, most frequently excluding dairy, followed by wheat. 14 (26%) start with ≥6 FED. Prescription of budesonide slurry was consistent among PG with doses of 1 and 2 mg/day in children &lt;10 and &gt;10 years, respectively.

Conclusions
The is the first Canadian study to assess the variation in management of children with EoE by PG. Overall, PG demonstrated good adherence to the guidelines in terms of initial diagnosis, but differences in maintenance therapy choice and timing of endoscopies. The results highlight a need for standardized management algorithms to deliver uniform care to this growing group. Grounding these guidelines in evidence will warrant a significant investment in further paediatric EoE research.

Funding Agencies
None
A15 EFFICACY AND SAFETY OF FILGOTINIB AS INDUCTION THERAPY FOR PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 2B/3 SELECTION STUDY
Authors: Feagan B G , Loftus E V , Danese S , Vermeire S , Sandborn W J , Ritter T , Mehta R , Seidler U , Seibold F , Beales I , Kim H , McNally J , Yun C , Zhao S , Liu X , Tasset C , Besuyen R , Watanabe M , Schreiber S , Rogler G , Hibi T , Peyrin-Biroulet L 
Published: March 2021

Abstract

Aims
The SELECTION (NCT02914522) Induction Studies evaluated the efficacy/safety of filgotinib (FIL), a preferential JAK1 inhibitor, as induction therapy for patients (pts) with moderately to severely active ulcerative colitis (UC) who were biologic-naïve but failed conventional therapy (Induction Study A) or failed prior biologics (Induction Study B).

Methods
Pts were randomized 2:2:1 to once–daily FIL 200mg, FIL 100mg or placebo (PBO). The primary (clinical remission), key secondary (Mayo Clinic Score [MCS] remission, endoscopic remission, and histologic remission), and exploratory endpoints (MCS response and endoscopic improvement) were assessed at Week 10.

Results
In both studies, baseline demographics and disease characteristics were similar across treatment groups. In Study A, 659 pts were randomized and treated. Baseline mean MCS was 8.6 and 56% had a Mayo endoscopic subscore (ES)=3. A significantly higher proportion of biologic-naïve pts on FIL 200mg achieved clinical remission vs PBO and all key secondary endpoints (Table). In Study B, 689 pts were randomized and treated. Baseline mean MCS was 9.3 and 78% had ES=3. Prior treatment failures were: anti-TNF (86%), vedolizumab (52%) and both (dual-refractory; 43%). A significantly higher proportion of biologic-experienced pts on FIL 200mg achieved clinical remission vs PBO. In Studies A and B, a greater proportion of pts on FIL 200 mg achieved an MCS response and endoscopic improvement vs PBO.
The rates of AEs, serious AEs and discontinuations due to AEs were similar across FIL and PBO groups during induction. In the PBO, FIL 100mg and FIL 200mg groups, serious infections occurred in 0.7%, 0.7% and 0.4% pts in Study A and 1.4%, 1.4% and 0.8% pts in Study B; H Zoster occurred in &lt;1% in both groups for both cohorts.

Conclusions
SELECTION included a high proportion of dual-refractory pts, and pts with severe endoscopic disease. Both doses of FIL were well tolerated. Filgotinib 200mg was effective induction therapy for both biologic-naïve/-experienced pts with moderately to severely active UC.

Funding Agencies
None
A21 ULCERATIVE COLITIS-ASSOCIATED E. COLI PATHOBIONTS POTENTIATE COLITIS IN SUSCEPTIBEL HOSTS.
Authors: Yang H , Mirsepasi-Lauridsen H , Struve C , Allaire J M , Sivignon A , Vogl W , Bosman E S , Ma C , Fotovati A , Reid G , Li X , Petersen A M , Gouin S , Barnich N , Jacobson K , Yu H , Krogfelt K , Vallance B 
Published: March 2021

Abstract

Background
Ulcerative colitis (UC) is a chronic inflammatory condition linked to intestinal microbial dysbiosis, including the expansion of E. coli strains related to extra-intestinal pathogenic E. coli. These “pathobionts” exhibit pathogenic properties, but their potential to promote UC is unclear due to the lack of relevant animal models.

