bluuebunny/crossref_metadata_2025 huggingface dataset:
A98 EXCITATION OF LUMBAR SPLANCHNIC AFFERENT NERVES BY FECAL SUPERNATANTS FROM INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Abu Omar A A , Reed D E , Lomax A E
Published: February 2020

Background

Increased excitability of extrinsic afferent nerves has emerged as an important cause of visceral pain during inflammatory bowel disease (IBD). However, little is understood regarding what role, if any, the intestinal microbiota plays in pain development during IBD. Therefore, we aimed to determine the effects of fecal supernatants (FS) from patients with IBD on lumbar splanchnic afferent nerves (LSN).

Aims

We aimed to determine the effects of fecal supernatants (FS) from patients with IBD on lumbar splanchnic afferent nerves (LSN).

Methods

Fecal samples from 8 patients with active IBD (4 Crohn’s disease (CD) patients and 4 ulcerative colitis (UC) patients) and 6 healthy volunteers (HV) were suspended in normal saline solution at 0.5gm/4 ml. In vitro extracellular recordings of action potential discharge were obtained from LSN of the distal colon from control mice. LSN afferents were classified based on their responses to colonic distention into low threshold (LT), high threshold (HT), wide dynamic range (WDR) and mechanically insensitive (MIS) units. FS was applied intraluminally for 20 min after which afferent nerve sensitivity for colonic distension was re-assessed.

Results

FS from IBD patients increased the basal firing frequency of afferent nerves compared to vehicle control (P value <0.0001 in both CD and UC experiments). Furthermore, FS from CD augmented the mechanosensitivity of the overall activity of the units with 35% increase in the units’ discharge compared to vehicle control with a significant effect on HT and MIS units. Conversely, FS from HV decreased the basal firing frequency of afferent nerves compared to vehicle control (P value < 0.01). Moreover, FS from HV induced 60% reduction in the mechanosensitivity of the overall activity of the units with a significant effect on HT and WDR units.

Conclusions

These results suggest that FS from IBD patients contain mediators that can activate LSN. These changes would lead to an increased afferent input to the CNS, which could exacerbate pain. On the other hand, control FS from HV contain mediators that suppress the activity of LSN. Further characterization these mediators has the potential to lead to new targets for pain management in IBD.

Funding Agencies

CCC, CIHR
A99 IMPACT OF OSMOTIC PERTURBATIONS ON THE GUT MICROBIOTA AND HOST HEALTH
Authors: Pepin D M , Tropini C
Published: February 2020

Background

Osmotic diarrhea is a prevalent condition concurrent with diverse pathologies such as Crohn’s disease and is due to unabsorbed solutes in the gastrointestinal contents inhibiting normal water absorption. Osmotic laxatives such as polyethylene glycol (PEG) take advantage of this process to counteract constipation. However, short-term PEG treatment impacts the gut microbial community, and in humanized and conventional mice leads to disappearance of the abundant and prevalent bacterial family S24-7, while increasing the relative abundance of a related family, Bacteroidaceae. Excitingly, despite community re-equilibration over weeks, S24-7 is capable of superseding other bacterial members and reach its original levels when reintroduced into the environment. My central hypothesis is that the depletion of S24-7 during osmotic diarrhea is due to its deficiency of stress response pathways required to counteract increased osmolality. However, in the absence of this stress, S24-7 is capable of exploiting a unique interaction with the immune system to successfully recolonize.

Aims

To shed light on this, I will pursue the following two aims: Aim 1: Compare the growth, survival and expression profiles of S24-7 and B. thetaiotaomicron in a bi-colonized gnotobiotic mouse model before, during and after osmotic perturbation to identify candidate genes involved in response to osmotic perturbation. Aim 2: Identify changes in S24-7 gene expression during recolonization and evaluate the host immune response.

Methods

Gnotobiotic mice were first colonized with S24-7 and then B. thetaiotaomicron, treated with PEG for 6 days and monitored during recovery and recolonization for 20 days. Fecal pellets were used to quantify bacterial abundances via qPCR and bacterial gene expression analysis through metatranscriptomics. Mouse serum was used for ELISA immunoassays to compare adaptive immune responses through serum IgG as well as to quantify glycine betaine levels.

Results

During PEG treatment S24-7 became undetectable and recolonized to pre-treatment levels during recovery. Using genomic and metagenomic annotation we have identified that S24-7 isolates do not possess the glycine betaine transport system, which is present in B. thetaiotaomicron (Figure 1). B. thetaiotaomicron reduced host serum glycine betaine levels, unlike S24-7. In S24-7 mono-colonized mice, S24-7 specific serum IgG was not detectable. However, once mice were co-colonized with B. thetaiotaomicron, both S24-7 and B. thetaiotaomicron specific IgG is detected, identifying an interesting relationship between S24-7 and the adaptive immune system that may shed light on its unique recolonization.

Conclusions

By studying S24-7 sensitivity to osmotic stress and its robust colonization abilities we are shedding light on the mechanisms of microbiota response to perturbations that are commonly experienced by the human gut.

Funding Agencies

None
A107 PATIENT PERSPECTIVES ON THE LONG-TERM MANAGEMENT OF CELIAC DISEASE
Authors: Elias E , Silvester J , Graff L A , Bernstein C N , Rigaux L , Duerksen D
Published: February 2020

Background

Celiac disease (CD) is a common chronic gastrointestinal illness with a range of manifestations. The only available treatment is strict gluten avoidance, therefore patients are effectively self-managed. Despite the critical role patients play in their treatment, patient perspectives on long-term CD care have not been formally assessed and are therefore not represented in current clinical guidelines.

