bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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 >50 new patients per year; 9/16 centres have >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 <10 and >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

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 <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

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

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 <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

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

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

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

NOT PUBLISHED AT AUTHOR’S REQUEST

Funding Agencies: CIHRScholarship Universite de Sherbrooke FMSS Abdenour-Nabid, MD
A41 LINKING THE APPENDIX MICROBIOME WITH INFLAMMATORY BOWEL DISEASES
Authors: Arjomand Fard N , Armstrong H , Carroll M W , Huynh H Q , Wine E
Published: March 2021

Background

The appendix has been shown to be associated with the pathogenesis and health outcomes in inflammatory bowel diseases (IBD). Specifically, post appendectomy patients are found to be protective for development of ulcerative colitis (UC); however, mechanisms of appendix involvement remain unclear.

Aims

Our aim is to examine the microbes associated with the appendix of IBD patients by identifying changes in microbe abundance and interactions with the host in patient cecum luminal washes, collected from close to the neck of the appendix during colonoscopy. We hypothesize that microbes originating in the appendix of IBD patients, through interactions with host-cells in a disrupted microenvironment in the appendix, could contribute to the pathogenesis of UC.

Methods

Shotgun metagenomics was performed on cecum luminal washes of IBD patients and non-IBD controls. Guided by the metagenomic results, we performed gentamicin protection assays to determine virulence of microbes of interest using Caco2 intestinal epithelial cells. Co-culturing them with human host cells in vitro will identify relevant disease-related factors secreted by microbes and/or host cells using disease models and multiomic approaches.

Results

Shotgun metagenomics results showed that among numerous microbes, several bacterial taxa demonstrated differences in abundance between IBD and non-IBD patients: Flavonifractor, Bacteroide fragilis, and Alistipes represented 8%, 10%, and 21% abundance respectively in non-IBD patients, while in IBD patients they were present below 0.1%. In contrast, Bacteroide vulgatus and Escherichia coli were about 9% and 69% respectively, in IBD patients, whilst they were present at 1.7% and 1.2% in non-IBD patients, respectively. Following our recent method for validating pathobionts (Armstrong, 2019), we used the gentamicin protection assays to assess the ability of these bacteria to invade Caco2 cells, demonstrating a correlation between invasive potential of these microbes and cecal abundance. Mechanistic experiments, aimed at identifying factors impacting invasion, are in progress.

Conclusions

These results provide preliminary, but promising findings suggesting mechanisms by which microbiota possibly originating in the appendix may show altered virulence, which may be related to changes in the appendix microenvironment in IBD. With plans in place to increase our patient cohort we will validate these findings. Identifying and profiling these microbes in IBD patients can help improve the understanding of mechanisms underlying microenvironment changes within the appendix and the gut, which could shed light on the role of the appendix in IBD pathogenesis and clarify how microbes drive inflammation in IBD.

Funding Agencies

CIHR
A44 FATTY ACID COMPOSITION OF THE MEDITERRANEAN DIET PROTECTS AGAINST SPONTANEOUS COLITIS IN THE MUCIN-2 DEFICIENT MURINE MODEL
Authors: Haskey N , Ye J , Barnett J A , Birnie B W , Verdugo Meza A A , Ghosh S , Gibson D L
Published: March 2021

Background

A Mediterranean diet (MD) has been proven efficacious in reducing inflammation in many chronic conditions, mediated by the interaction between diet, the gut microbiota and the immune system. The role of the MD as a dietary management strategy in the management of colitis requires further elucidation. While high fat diets have been shown to result in dysbiosis, our lab has clarified that the type of fat, not total calories derived from fat, predict gut dysbiosis and immunity in murine models of colitis. The n-6 polyunsaturated fatty acids (PUFA) promote colitis, however monounsaturated fatty acids (MUFA) protect against colitis. We hypothesize that a blend of fats, similar to the MD (high MUFA, low n-6 PUFA) will promote gut health beneficial to colitis.