Aims
We explored the potential to establish a mouse model of GI infection by the UC-associated E. coli strain p19A, as well as characterize the pathogenic features of p19A.

Methods
We used a representative UC pathobiont strain (p19A), and mice lacking single immunoglobulin and toll-interleukin 1 receptor domain (SIGIRR), a deficiency increasing susceptibility to gut infections. Vancomycin-pretreated Sigirr-/- mice were subsequently gavaged with the control E. coli DH10B (a derivative of commensal strain K-12) or p19A. One day after infection, mice were exposed to 2.5% dextran sodium sulfate (DSS) in their drinking water for another 4 days.

Results
Strain p19A was found to adhere to the cecal mucosa of Sigirr-/- mice, causing modest inflammation. Moreover, it dramatically worsened DSS-induced colitis. This potentiation was attenuated using a p19A strain lacking α-hemolysin genes, or when we targeted pathobiont adherence using a p19A strain lacking the adhesin FimH, or following treatment with FimH antagonists.

Conclusions
Thus, UC pathobionts adhere to the intestinal mucosa, and worsen the course of colitis in susceptible hosts in a manner dependent on specific virulence factors, including α-hemolysin and FimH.

Funding Agencies
CCC, CIHR
A25 THE RISING GLOBAL INCIDENCE OF PEDIATRIC INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW OF POPULATION-BASED STUDIES
Authors: Kuenzig E , Fung S G , Marderfeld L , Mak J W , Kaplan G G , Ng S C , Wilson D C , Cameron F L , Henderson P , Kotze P G ,   InsightScope, Benchimol E I 
Published: March 2021

Abstract

Background
The incidence of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is increasing internationally, particularly in developing nations where rates were historically low. Previous reports of the incidence and prevalence of pediatric-onset IBD have identified a paucity of population-based studies.

Aims
We reviewed the global trends in incidence of pediatric IBD using evidence from population-based studies.

Methods
(PROSPERO CRD42019125193) We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from 01/2010-02/2020 to identify population-based studies reporting the incidence of pediatric-onset IBD, CD, and UC. Included studies combined childhood and adolescent-onset IBD (onset &lt;21y). Changes in incidence since 2000 were plotted by continent, with data from 2000–09 provided by our previous systematic review1. To depict trends, multiple times points reported in single studies were connected on graphs. When incidence was reported as an aggregated estimate over a range of years, data was plotted using the midpoint of the interval.

Results
Of 8096 abstracts screened, 74 studies described the incidence of IBD, CD, or UC in 33 countries (Figure panel A). The incidence of pediatric-onset IBD is highest in Northern Europe and North America, and lowest in Southern Europe, Asia, and the Middle East. This geographical distribution is similar in UC, while incidence of pediatric-onset CD is highest in North America and Northern Europe, followed by Australia. Trends in incidence over time, stratified by continent, are reported in Figure, panel B. Significantly increasing incidence of IBD, CD, and/or UC was reported in China, Bahrain, Canada, New Zealand, Australia, Singapore, Saudi Arabia, and most European countries. Very Early Onset (VEO) IBD significantly increased in Canada, however Saudi Arabia reported decreasing incidence of VEO-CD but stable incidence of VEO-UC.

Conclusions
Conclusion: Incidence of pediatric-onset IBD are highest in Northern Europe and North American and are increasing globally. There remains a paucity of studies from many parts of the world on the incidence pediatric IBD. Further research is needed to understand the pathogenesis of the rising incidence of pediatric IBD, including work to understand the genetic, environmental, immunological and microbiome alterations leading to the increasing rates in children.
References: 1Benchimol, Fortinsky et al. Inflamm Bowel Dis 2011;17:423–39.