Aims

To determine the opinions of CD patients on the need for long-term CD follow-up, the utility of various aspects of CD follow-up, and the areas in which further information is desired.

Methods

The Manitoba Celiac Disease Cohort includes newly diagnosed adults with elevated TTG and/or EMA antibodies and Marsh III histology. At the 24-month follow-up visit, participants were asked to rate the utility of various aspects of CD care from 1–5 (low-high) and their desire for further information on CD-related issues from 1–6 (low-high).

Results

A total of 213 patients were recruited and 137 participants completed the online survey (median age 41 [interquartile range 29–57] years; 68% female). Adherence to a gluten free diet was variable, with 29% of patients having TTG antibodies above the upper limit of normal.

Two-thirds of participants felt they should be seen regularly for their celiac disease, while 79.8% of those who wished to be followed felt they should be seen every 6–12 months. Blood tests were the most highly rated component of CD care (scored ≥4 by 78% of respondents). Celiac symptom review, information on research in celiac disease, and the opportunity to ask questions about vitamins and supplements were also positively regarded. Diet review was not generally considered helpful. 79% of patients desired further information on research in CD, while approximately 60% desired information on the long-term complications of CD and the risk of nutritional deficiencies.

Conclusions

The majority of CD patients find regular specialist follow-up helpful, particularly for biochemical assessment of disease activity and its complications. Further information on CD research and the long-term complications of CD should be addressed in follow-up visits. These aspects of follow-up care should be reflected in future guidelines.

Funding Agencies

None
A137 COLONOSCOPY RELATED ADVERSE EVENTS IN A POPULATION-BASED COLON SCREENING PROGRAM
Authors: Tomaszewski M , Sanders D , Enns R A , Gentile L , Nash C , Cowie S , Petrunia D , Mullins P , Azari-Razm N , Bykov D , Telford J J
Published: February 2020

Background

The British Columbia Colon Screening Program (BCCSP) is a population-based program enrolling 50–74 year old individuals for biennial FIT (OC-Sensor, cut-off 10 mcg/g) with follow-up colonoscopy for positive FIT. The neoplasia detection rate is 50–55% and over 75% of colonoscopies have a specimen taken. Previously reported colonoscopy adverse event rates for FIT based screening programs vary widely: 0.03–6.2% and 0–2.7% for bleeding and perforation, respectively. Mortality as a result of colonoscopy is rare but has been reported in 0.0004%-0.0074% of colonoscopies. The rate of colonoscopy related adverse events in BCCSP participants is unknown.

Aims

To determine the rate of colonoscopy related serious adverse events within the BCCSP.

Methods

This is a retrospective cohort study of all participants undergoing colonoscopy in BCCSP from November 15, 2013 to December 31, 2017. BCCSP contacts screening participants by phone 14 days post colonoscopy to determine unplanned medical visits the day prior (during bowel preparation) or following the colonoscopy. Unplanned events underwent chart review if the event was a perforation, cardiovascular or respiratory event, or resulted in death, hospitalization, or significant intervention including repeat colonoscopy, interventional radiology, surgery, blood transfusion, cardioversion, casting of a fracture or suturing of a laceration. Chart review was conducted by a Colonoscopy Lead and reviewed by BCCSP Quality Committee. Unplanned events were defined as serious adverse events (SAE) if they resulted in death, hospitalization or significant intervention and further classified as probably, possibly, or unlikely related to the colonoscopy.

Results

A total of 108,004 colonoscopies were performed. Unplanned events were reported in 1753 participants, of which 586 met criteria for review. Of these, 578 were confirmed unplanned events and 409 were SAEs of which 367 (89.7%) were probably, 22 (5.4%) possibly and 20 (4.9%) unlikely associated with colonoscopy. 36/10,000 colonoscopies were associated with a SAE that was probably or possibly related: perforation in 5/10,000, bleeding 22/10,000. Three deaths occurred in the 14 days following colonoscopy that were probably (2 perforations) or possibly related to the colonoscopy (0.3/10,000).

Conclusions

The BCCSP has a colonoscopy SAE rate in keeping with previous publications, particularly in the context of a very high proportion of procedures associated with polypectomy, a known risk factor for perforation and bleeding. This study will help inform screening participants about the risks of colonoscopy in the BC program. Future studies are required to confirm these rates using hospital admission data.

Funding Agencies

None
A148 EFFICIENCY IN THE ENDOSCOPY UNIT: CAN WE ‘TURN AROUND’ ROOM TURNOVER?
Authors: Tan C M , Tinmouth J , Bernstein M
Published: February 2020

Background

Endoscopy units across Canada are being challenged to meet the growing demand for procedures despite limited resources, highlighting the need to optimize endoscopy unit efficiency. Earlier studies have found that non-procedural factors, such as room turnover, represent an ideal target to improve efficiency.

Aims

The objective of this research project was to identify practices that will improve efficiency for routine outpatient gastrointestinal (GI) procedures at Sunnybrook Health Sciences Centre (SHSC). There were 2 sub-aims: 1) to understand practices at Toronto hospitals that shorten room turnover time and 2) to describe the variation in room turnover time at SHSC.

Methods

Sub-aim #1: A survey of endoscopy units at five other Toronto hospitals was completed. Questions were designed to gain a better understanding of routine practices and any initiatives undertaken to improve room turnover efficiency.