Aims

Using a murine model of chronic intestinal inflammation, the aim of this study was to investigate the effects of dietary fatty acids on colitis by studying dietary fats in isolation from each other, as well as in a fatty acid profile similar to the blend contained in the MD.

Methods

Mice lacking the mucin 2 gene (Muc 2-/-) were weaned on to a 9-week, high fat (41%), isocaloric, isonitrogenous diet where the fat was derived from corn oil, olive oil, milk fat or a MD fat blend (28% MUFA, 8% SFA, 4% n-6 PUFA, 1% n-3 PUFA). The MD fat blend mimicked the fat profile consumed in the human diet. Disease activity, colon histology, cytokines (serum and colonic expression), cecal short chain fatty acids, intestinal permeability, glucose tolerance and gut microbiota (16S rRNA) were analyzed.

Results

Muc 2-/- fed the MD were protected from developing the most severe form of colitis, showing significantly lower disease activity and the absence of rectal prolapse. Histological damage was more severe in the corn oil and milk fat groups which coincided with an increase in infiltrating inflammatory cells and increased mucosal ulcerations. MD and milk fat diets exhibited enhanced intestinal permeability, glucose tolerance, intestinal alkaline phosphatase compared to the corn oil diet. Lower colonic mRNA levels of pro-inflammatory RELM-ß and IL-6 were also seen in the MD and MF diet in comparison to corn oil diet with the milk fat eliciting unique protective immune responses as evidenced by increased expression of IL-22 and Reg3-γ. Differences in alpha-diversity were seen between the MD and milk fat diets, beta-diversity revealed differences in taxa between diet groups.

Conclusions

The fatty acid profile of the MD protects against the development of spontaneous colitis in the Muc2-/- mouse model. In summary, not all dietary fats aggravate colitis, and some may be beneficial during colitis. A diet low in n-6 PUFA and high in MUFA is recommended.

Funding Agencies

CCCCFDR
A45 A NOVEL PH-SENSITIVE OPIOID ANALGESIC THAT SELECTIVELY INHIBITS NOCICEPTION IN DSS-INDUCED COLITIS
Authors: Yu Y , Jiménez-Vargas N N , Tsang Q K , Lopez Lopez C , Jaramillo Polanco J , Stein C , Lomax A E , Reed D E , Bunnett N , Vanner S
Published: March 2021

Background

Opioid drugs are used to treat pain in inflammatory bowel disease (IBD) but their side effects can cause serious morbidity. Therefore, we tested a novel opioid analgesic, ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) which selectively activates peripheral µ-opioid receptors at acidic pH, as occurs in inflamed tissue.

Aims

Evaluate whether NFEPP causes analgesia in the inflamed colon of DSS-colitis mice using both in vitro and in vivo techniques.

Methods

To measure the visceral motor reflex (VMR) in response to colorectal distention, EMG electrodes connected to a telemetric transmitter were implanted in mice (c57BL/6), after 10 days recovery acute dextran sodium sulfate (DSS) colitis was induced (5 days 2.5% DSS, 2 days water). VMR was measured 30 min after s.c. injection of vehicle or 0.2 mg/kg of NFEPP or fentanyl. Motility was assessed by fecal pellet count 1 hour after NFEPP. Colonic tissue pH was evaluated using the SNARF-4F-5 carboxylic acid probe. Excitability of mouse dorsal root ganglia (DRG) neurons was measured by recording the rheobase (minimum input current to fire an action potential) after superfusion of NFEPP (300 nM, 10 min) or vehicle at pH 6.5 or 7.4. Colonic afferent nerve responses to probing with a von Frey filament (1 gm) were examined before and after exposure to NFEPP (300 nM, 5 min superfusion) at pH 6.5 and 7.4 respectively. The data was analyzed with Welch’s t-test, 1- or 2-way ANOVA with post hoc Dunnett or Bonferroni or Tukey’s test.