Funding Agencies
None
A29 NOVEL FECAL BIOMARKERS THAT PRECEDE CLINICAL DIAGNOSIS OF ULCERATIVE COLITIS
Authors: Galipeau H J , CAMINERO FERNANDEZ A , Turpin W , Bermudez-Brito M , Santiago A , Libertucci J , Constante M , Raygoza Garay J , Rueda G H , Clarizio A V , Smith M I , Surette M , Bercik P , Croitoru K , Verdu E 
Published: March 2021

Abstract

Background
Altered gut microbiota composition and function has been associated with inflammatory bowel diseases (IBD) including ulcerative colitis (UC), but causality and mechanisms remain unknown. Most studies have examined patients with active or treated disease and little is known about microbial compositional or functional changes that occur before disease onset.

Aims
We studied a longitudinal cohort of subjects at risk for IBD to define the fecal microbial composition and function in subjects prior to UC onset (pre-UC) and at diagnosis (post-UC), and in matched at-risk subjects that remained healthy.

Methods
Fecal samples were collected from healthy individuals at-risk for IBD (pre-UC; n=13) and subjects were followed longitudinally until UC diagnosis (post-UC, n=9), at which point another fecal sample was collected. Fecal samples from a cohort of matched at-risk individuals that did not develop UC were used as healthy controls (n=48). We applied 16S rRNA gene sequencing, next generation shotgun sequencing, in vitro proteolytic assays and gnotobiotic colonizations to define the microbial composition and proteolytic function in fecal samples.

Results
The microbiota of post-UC subjects clustered separately from pre-UC and HC subjects, based on bray-curtis and unweighted UniFrac, had reduced alpha-diversity, and had reduced abundance of Aldercreutzia compared to pre-UC and HC. In vitro functional analysis revealed increased fecal proteolytic and elastase activity in pre-UC and post-UC samples compared to HC. Metagenomics identified pathways and gene families related to protein metabolism and proteases/peptides that were significantly different between HC and pre-UC samples, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia, and other potentially beneficial taxa, and directly correlated with Bacteroides vulgatus, a known proteolytic taxon. High elastase activity was confirmed in Bacteroides isolates from fecal samples. Bacterial contribution and functional significance of the proteolytic signature was investigated in germ-free adults and litters born from dams colonized with HC, pre-UC or post-UC microbiota. Mice colonized with pre-UC microbiota at adulthood or neonatally developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC colonized mice.

Conclusions
We have identified increased fecal proteolytic activity that precedes clinical diagnosis of UC and associates with gut microbiota changes. This may constitute a non-invasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with anti-proteases.

Funding Agencies
CAG, CCC, CIHR
A30 DIFFERENCES BETWEEN HUMAN AND MOUSE INTESTINAL EPITHELIAL CELLS IN THEIR INNATE IMMUNE RESPONSES TO BACTERIAL AND HOST STIMULI.
Authors: Allaire J M , Poon A , Crowley S M , Han X , Stahl M , Bressler B , Jacobson K , Vallance B 
Published: March 2021

Abstract

Background
Intestinal epithelial cells (IEC) reside in close contact with the gut microbiota. It is thus important that IEC are hypo-responsive to bacterial products to prevent maladaptive inflammatory responses in the gut, such as those seen in Inflammatory bowel diseases (IBD). This suppression of innate immune signaling in IEC is in part due to their strong expression of Single Ig IL1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor (TLR) signaling. IL37, a newly recognized anti-inflammatory cytokine has been shown to strongly inhibit innate signaling in cells by binding to, and signaling through SIGIRR, leading to suppression of various forms of inflammation in mice. Few studies have looked at the function of IL-37/SIGIRR in IEC and their potential use to balance inflammatory responses. Notably, while many groups have studied IEC immune response in vitro, using transformed IEC lines, our focus is on primary-derived IEC which more accurately reflect in vivo responses.

Aims
To characterize IEC intrinsic and species-specific immune responses elicited by bacteria and host products as well as the role of IL37/SIGIRR in regulating this innate signaling.

Methods
We used organoid to study the innate immune responses of primary IEC derived from human or mouse colon (colonoids). After stimulation with inflammatory stimuli (IL1β, FliC and LPS), qPCR, ELISA, Milliplex Multiplex Assay and Western blot were used to determine modification in signalling pathway and cytokine/chemokine secretion.