Sub-aim #2: Median room turnover time from April 2018 to March 2019, defined as ‘patient out’ to ‘patient in’, was reported in an anonymized fashion for the following categories: 1) by endoscopist, 2) by nurse, and 3) by unique endoscopist-nurse pair. Only data from routine outpatient endoscopic procedures (e.g. colonoscopy, gastroscopy, flexible sigmoidoscopy) were included. In order to evaluate turnover times by endoscopist-nurse pair, consecutive cases not performed by the same pair were excluded. Procedures affected by patient- and transportation-related delays were also excluded.

Results

Of the five centers surveyed, three allocated 5 minutes for turnover and two allocated 10 minutes. All centers reported tracking turnover time and four centers reported undertaking initiatives to decrease turnover time such as involving a flow team, hiring team attendants, and sharing performance data.

Over the 12-month period, 2504 routine outpatient GI endoscopic procedures were performed at SHSC, with 803 cases meeting inclusion criteria. Median turnover time for the unit was 6 minutes, ranging from 5 to 9 minutes across endoscopists, 5 to 7 minutes across nurses, and 3 to 10 minutes across unique endoscopist-nurse pairs (Figure 1). Efficiency of endoscopist-nurse pairs did not correlate with the number of cases performed as a pair over the 12-month period.

Conclusions

Endoscopy room turnover times at SHSC are similar to those reported by other local centers, with important variation across endoscopists and nurses. The next phase of this study will involve directly observing each of the most and least efficient individuals and pairs and recording common practices. It is anticipated that these findings will enable us to identify efficient practices that should be incorporated into standard operating procedures and training for endoscopy room personnel.

Funding Agencies

None
A164 UPTAKE OF FECAL CALPROTECTIN IN PRACTICE: PATTERNS IN A TERTIARY GI REFERRAL CENTRE
Authors: Kundra A , Ritchie T , Ropeleski M
Published: February 2020

Background

Fecal Calprotectin (FC) is helpful in distinguishing functional from organic bowel disease. Also, it has proven useful in monitoring disease activity in inflammatory bowel disease (IBD). The uptake of its use in clinical practice has increased considerably, though access varies significantly. Studies exploring current practice patterns among GI specialists and how to optimize its use are limited. In 2017, Kingston Health Sciences Centre (KHSC) began funding FC testing at no cost to patients.

Aims

We aimed to better understand practice patterns of gastroenterologists in IBD patients where there is in house access to FC assays, and to generate hypotheses regarding its optimal use in IBD monitoring. We hypothesize that FC is not being used in a regular manner for monitoring of IBD patients.

Methods

A retrospective chart audit study was done on all KHSC patients who had FC testing completed from 2017–2018. Qualitative data was gathered from dictated reports using rigorous set definitions regarding indication for the test, change in clinical decision making, and frequency patterns of testing. Specifically, change in use for colonoscopy or in medical therapy was coded only if the dictated note was clear that a decision hinged largely on the FC result. Frequency of testing was based on test order date. Reactive testing was coded as tests ordered to confirm a clinical flare. Variable testing was coded where monitoring tests that varied in intervals greater than 3 months and crossed over the other set frequency codes. Quantitative data regarding FC test values, and dates were also collected. This data was then analyzed using descriptive statistics.

Results

Of the 834 patients in our study, 7 were under 18 years old and excluded. 562(67.34%) of these patients had a pre-existing diagnosis of IBD; 193 (34%) with Ulcerative Colitis (UC), 369 (66%) with Crohn’s Disease (CD). FC testing changed the clinician’s decision for medical therapy in 12.82% of cases and use for colonoscopy 13.06% of the time for all comers. Of the FC tests, 79.8% were sent in a variable frequency pattern and 2.68% with reactive intent. The remaining 17.5% were monitored with a regular pattern, with 8.57% patients having their FC monitored at regular intervals greater than 6 months, 7.68% every 6 months, and 1.25% less than 6 months. The average FC level of patients with UC was 356.2ug/ml and 330.6 ug/ml for CD. The mean time interval from 1st to 2nd test was 189.6 days.

Conclusions

FC testing changed clinical decisions regarding medical therapy and use for colonoscopy about 13% of the time. FC testing was done variably 79.8% of the time, where as 17.5% of patients had a regular FC monitoring schedule. An optimal monitoring interval for IBD flares using FC for maximal clinical benefit has yet to be determined. Large scale studies will be required to answer this question.

Funding Agencies

None
A168 IS ROUTINE SCREENING FOR HEREDITARY COLORECTAL CANCER FEASIBLE IN AN OUTPATIENT GASTROENTEROLOGY PRACTICE?
Authors: Smith B C , Yonge J , Macdonnell C A , Poon J , Galorport C , Gillies A , Chow R , Enns R A , Telford J J
Published: February 2020

Background

Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC), with a reported prevalence of 2–5% of all CRC cases. A study by Kastrinos et al. found that a simple 3 item survey identified 77% of individuals at high risk for hereditary CRC. Implementation of this questionnaire at a gastroenterology office may help identify patients at risk for LS and other hereditary CRC.

Aims

To assess whether implementation of a validated questionnaire to screen for hereditary CRC is feasible in an outpatient gastroenterology clinic.

Methods

Adult gastroenterology outpatients who consented to participate in the study completed the screening questionnaire. Those who had previously been assessed by the Hereditary Cancer Program were excluded. Each subject was asked the following three questions: (1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50? (2) Have you had CRC or polyps diagnosed before age 50? (3) Do you have ≥3 relatives with CRC?. Answering yes to any question was considered a positive screen.