Results

NFEPP significantly inhibited the VMR in response to distension in mice with colitis compared to vehicle (decreased response by 65%, P<0.001). NFEPP had no effect in control mice. Conversely, fentanyl caused a similar decreased response in both groups (DSS 79% and control 67%, P<0.001). Pelleting was not affected by NFEPP injection in either group compared to vehicle. The pH measurement revealed a more acidic environment in DSS colonic tissue (ΔpH0.37±0.14, P<0.05) compared to controls. In patch-clamp studies, NFEPP decreased DRG excitability at pH 6.5 compared to the baseline and vehicle (increased rheobase 53.84%, P<0.01 and 36.36%, P<0.05 respectively) but had no effect at pH 7.4. In colonic afferent nerve recordings, NFEPP significantly attenuated afferent responses (28.9% P<0.01) to probing at pH 6.5 but also had no effect at pH 7.4.

Conclusions

This pH-selective opioid agonist significantly inhibits pain at the site of inflammation where the tissue pH is acidic but has no effect in tissues where the pH is in the physiological range. Thus, NFEPP could be an effective opioid analgesic in IBD while being devoid of any unwanted side effects.

Funding Agencies

CCC
A51 ENTERIC PARASITE INFECTION-INDUCED ALTERATION OF THE GUT MICROBIOTA REGULATES INTESTINAL GOBLET CELL BIOLOGY AND MUCIN PRODUCTION VIA TLR2 SIGNALING
Authors: Yousefi Y , Wang H , Haq S , Grondin J , Surette M , Khan W I
Published: March 2021

Background

Goblet cells (GCs) are the major source of mucin which are the main components of the mucus layer that represents the front line of innate defense in the gastrointestinal (GI) tract. Hyperplasia of GCs and increased mucin production are observed in many enteric nematode infections such as Trichuris muris infection. Increased mucin production contributes to parasite clearance by trapping in mucus and inhibiting motility. The GI tract contains trillions of commensal microbes, and these microbes control mucin production from GCs by activating different signaling cascades. During nematode parasite infection due to the coexistence of parasites and microbiota in close proximity of GCs in gut, it is likely that this nematode-microbiota interaction plays an important role in mucin production. Toll-like receptors (TLRs), components of the innate immune system, sense gut microbiota stimuli. The human GC-like cell line, LS174T, expresses TLR2 mRNA which was enhanced by stimulation with synthetic TLR2 ligands. We hypothesize T. muris-induced altered microbiota modulates GC response and mucin production via TLR2 signaling.

Aims

To elucidate the role of T. muris-induced altered gut microbiota in the regulation of intestinal GC response and mucin production via host TLR2 signaling.

Methods

C57BL/6 mice were infected by gavage with ~300 T. muris eggs and infectivity was confirmed by worm burden. Microbiota was analyzed by 16s rRNA sequencing. Colonic GCs response, mucins and TLR2 expression and cytokines production were assessed in germ-free (GF) mice receiving non-infected and T. muris-infected microbiota (collected on day 36 post-infection to exclude worms). Muc2 and Muc5ac expression were assessed in wild-type (WT) and TLR2 deficient (TLR2-/-) mice transplanted with T. muris-infected microbiota following antibiotic treatment.

Results

We observed a difference in microbial composition between non-infected and T. muris infected mice. Transfer of T. muris-infected microbiota into GF mice significantly increased GC numbers and TLR2 expression as well as up-regulated Muc2 and Muc5ac expression and IL-4, IL-13 production compared to GF mice with non-infected microbiota. Antibiotic-treated TLR2-/- mice after receiving microbiota from T. muris-infected mice showed significantly decreased expression of Muc2 and Muc5ac compared to antibiotic-treated WT mice receiving the same microbiota.

Conclusions

T. muris-induced altered microbiota influences intestinal GC response and mucin production via TLR2. In addition to enhancing our understanding on the interaction of parasite with resident microbiota in host defense, this study provides new information on TLR2 based innate signaling in the regulation of GC biology and mucin production.