Results
Using colonoids derived from healthy donors, we demonstrated that unlike transformed cell lines or mouse IEC, human IEC respond only to the bacterial product FliC, and not to LPS or IL1β. We further characterized human colonoid innate immune responses and despite significant inter-individual variability upon FliC stimulation, all organoids released several chemokines (IL8, CXCL1, CXCL2, CCL2 and CCL20). We showed for the first time that IL37 attenuated these innate immune responses through inhibition of intracellular signaling pathways (p38 and NFkB). Using colonoids derived from wildtype and Sigirr deficient mice, we found that mice IEC were responsive to IL1b and FliC and that the suppressive effects of IL37 were Sigirr dependent.

Conclusions
Our results show that human IEC show variability among individuals in the magnitude of their innate immune responses, and these responses differ from those obtained from transformed cells and primary mouse IEC. For the first time, we show that IL37 suppresses IEC innate immune responses, through its ability to signal through Sigirr. Further investigations will assess the ability of IL37 to control inflammation of IEC derived from IBD patients, as a potential therapeutic to promote gut health.

Funding Agencies
CAG, CIHRMSFHR
A35 ASSOCIATIONS BETWEEN AUTONOMIC DYSFUNCTION, COLONIC DYSMOTILITY AND ABSENT DEFECATION REFLEXES IN PATIENTS WITH CHRONIC REFRACTORY CONSTIPATION
Authors: Liu L , Milkova N , Ali M , Sharma K , Huizinga J D , Chen J 
Published: March 2021

Abstract

Background
A defecation reflex involves sensory information from the colon sent to the central nervous system which results in propulsive motor patterns in the colon through programmed neural activity from the autonomic nervous system. Neurological causes of constipation are recognized but specific neurological pathways that contribute to pathophysiology of the disease is underexplored. Diagnosis and treatment usually do not involve the autonomic nervous system.

Aims
Our objective was to assess autonomic dysfunction and abnormal defecation reflexes as a possible cause of chronic constipation.

Methods
Defecation reflexes were assessed by high-resolution colonic manometry through balloon distention, meal intake, and rectal bisacodyl. Specific heart rate variability (HRV) parameters were used to assess general orthostatic autonomic reactivity, and autonomic functioning during high resolution colonic manometry, in 14 patients with chronic refractory constipation considered for surgery.

Results
All patients had a unique combination of motility, reflex ability and HRV profiles. Patients overall did not generate HAPWs or had lower HAPW amplitude and lower propulsive activity compared to healthy individuals. Half of the 14 patients were tested to have high sympathetic tone based on Baevsky’s stress index prior to HRCM, and 11 of the patients had sympathetic hyper-reactivity and/or low parasympathetic reactivity to at least one type of colonic stimulation during HRCM. Abnormal autonomic tone or autonomic reactivity to colonic stimulation was present in all four patients with absence of the vagosacral defecation reflex. Five of the seven patients with absence of the sacral defecation reflex showed high sympathetic tone or high sympathetic reactivity to stimulation. Only two patients had abnormality in coloanal coordination and this was associated with low parasympathetic reactivity to stimulation in both patients.

Conclusions
The assumption that colonic resection was needed to remove an inert colon was wrong in most patients, but most patients had some form of reflex abnormality. Sympathetic dominance far outweighed parasympathetic dysfunction. Incorporation of assessments of defecation reflexes and autonomic nervous system activity into diagnosis of chronic refractory constipation provides a comprehensive pathophysiological understanding of specific defective neurological pathways contributing to dysmotility. This forms the basis for our individualized treatment efforts through sacral neuromodulation.

Funding Agencies
CIHR
A40 MATRISOMIC ANALYSIS OF PRE-NEOPLASTIC GASTRIC SUBEPITHELIAL MICROENVIRONMENT FROM SIGNALING-IMPAIRED TELOCYTES MOUSE MODEL
Authors: Alfonso A B , Pomerleau V , Reyes-Nicolas V , Levesque D , Raisch J , Boisvert F , Perreault N 
Published: March 2021

Abstract
NOT PUBLISHED AT AUTHOR’S REQUEST
Funding Agencies: CIHRScholarship Universite de Sherbrooke FMSS Abdenour-Nabid, MD