Results

A total of 288 patients were screened, with 12 (4.2%) screening positive for question 1, 28 (9.7%) screening positive for question 2, and 8 (2.8%) screening positive for question 3. In total, 14.2% of individuals surveyed screened positive.

Conclusions

Utilization of a simple 3-question survey as part of regular patient intake in a gastroenterology office resulted in 14.2% of individuals screening high-risk for hereditary CRC. This is similar to the 15% screen positive rate in the original study of individuals with CRC. Further research is needed to determine whether a physician’s knowledge of the questionnaire results will change management and whether a positive screen leads to a confirmed diagnosis of LS and other hereditary colorectal cancers.

Funding Agencies

None
A169 DEVELOPMENT OF A DECISION TOOL TO IMPROVE UTILISATION OF RECOMMENDED SURVEILLANCE INTERVALS FOR INDIVIDUALS WITH COLORECTAL POLYPS: A FOCUS GROUP ANALYSIS
Authors: Lee E , Singh H , Simms A , Restall G , Shafer L , Walker J , Park J
Published: February 2020

Background

Several studies have demonstrated a high utilization of colonoscopy at shorter and longer time intervals than guideline recommendations. Innovative methods are required to increase adherence to recommended timing.

Aims

1) Explore current approaches used by endoscopist (EPs) and primary care providers (PCPs) to determine and communicate colonoscopy surveillance intervals (SI) between EPs, PCPs, and patients.

2) Obtain feedback for refining a decision tool to facilitate recommended SI.

3) Determine participant agreement of recommended SIs with current guidelines.

Methods

We conducted 4 focus groups (FGs); 3 FGs included EPs (n=12) and EPs in training (n=6); 1 FG included PCPs (n=4). FG questions explored use of guidelines, communication and follow-up practices with PCPs, EPs and patients, and challenges to follow-up.

Participants were also asked for feedback about a prototype polyp SI decision tool that was developed using an algorithm synthesizing current Canadian Association of Gastroenterology, US Multisociety Task Force, and expert panel guidelines on SI. FGs were audio-recorded and transcribed for qualitative content analysis. FGs were analysed separately, then compared for similarities and differences. Finally, participants individually made interval recommendations for 7 common endoscopy scenarios. Responses were analyzed for agreement with the guidelines used to develop the decision tool.

Results

EPs reported not routinely referring to guidelines and were confident in their memory of the intervals although some reported checking occasionally. Many indicated they may use the tool in a web based or mobile application for more complicated scenarios, although some would never use it. Concerns regarding the tool included being up to date with research evidence and having required data to input on hand. PCPs reported the tool may be useful as a communication aid to involve patients in decision making. A challenge noted in all FGs was role confusion regarding communicating, tracking, and scheduling patients’ future procedures on time.

Analysis of EPs (n=9) responses to the 7 scenarios showed that percent agreement with guidelines was low: 44% scored below 50% correct. Participants with the highest agreement scored 6/7; responses with the lowest agreement scored 0/7. The most common score was 3/7.

Conclusions

EPs appeared to be overconfident in their recommendations, but many were open to trying a website or mobile application decision tool to make evidence-based colonoscopy SI recommendations. Understanding, among PCPs and EPs, regarding responsibility for communicating results and scheduling follow-up surveillance for patients was inconsistent. Participant feedback informed development of a mobile application that is currently being pilot tested.

Funding Agencies

Research Manitoba
A174 RARE BUT DEADLY: AN APPROACH TO MANAGEMENT OF DUODENAL VARICEAL HEMORRHAGE
Authors: Dahiya M , Tomaszewski M , Ou G , Ramji A
Published: February 2020

Background

Common etiologies of upper gastrointestinal bleeding (UGIB) in cirrhotic patients with portal hypertension include gastroesophageal varices (GOV), portal hypertensive gastropathy (PHG) and gastric antral vascular ectasia (GAVE). Less commonly, patients with portal hypertension develop varices in ectopic sites, including the rectum, biliary tree and duodenum. Ectopic varices are rare, contributing to 1–5% of all variceal bleeding, of which 17% is from duodenal varices.

Aims

To describe the management of duodenal variceal hemorrhage.

Methods

A case report and literature review was performed.

Results

Case report:

We present a case of recurrent UGIB in a 59-year-old male with decompensated cirrhosis due to non-alcoholic steatohepatitis (CP-C; Meld 14). Initial endoscopy was negative for GOV, peptic ulcer, PHG, and GAVE, but an erosion over a mucosal bulge in the third segment of the duodenum was identified, raising possibility of vascular malformation versus ectopic varix. There was active bleeding after water provocation, so clips were deployed for hemostasis. CT imaging showed mesenteric venous collaterals abutting the duodenum, again raising possibility of duodenal varix, which was ultimately confirmed by endoscopic ultrasound (EUS). Patient had recurrent overt bleeding despite beta-blockage for prophylaxis, endoscopic clipping on four separate occasions, attempted angioembolization by interventional radiology, and cyanoacrylate glue. Transjugular intrahepatic porto-systemic shunt (TIPS) was not possible due to portal vein occlusion, so he underwent EUS-guided cyanoacrylate glue a second time.

Literature review:

Ectopic varices are rare, contributing to 1–5% of all variceal bleeding, of which 17% is from duodenal varices. Duodenal variceal hemorrhage can lead to hemorrhagic shock, and is potentially life threatening, with quoted mortality rates of 40%. Unfortunately, duodenal varices can be difficult to identify. Diagnosis is often delayed due to a combination of lower awareness and endoscopic challenges given the unusual serosal and submucosal location.