Funding Agencies

NSERC
A53 STUDYING THE ROLE OF ASCL2 IN THE ESOPHAGEAL EPITHELIUM USING ORGANOIDS
Authors: Hamilton M , Jean D , Giroux V
Published: March 2021

Background

The esophagus is lined with a stratified squamous epithelium that assure protection against the austere environment found in the esophageal lumen. The maintenance of this epithelium is ensured by a rare population of cells: stem cells. Those cells have increased capacity of self-renewal and multipotency, which is the capacity to give rise to every cell types of a tissue. The marker Krt15 was used to identify the first stem cell population in the esophagus. Krt15+ cells display an extended lifespan and they are radioresistant, multipotent and capable of self-renewal. Moreover, it was observed by RNA sequencing that the expression of the transcription factor ASCL2 is strongly increased in Krt15+ cells compared to Krt15- cells. Interestingly, ASCL2 is necessary to maintain the stemness of Lgr5+ intestinal stem cells. It is also a target of the Wnt/β-catenin pathway. The overall goal of this project is to determine the role of ACSL2 in the maintenance of esophageal stem cells and to identify its binding partners since ASCL2 needs to dimerize to efficiently bind DNA.

Aims

Confirm that esophageal organoids are adapted to study ASCL2 in the esophagus.

Methods

Esophageal organoids were established from esophageal epithelial cells from wildtype mice. Following this, organoids were treated with an inhibitor of the Notch pathway (DAPT) to induce hyperplasia or infected with lentiviruses to invalidate Ascl2 (CRISPR/Cas9 approach).

Results

To validate that Ascl2 plays an important role in esophageal cell proliferation, Notch pathway was inhibited through DAPT treatment in esophageal organoids to induce hyperplasia, which was confirmed by increased number of proliferative cells (Ki-67+). ASCL2 protein expression was also increased in DAPT-treated organoids supporting its role in proliferation and confirming that organoid is a good model to study ASCL2 role in esophageal epithelial cells. In this optic, organoids lines invalidated for Ascl2 (CRISPR/Cas9 approach) were established. Our preliminary results suggest that Ascl2 loss affects cell proliferation and organoid size under normal conditions.

Conclusions

The expression of ASCL2 correlates with hyperplasia which supports its role in esophageal epithelium homeostasis.

Funding Agencies

Canada research chair et NSERC
A58 HERPES ZOSTER VIRUS INFECTION IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE: SINGLE CENTER EXPERIENCE
Authors: Al-Khuzaei A
Published: March 2021

Background

Patients with IBD receive a variety of medications that modulate the immune response. However, many medications render patients more susceptible to opportunistic infections. Varicella zoster virus (VZV) infection, in particular, has been well reported in IBD patients, mostly in CD. Chickenpox results from primary VZV infection, and is predominantly seen in the pediatric population. Primary prevention via vaccination for VZV, plays an important role in preventing infections in IBD patients before they start immunomodulators, corticosteroid or biologic therapy. Given the advent of zoster vaccines, it is important to determine if IBD patients should be considered for immunization at a younger age.

Aims

1) To document the prevalence of herpes zoster virus (HZV) infection patients with IBD and to further investigate the characteristics of susceptible hosts

2) To assess the severity of herpes zoster in this patient population

Methods

A single center retrospective cohort study was conducted at the Montreal Children’s Hospital. Pediatric IBD patients (age < 18 years) who developed HZV from 2004- 2019 were identified. Data regarding HZV infection, location, severity, treatment, complications and list of all immunosuppressive medications at the time of HZV infection were retrieved as well as data regarding demographics, medical history, vaccination status including Varicella vaccine, and disease behavior.

Results

A total of 9 patients were identified from who had VZV infection or HZV. Eight out of 9 patients, had CD and one patient had UC, and 6 out of 8 CD patients had had extensive disease. The vaccine status was up to date in 6 out of 9 patients, and varicella serology was identified prior to starting steroids or biologic agents.