Evidence-based guidelines for the management of ectopic varices are limited. For this reason, our current management strategies rely heavily on local expertise. Splanchnic vasoconstrictor medication, endoscopic ligation, EUS guided gluing, interventional radiology guided embolization, TIPS, balloon retrograde transvenous obliteration and surgical shunts are potential therapeutic options to manage the acutely bleeding varix. Following a variceal bleed, liver transplantation should be considered in eligible patients with no other contraindications.

Conclusions

Duodenal varices are a rare, potentially fatal, and underrecognized cause of gastrointestinal bleeding in patients with portal hypertension. Definitive therapy currently relies upon local expertise in the absence of clear guideline-based therapy.

Funding Agencies

None
A184 NON-CIRRHOTIC HYPERAMMONEMIA SECONDARY TO EXTRAHEPATIC PORTOSYSTEMIC VENOUS SHUNT PRESENTING AS A CONGNITIVE DYSFUNCTION: A CASE REPORT AND LITERATURE REVIEW
Authors: Abdel Moaein T , Ilnyckyj A , Bhangoo S
Published: February 2020

Background

Hyperammonemia secondary to liver disease is a very common cause of hepatic encephalopathy (HE) and it is easily recognized in patients with advanced liver disease. Non-cirrhotic causes of hyperammonemia are rare, particularly extrahepatic portosystemic venous shunts (EPS). The majority of these shunts are between a mesenteric vein and the inferior vena cava. We report a case of a non-cirrhotic hyperammonemia secondary to a shunt between the superior mesenteric vein (SMV) and the right renal vein (RRV) that presented with encephalopathy. Diagnosis was delayed due to lack of awareness of non-cirrhotic hyperammonemia underscoring the importance of measuring ammonia in all patients presenting with encephalopathic symptoms irrespective of their liver function.

Aims

To report our experience with a patient with unexplained cognitive dysfunction that was eventually attributed to hyperammonemia secondary to a rare non-cirrhotic portosystemic shunt. Also, we discuss the differential diagnoses of non-cirrhotic hyperammonemia and the pathophysiology, classification and diagnosis of spontaneous portosystemic shunts.

Methods

A retrospective chart review

Results

A 57-year-old woman with longstanding essential tremors on topiramate presented with a 30-month history of recurrent disabling episodes of unexplained “zoning out”. Her neurologists undertook extensive investigations which excluded primary neurological conditions. These episodes persisted despite discontinuation of topiramate, treatment of urinary tract infection (UTI) and continuing daily prophylactic antibiotics for recurrent UTIs as presumed etiologies. Due to her unexplained and disabling symptoms she was referred to an internist.

During further evaluation, ammonia level was measured for first time, in the absence of any obvious features of chronic liver disease, and the level was strikingly elevated 152uml/l. Hence, an abdominal CT was obtained and revealed a prominent shunt between SMV and RRV.

The patient was diagnosed with non-cirrhotic hyperammonemia secondary to EPS. She is currently stable on lactulose and rifaximin with a drop in her ammonia level to 63uml/l, and an interventional radiological procedure is being considered.

Conclusions

While hyperammonemia is most commonly related to liver failure, our case highlights the importance of awareness of non-cirrhotic hyperammonemia. Any unexplained change in level of consciousness, cognition and/or behavior merits measurement of serum ammonia irrespective of clinical liver status.

Funding Agencies

None
A187 CHOLESTATIC LIVER DISEASE AND BRAIN DYSFUNCTION: ROLE OF THE ARYL HYDROCARBON RECEPTOR
Authors: Mathews A J , Vicentini F , Swain L , Swain M , Sharkey K A
Published: February 2020

Background

Cholestatic liver disease is associated with immune-mediated inflammatory liver injury. This disorder is also associated with brain dysfunction and behavioural changes, notably fatigue, depression and social withdrawal. The mechanisms leading to these central nervous system abnormalities are unknown, however, they are associated with neuroinflammation. Microglia and astrocytes are two glial populations that play key roles in neuroinflammation. Activated glia display morphological changes, secrete cytokines, and mediate electrophysiological changes, altering the normal functioning of the brain. The aryl hydrocarbon receptor (AhR) is a transcription factor involved in the immune response. AhR is present on glia and its’ activation has been shown to reduce neuroinflammation. The role of the AhR in cholestatic liver disease has yet to be examined.

Aims

To study the function of the AhR in a model of cholestic liver disease. We will test the hypothesis that activation of AhR in the brain will reduce neuroinflammation and behavioral deficits observed in cholestatic mice.

Methods

Male C57Bl/6J mice had cholestasis induced by bile duct ligation (BDL); comparisons were made to sham-operated controls. Mice were tested for social interaction with a 4-week old juvenile in their home cage and the number of social interaction attempts quantified. Next, mice were euthanized, brains were removed and processed for immunohistochemistry. Brain sections were stained for markers of microglia (IBA-1) and astrocytes (GFAP). Microglia were counted and astrocyte activation was qualitatively assessed. PCR was used to quantify gene expression of AhR and its downstream gene targets (eg. CYP1A1) in mice that recived treatment with beta-napthoflavone (BNF), an AhR agonist, or in vehicle treated controls.

Results

BDL mice made significantly fewer attempts to interact with the juvenile as compared to controls (P<0.05). We also observed a significant increase in IBA-1 immunoreactive cell numbers in both the CA1 region of the hippocampus and the hypothalamic paraventricular nucleus (PVN, P<0.05). BDL mice also displayed marked increases in GFAP+ staining in the PVN, but not the CA1, in contrast to sham controls. Lastly, we found that BNF significantly upregulated CYP1A1 (P<0.05) in the liver and prefrontal cortex of mice. We are currently examining whether BNF can reduce neuroinflammation and improve decreased social interaction in cholestatic mice.