Eight out of nine patients were on biologics. Eight patients had local disease, skin only, and one patient had systemic disease with HZV meningitis. Four out of 9 patients had their biologic medications either stopped or the next doses were delayed, while other medications including steroids, methotrexate, thiopurines were continued. Five patients were treated with intravenous acyclovir then oral valacyclovir. The rest started on oral valacyclovir and then switched to intravenous acyclovir due to systemic disease. The overall prognosis of the illness was good, and it resulted in full resolution, including the meningitis case.

Conclusions

Our study suggests that being on biologic medication plays a significant role in increasing the chances of reactivation of HZV. Although the severity of the HZV infection in our study is limited to skin involvement, there was one systemic infection. Close attention and mandatory documentation of vaccination status is prudent especially prior to starting immunosuppressive medications. Further studies are needed to determine if these patients should be vaccinated with recombinant zoster vaccine.

Funding Agencies

None
A63 REFINING THE CANADIAN ASSOCIATION OF GASTROENTEROLOGY GUIDELINE ON SCREENING IN PERSONS WITH A FAMILY HISTORY OF NONHEREDITARY COLORECTAL CANCER OR ADENOMA: A MODIFIED DELPHI PROCESS
Authors: Tinmouth J , Paramalingam A , Bellini A , Cotterchio M , Dekker E , Doctorow R , Hassan C , Haddad E , Lofters A , MacIntosh D , Martin J , McCurdy B , Murray I , Naglie H , Paroschy-Harris C , Rabeneck L , Stogios C , Telford J J , Venkatesh R , Wong C , Zenlea T , Dube C
Published: March 2021

Background

In 2018, the Canadian Association of Gastroenterology (CAG) published an extensive systematic review and guideline on screening in persons with a family history (FHx) of nonhereditary colorectal cancer (CRC) and adenoma. While CAG’s recommendations were evidence-based, some recommendations lacked precision (e.g. ranges for some start ages & intervals) and screening cessation age was not addressed, leading to implementation challenges for practitioners and CRC screening programs.

Aims

To review and update the evidence since the 2018 guideline and to formulate implementable recommendations in the Ontario context that are aligned with the CAG guideline.

Methods

ColonCancerCheck (Ontario’s organized CRC screening program) conducted a modified version of the literature search used by CAG (Jan 2017 - Sept 2019). A 19-member expert panel with Canadian and international representatives from endoscopy, primary care, epidemiology, organized CRC screening programs, Ontario’s cancer system and the general public refined the recommendations of the CAG guideline for the purposes of implementation in an organized CRC screening program using a modified Delphi process. This iterative process involved a series of webinars and anonymous survey rounds where the panel reviewed evidence materials and provided online feedback to develop, refine & achieve consensus on screening recommendations in persons with a FHx of CRC/adenoma. Consensus was achieved if ≥75% of members agreed or strongly agreed with the statement.

Results

Six new systematic reviews and 2 new guidelines were identified. New evidence included data on the absolute risk (10 year & lifetime risk) of CRC by type of FHx, as well as the performance of fecal immunochemical testing (FIT) and barriers to CRC screening in persons with a FHx of CRC. The expert panel participated in 3 webinars and 4 online surveys to arrive at consensus. Panel recommendations and level of consensus will be reported for the 6 statements (Table).

Conclusions

Building from the CAG guideline, we derived evidence-based and implementable recommendations for screening persons with a FHx of CRC or adenoma.

Funding Agencies

Ontario Health (Cancer Care Ontario)
A72 NON-INVASIVE PREDICTION OF ESOPHAGEAL VARICES BY TRANSIENT ELASTOGRAPHY AND PLATELET COUNT IN PATIENTS WITH HEPATITIS B AND ADVANCED CHRONIC LIVER DISEASE: VALIDATION OF BAVENO VI AND EXPANDED BAVENO VI CRITERIA
Authors: Zoughlami A , Serero J , Sebastiani G , Deschenes M , Wong P , Khan A Q
Published: March 2021

Background

Patients with compensated advanced chronic liver disease (cACLD) are at higher risk of developing complications from portal hypertension, including esophageal varices (EV). Baveno VI and expanded Baveno VI criteria, based on liver stiffness measurement (LSM) by transient elastography combined with platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for large esophageal varices needing treatment (EVNT). This approach has not been validated in patients with chronic hepatitis B virus (HBV) infection, who have etiology-specific cut-off of LSM for liver fibrosis.

Aims

We aimed to validate the Baveno VI and expanded Baveno VI criteria for EVNT in HBV patients with cACLD.

Methods

We performed a retrospective analysis of HBV patients who underwent LSM in 2014–2020. Inclusion criteria were: a) diagnosis of cACLD, defined as LSM >9 kPa; b) availability of EGD and platelets within 1 year of LSM. Baveno VI (LSM <20 kPa and platelets >150,000) and expanded Baveno VI criteria (LSM <25 kPa and platelets >110,000) were tested for EGD sparing. Diagnostic performance of these criteria against gold standard (EGD) was computed and compared to patients with hepatitis C virus (HCV) infection and nonalcoholic steatohepatitis (NASH) etiologies, where these criteria have been widely validated. In these patients, the threshold for cACLD definition was >10 kPa.

Results

A total of 287 patients (mean age 56, 95% Child A) were included, comprising of 43 HBV (58% on antiviral therapy), 134 HCV and 110 NASH patients. The prevalence of any grade EV and EVNT was 25% and 8% in the whole cohort, with 19% and 5% in HBV patients, respectively. Table 1 reports diagnostic performance, spared EGD and missed EVNT according to non-invasive criteria and cACLD etiology. Both Baveno VI and expanded Baveno VI criteria performed well in patients with HBV-related cACLD. There was no significant difference on diagnostic performance of these non-invasive criteria across the cACLD etiologies.

Conclusions

These results support use of non-invasive criteria based on LSM and platelets to spare unnecessary EGD in patients with HBV and cACLD. Baveno VI and expanded Baveno VI criteria can improve resource utilization and avoid invasive testing in context of screening EGD for patients with HBV-related cACLD.

Funding Agencies

None
A74 INCREASING RATES OF CT IMAGING IN THE EMERGENCY DEPARTMENT AMONG PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Kandel R , Merlano M , Tan P , Brar G , McCurdy J D
Published: March 2021

Background

Computed tomography (CT) imaging of the abdomen is often performed in the emergency department (ED) to exclude urgent pathology in patients with Inflammatory Bowel Disease (IBD). However, concerns over excessive radiation exposure from repeated use have led to expert consensus guidelines advising against CT imaging unless there is suspicion of complications (obstruction, perforation, abscess) or a non-IBD cause for symptoms.

Aims

Our study aimed to determine trends in abdominal CT utilization and findings among patients with IBD in the ED.

Methods

We performed a retrospective cohort study between 01/01/2009 and 31/12/2018 at a single academic center. We identified ED encounters for adults (age ≥17 years) with a pre-existing diagnosis of IBD from our institutional database and determined the proportion resulting in an abdominal CT scan within 72 hours of presentation. IBD subtypes were classified based on ICD-10 claims: K50.90* for Crohn’s disease (CD), K51.90* for Ulcerative colitis (UC) and IBD undifferentiated (IBDU) for patients with both claims. A time trend analysis was performed using a generalized linear model that assumed a Poisson distribution. CT scans were classified according to the dominant imaging finding. For this part we excluded studies performed within 1-month of surgery or those re-assessing a known abscess or malignancy.