Conclusions

Cholestatic liver damage was associated with impaired social behavior. Further, glial activation, an indicator of neuroinflammation was increased in components of the limbic system associated with the response to stress, learning, and memory. Future experiments will address whether activation of the AhR will ameliorate neuroinflammation and behavioral changes observed in mice with cholestatic liver injury.

Funding Agencies

CCC, CIHR
A196 INCIDENCE OF PEDIATRIC EOSINOPHILIC ESOPHAGITIS IN EDMONTON ZONE AND RISK OF STRICTURING AT DIAGNOSIS
Authors: Burnett D , Persad R , Huynh H Q
Published: February 2020

Background

Eosinophilic esophagitis (EoE) is a common cause of esophageal dysfunction in children. A subset of children have a more severe phenotype of EoE, complicated by esophageal stricturing. Limited work has been done to characterize this phenotype.

Aims

To determine the incidence of EoE, and the frequency of esophageal stricturing in pediatric EoE.

Methods

We retrospectively identified all new cases of EoE at the Stollery Children’s Hospital from 2015–2018 using esophageal biopsy reports for the province of Alberta (CoPath database), EoE clinic lists and an OR database for esophageal dilatation at the Stollery. Electronic medical records (EMR) were reviewed to confirm EoE diagnosis. For each confirmed case, clinical data was captured from the outpatient EMR and gastroscopy/pathology reports. A review of peri-endoscopy OR/nursing charts was performed on a subset of patients (n=75) to capture scope adverse event. Statistics Canada 2016 census data was used to calculate incidence rates.

Results

185 new cases of EoE were diagnosed at our center during the study period (see table). For patients < 15 years old living in Edmonton zone (n=73), the incidence over the 4 years was 11.1 cases per 100,000 person years {8.7 (0–4 year-old), 7.6 (5–9 year old), and 18.1 (10–14 year old)}. There was limited variation in incidence in the 4 years (9.1–12.1 per 100,000 person years). 8 of 185 (4%) patients had endoscopically confirmed esophageal strictures, 4 of which required mechanical dilation (mean 3.75 dilations per patient, range 1–6). 11/185 (5.9%) patients had more subtle signs of esophageal narrowing, but no strictures. No perforations or episodes of significant bleeding were reported in peri-endoscopy charts reviewed for 239 gastroscopes, including 16 dilations. Pain was reported after 15% of all scopes, including 50% of the 28 scopes with strictures and 63% of the 16 scopes involving dilations.

Conclusions

Edmonton zone has one of the highest incidences of EoE reported in children. In this cohort, 4% had esophageal stricture (half required dilatation) and 5.9% had more subtle narrowing. Patients with strictures were older, had more frequent food impaction and longer duration of symptoms (Table). This data will be included in an ongoing multicenter case-control study across Canada.

Funding Agencies

CAGWomen and Children’s Health Research Institute (Univ. Alberta)
A204 ANALYSIS AND CHARACTERIZATION OF THE EXCRETED AND SECRETED PRODUCTS OF PARASITIC HELMINTHS AS IMMUNOMODULATORS OF INFLAMMATORY BOWEL DISEASE
Authors: Siciliani E A , Arai T , Geary T , Lopes F , Jardim A
Published: February 2020

Background

Parasitic helminths are known for their exceptional ability to modulate the host immune response in order to favour their survival. The excretory/secretory products (ESP), from Trichuris and Ascaris species are of keen interest for inflammatory bowel disease (IBD). Crohn’s disease and ulcerative colitis patients have benefitted from the administration of ova of T. suis in clinical trials, whereby symptoms were remediated through the ingestion of parasite ova, which subsequently hatch in the intestine. Our previous work has demonstrated the ability of T. suis ESP to downregulate secretion of inflammatory cytokines (TNF-α, IL-12) and increase the secretion of anti-inflammatory cytokines (IL-10) in murine bone marrow-derived macrophages.

Aims

This research aims to unveil the mechanisms of immune modulation by parasitic helminths in the context of IBD. We aim to characterize the cellular response in vitro, as well as the systemic response in vivo, in order to better characterize the scope of immune modulation that occurs with treatment.

Methods

Human peripheral blood mononuclear cell (PBMC) monocytes were purified and treated with helminth-derived products. The products were removed, and fresh media was added containing lipopolysaccharide (LPS) to stimulate cells. Supernatants were collected for cytokine analysis and cells were lysed and frozen.

Mice were given 3% DSS or regular water for five days, and subsequently administered treatment with helminth-derived products, or a PBS control, once daily by intraperitoneal injection for 3–4 days. Weights were measured daily. On day 9 mice were sacrificed, colons lengths were measured, and spleens were collected for further analysis.

Results

We found that human PBMC monocytes treated with the ESP from T. suis and A. suum had decreased secretion of inflammatory cytokines (TNFα) and increased secretion of anti-inflammatory cytokines (IL-10).

Additionally, we found that heminth products from A. suum had the ability to reverse the symptoms of weight loss and colon shrinking in DSS-mice compared to the control. Specifically, mice with DSS-induced colitis treated with metabolites increased their weight more than the PBS control (P < 0.0001) and had a longer colon compared to the PBS control (P < 0.001).

Conclusions

Taken together, these data generate an interest for intestinal helminth products as immunomodulators regarding treatment for patients suffering from inflammatory bowel disease (IBD).

Funding Agencies

NSERC and FRQNT
A206 SUSCEPTIBILITY OF HNF4AΔIEC MICE TO SALMONELLA INFECTIONS
Authors: Pupo Gómez D , Reyes-Nicolas V , Marrero G , Perreault N , Menendez A , Boudreau F
Published: February 2020

Background

Inflammatory bowel diseases (IBD) are a group of chronic disorders that affect more than 233 000 Canadians and for which there is not yet an effective treatment. In addition, IBD is a multifactorial disease depending on genetic, immune and environmental dysregulations. The gastrointestinal epithelium plays an important role as a barrier that protects against antigens and bacterial products that are in the lumen. It is well recognized that a defect in the integrity of the barrier and its functions may be involved in the development of these diseases. On the other hand, our laboratory has shown that the conditional deletion of HNF4alpha nuclear receptor (Hnf4a) in the intestinal epithelium of mice can lead to the development of chronic inflammation of the intestine. However, the impact of the loss of this transcriptional factor on the epithelial barrier is still controversial.

Aims

To evaluate the impact of Hnf4a deletion on the epithelial barrier during bacterial infections.

Methods

We used a tamoxifen-inducible Cre-loxP system to delete the Hnf4a gene in the intestinal epithelium of 2-month-old mice, that were then infected with an attenuated strain of Salmonella typhimurium (SB1003) during 4 days. S. typhimurium loads were determined in cecum and colon content, and in liver, spleen tissues by plating homogenates on LB agar supplemented with streptomycin. Also, histological examinations and gene expression of selected targets were assessed between mutant (Hnf4aΔIEC) and control mice.

Results

The tamoxifen-inducible Cre-loxP system was able to delete intestinal Hnf4a gene expression with almost 100% of efficacy. Analysis by qPCR showed that the infection caused significant changes on the response of different infection responsive components (Relmβ, Muc2 and IL-33) in mutant mice. In addition, morphological analyses revealed an increase in the infiltration of immune cells and the number of goblets cells, indicative of an increase in the susceptibility to Salmonella typhimurium (SB1003) infection of the mutant mice.

Conclusions

Altogether, our results suggest that Hnf4a could be involved or play an important role as a modulator of the intestinal epithelial barrier function during Salmonella typhimurium (SB1003) infection. Therefore, understanding the mechanisms involved in this process could allow the development of better therapies for IBD.

Funding Agencies

CIHR
A217 DEFINING THE RELATIONSHIP BETWEEN DIETARY FIBERS AND INFLAMMATORY RESPONSE IN PEDIATRIC INFLAMMATORY BOWEL DISEASES
Authors: Mander I K , Jerasi J , Dickner R , Carroll M W , Huynh H Q , Armstrong H , Wine E
Published: February 2020

Background

The incidence rates of inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC) are increasing in children. Although the etiology of IBD is poorly understood, factors such as urban lifestyle, diet, increased hygiene, and reduced microbial biodiversity have been implicated as risk factors. Compositional changes and reduced microbial biodiversity have been linked to therapy failure in pediatric IBD. Non-digestible dietary carbohydrates, such as fiber, must undergo fermentation by gut microbiota within the large bowel, producing short chain fatty acids (SCFAs). Animal studies have shown that dietary fibers can inhibit IBD-associated inflammation, and clinical trials have demonstrated that SCFAs can prevent intestinal atrophy and allow for tissue recovery in IBD patients. In disease settings with altered gut microbes, fermentation of dietary fibers may be greatly affected. Unfermented fibers interact with receptors on host immune cells and can induce proinflammatory immune response, production of oxygen species and inflammation, or an inhibition of proinflammatory receptors.

Aims

Based on this rationale, we hypothesize that dysbiosis in the IBD gut leads to decreased fiber fermenting microbes, resulting in reduced SCFA production. This contributes to increased inflammatory responses both in in vitro cell lines, as well as ex vivo patient biopsies. Because intact fibers can bind to host cell receptors, this promotes inflammatory response and continued dysbiosis.

Methods

To assess effects of intact fiber on immune cells, macrophage and T-cell in vitro cultures were used to measure cytokine response to inulin (5mg/mL) and oligofructose (5mg/mL) through ELISAs/qPCR. These cell lines and ex vivo patient biopsies were treated with whole fibers and IL-1β secretion was measured. Fibers were also pre-fermented with microbes of interest or whole microbe patient intestinal washes and used to treat cell lines and patient biopsies.

Results

Whole fibers induced a pro-inflammatory response in macrophage cells but not T-cells, and this pro-inflammatory response was mitigated by pre-fermenting the fibers. Intestinal washes from severe IBD patients were unable to successfully ferment oligofructose or reduce fiber-associated inflammation in macrophage cell lines, whereas washes from remission or non-IBD samples reduced IL-1β. Oligofructose was found to increase IL-1β secretion in UC and CD patient biopsies, but not in non-IBD specimens. This increase was also correlated with disease severity.

Conclusions

These results indicate that a lack of fiber-fermenting microbes and presence of whole fibers can lead to pro-inflammatory responses, both in cell lines and patient biopsies. However, the presence of appropriate fermenting microbes can reduce fiber-associated inflammation.