Results

A total of 14783 encounters were identified. Among these encounters 3000 CT scans were performed: 2000 for patients with CD (21.9%), 652 for UC (16.5%) and 348 for IBDU (20.4%). The rates of CT utilization significantly increased by 2.7% (95% CI, 1.2–4.3; p=0.0004) in patients with CD, by 4.2% (95% CI, 1.7–6.7; p=0.0009) in patients with UC and by 6.3% in patients with IBDU (95% CI, 2.5–10.0; p=0.0011). Among the eligible CT scans performed for CD, the following dominant findings were reported: normal (25%), inflammation (23%), obstruction (23%), penetrating (18%) and unrelated to IBD (8.6%). In contrast, the following findings for patients with UC were reported: normal (20%), inflammation (39%), obstructive (19%), penetrating (8%) and unrelated to IBD (15%).

Conclusions

In this single center study, a steady increase in CT utilization in the ED was observed in patients with IBD. Interestingly, only a small proportion of the CT scans demonstrated urgent findings. Future studies are required to determine the factors that contribute to the ongoing increase in CT utilization in this patient population.

Funding Agencies

None
A85 THE CLINICAL IMPACT OF COVID-19 DELAYS ON PLASTIC BILIARY STENT REMOVAL IN NOVA SCOTIA
Authors: Lim D R , Tsai M , Gruchy S E , Jones J , Williams G , Farina D , Kohansal A R
Published: March 2021

Background

The COVID-2019 pandemic continues to restrict access to endoscopy, resulting in delays or cancellation of non-urgent endoscopic procedures. A delay in the removal or exchange of plastic biliary stents may lead to stent occlusion with consensus recommendation of stent removal or exchange at three-month intervals [1–4]. We postulated that delayed plastic biliary stent removal (DPBSR) would increase complication rates.

Aims

We aim to report our single-centre experience with complications arising from DPBSR.

Methods

This was a retrospective, single-center, observational cohort study. All subjects who had ERCP-guided plastic biliary stent placement in Halifax, Nova Scotia between Dec 2019 and June 2020 were included in the study. DPBSR was defined as stent removal >=90 days from insertion. Four endpoints were assigned to patients: 1. Stent removed endoscopically, 2. Died with stent in-situ (measured from stent placement to documented date of death/last clinical encounter before death), 3. Pending removal (subjects clinically well, no liver enzyme elevation, not expired, endpoint 1 Nov 2020), and 4. Complication requiring urgent reintervention. Kaplan-Meier survival analysis was used to represent duration of stent patency (Fig.1).

Results

102 (47.2%) had plastic biliary stents placed between 2/12/2019 and 29/6/2020. 49 (48%) were female, and the median age was 68 (R 16–91). Median follow-up was 167.5 days, 60 (58.8%) subjects had stent removal, 12 (11.8%) died before replacement, 21 (20.6%) were awaiting stent removal with no complications (median 230d, R 30–332), 9 (8.8%) had complications requiring urgent ERCP. Based on death reports, no deaths were related to stent-related complications.

72(70.6%) of patients had stents in-situ for >= 90 days. In this population, median time to removal was 211.5d (R 91-441d). 3 (4.2%) subjects had stent-related complications requiring urgent ERCP, mean time to complication was 218.3d (R 94–441). Stent removal >=90 days was not associated with complications such as occlusion, cholangitis, and migration (p=1.0). Days of stent in-situ was not associated with occlusion, cholangitis, and migration (p=0.57). Sex (p=0.275), cholecystectomy (p=1.0), cholangiocarcinoma (p=1.0), cholangitis (p=0.68) or pancreatitis (p=1.0) six weeks prior to ERCP, benign vs. malignant etiology (p=1.0) were not significantly associated with stent-related complications.

Conclusions

Plastic biliary stent longevity may have been previously underestimated. The findings of this study agree with CAG framework recommendations [5] that stent removal be prioritized as elective (P3). Limitations include small sample size that could affect Kaplan-Meier survival analysis. Despite prolonged indwelling stent time as a result of COVID-19, we did not observe an increased incidence of stent occlusion or other complications.

Funding Agencies

None