Funding Agencies

CCCWCHRI, Weston Foundation
A231 UNDERSTANDING THE IMPACT OF TNF-ALPHA ANTAGONISTS ON THE SEVERITY OF NON-MELANOMA SKIN CANCER IN INFLAMMATORY BOWEL DISEASE AND THE CONSEQUENCES FOR THERAPY
Authors: Townsend C M , Khanna R , Wilson A
Published: February 2020

Background

Non-melanoma skin cancer (NMSC) accounts for at least 40% of all new cancer diagnoses in Canada annually and presents a significant cost to the health care system due to the volume of cases. The incidence of NMSC in patients with Inflammatory Bowel Disease (IBD) is higher when compared to the general population. Generally, in a non-IBD population, the risk of further NMSC progression is low, however, little data exists that highlights differences in clinical course of patients diagnosed with NMSC who have IBD and are TNF-α antagonist exposed. It is unclear if TNF-α antagonist therapy should be discontinued in this patient population.

Aims

Our goal is to determine whether TNF-α antagonist exposure in IBD is associated with a high risk NMSC presentation at diagnosis, as defined by the National Comprehensive Cancer Network (NCCN) stratification. Our secondary objectives include presence of positive margins following resection, presence of metastatic disease on initial presentation, requirement of additional therapy to treat NMSC, number of patients who had TNF-α antagonist therapy discontinued following diagnosis of NMSC and number of individuals with recurrent NMSC.

Methods

Four hundred and twenty-four IBD patients seen at London Health Sciences Centre were reviewed. We have identified 22 patients who were diagnosed with NMSC. Twelve patients had a pre-NMSC TNF-α antagonist exposure while 10 patients who developed an NMSC and had no TNF-α antagonist exposure prior to NMSC diagnosis.

Results

Preliminary results of the primary outcome demonstrate that fifty-percent (6/12) of patients who have been exposed to TNF antagonist therapy presented with a high risk NMSC lesion at diagnosis compared to 40% (4/10) who were not exposed (OR 5.16, 95%CI 0.47–57.00; p = 0.181). Preliminary results of the secondary outcomes suggest that 25% (3/12) of patients exposed to TNF-α antagonist had positive margins compared with 0% (0/10) of patients who were not exposed. No patients in either group presented with metastatic disease. Twenty-five percent (3/12) of patients in the exposed group received more advanced treatment compared with 0% (0/10) in the non-exposed group. Eight percent (1/12) of patients in the TNF-α antagonist group had their IBD therapy changed from a TNF-α antagonist to an alternative biologic class, and 17% of patients (2/12) in the TNF-α antagonist group had recurrent NMSC lesions.

Conclusions

In conclusion, preliminary results suggest that TNF-α antagonist exposure may be associated with higher risk NMSC lesion at presentation. Further expansion of the sample size is required to explore these hypotheses further.

Funding Agencies

None
A244 MATERNAL THIOPURINE AND ANTI-TUMOR NECROSIS FACTOR THERAPY DURING PREGNANCY IS ASSOCIATED WITH AN INCREASED RISK OF PLACENTAL-RELATED DISEASES
Authors: Tandon P , Lee E , Hitz L , Huang V
Published: February 2020

Background

Though previous studies have suggested that most therapies for inflammatory bowel disease (IBD) are safe during pregnancy, the effect of these medications on placental-related diseases remain unknown.

Aims

To determine the effect of gestational medication exposure on pregnancy-related outcomes in patients with IBD.

Methods

We retrospectively reviewed the University of Alberta and University of Toronto pregnancy databases to identify patients (age > 18) who underwent routine assessment by a gastroenterologist at least once during pregnancy (first trimester (T1), second trimester (T2), and third trimester (T3). Pregnancy-related outcomes (maternal, obstetrical, and neonatal) were recorded from obstetrical records. Low-birth weight (LBW) was defined as an infant weight < 2500g at birth. Pre-term delivery was defined as birth < 37 weeks gestation. Medication exposure, such as 5-aminosalicylates (5-ASA), thiopurines, steroids, and anti-tumor necrosis factor (TNF) therapy was recorded for each trimester. Categorical variables were statistically compared using the Chi-square (x2) test through the SPSS software.

Results

A total of 84 patients were included. Compared to those not exposed to thiopurines, patients exposed to thiopurine therapy during T2 had an increased risk of pre-term birth (26.7% vs. 7.7%, p=0.046) and pre-eclampsia (13.3% vs. 0%, p=0.008) and a trend towards an increased risk of placental abruption (6.7% vs, 0%, p=0.061). Furthermore, compared to those not treated with corticosteroids, those prescribed corticosteroid therapy during any trimester had an increased risk of pre-term birth (T1 exposure: 50% vs. 10.2%, p=0.024; T2 exposure: 37.5% vs. 8.5%. p=0.018; T3 exposure: 42.9% vs. 8.8%, p=0.008) and infants born with LBW (T1 exposure: 50.0% vs. 7.8%, p=0.009; T2 exposure: 37.5% vs. 8.2%, p=0.015; T3 exposure: 57.1% vs. 8.6%, p=0.0005). Those exposed to corticosteroids in T3 only had an increased risk of PPROM (60.0% vs. 7.5%, p=0.0003) and chorioamnionitis (14.3% vs. 0%, p=0.002). Finally, anti-TNF therapy in T2 was associated with an increased risk of pre-eclampsia (9.1% vs. 0%, p=0.040. 5-ASA therapy was not associated with an increased risk of any adverse pregnancy-related outcome. No medication increased the risk of other maternal (i.e. gestational diabetes, emergency Cesarean-section delivery) and neonatal (intensive care unit admission, congenital anomalies) outcomes.

Conclusions

Placental related diseases, such as pre-eclampsia, appear to be increased with maternal exposure to thiopurine and anti-TNF therapy during pregnancy. Larger studies are required to confirm these associations.

Funding Agencies

None