bluuebunny/crossref_metadata_2025_split huggingface dataset:
A31 OUTCOMES OF PATIENTS UNDERGOING REPEAT VIDEOCAPSULE ENDOSCOPY (VCE) PRESENTING WITH OBSCURE GASTROINTESTINAL BLEEDING (OGIB)
Authors: Krahn T , Suliman M I , Halloran B , Wasilenko S , Zepeda-Gomez S 
Published: February 2022

Abstract

Background
Videocapsule Endoscopy (VCE) as well as balloon-assisted enteroscopy (BAE) are useful tools in the diagnosis and management of obscure gastrointestinal bleeding (OGIB). There is limited data assessing the diagnostic yield of VCE in subjects with OGIB according to different subtypes: 1) obscure overt 2) inactive overt and 3) active overt.

Aims
We evaluated the diagnostic yield and outcomes of patients undergoing a second VCE in OGIB.

Methods
This is a retrospective analysis of all patients who underwent more than one VCE completed at the University of Alberta from January 1, 2015 to August 31, 2021. Demographic and background information was collected including previous endoscopy results, cross-sectional imaging, and subsequent interventions. Patient data was analyzed according to subtype of OGIB at presentation.

Results
During the study period, there were 59 subjects who met inclusion criteria. The indication for VCE was recurrent iron deficiency anemia (IDA), active OGIB, and/or inactive OGIB in 38 subjects. The median time to VCE after initial endoscopic evaluation was 61 days. Median age of cases was 61.5 years and 49% were female.
Initial VCE had clinically significant positive findings in 68% of cases (Table 1). The diagnostic yield was 75%, 56% and 74% in active OGIB, inactive OGIB, and IDA, respectively. Active bleeding or fresh blood was present in 33% of VCEs for active OGIB compared to 11% of inactive OGIB and 13% of subjects with IDA.
At second VCE investigation, there were positive findings in 42% of cases. Findings on second VCE differed from initial VCE in 17 of 38 cases. Findings that changed clinical management were found in 76% of patients after first and second VCE.
BAEs were performed in 20 subjects after VCE, with therapeutics applied in 75%. The most common findings were arteriovenous malformations (AVMs) (65%) and erosions/ulcers (15%).

Conclusions
The diagnostic yield of VCE is high in appropriately selected patients and did not significantly differ in patients with IDA, active, and inactive OGIB. Serial VCE is appropriate for the investigation of suspected recurrent small bowel bleeding when initial workup is nondiagnostic.

Funding Agencies
None
A37 EFFICACY AND SAFETY OF RISANKIZUMAB AS MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE: 52 WEEK RESULTS FROM THE PHASE 3 FORTIFY STUDY
Authors: Panaccione R , Ferrante M , Feagan B G , Sandborn W , Panes J , Peyrin-Biroulet L , Colombel J , Schreiber S , Dubinsky M , Baert F , Hisamatsu T , Neimark E , Huang B , Liao X , Song A , Berg S , Duan W , Pang Y , Pivorunas V , Kligys K , Wallace K , D’Haens G 
Published: February 2022

Abstract

Background
Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks.

Aims
FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB

Methods
Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time.

Results
Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P&lt;0.01); RZB 180mg was superior to PBO for clinical remission per CDAI and endoscopic response ( P&lt;0.01). Endoscopic remission and deep remission rates increased over time with 360mg, remained steady with 180mg, and decreased with PBO. Mean fecal calprotectin (FCP) and C-reactive protein (CRP) levels decreased with SC RZB, but increased with PBO, over 52wks. Exposure-adjusted event rates (per 100 pts-years) of serious adverse event (AE) were generally similar among groups (360mg, 21.0 E/100PY and 180mg, 19.5 E/100PY vs PBO, 19.3 E/100PY), as were AEs leading to drug discontinuation (4.8 E/100PY and 2.4 E/100PY vs 3.7 E/100PY), and serious infections (6.0 E/100PY and 3.0 E/100PY vs 5.0 E/100PY).

Conclusions
In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated.

Funding Agencies
AbbVie
A39 TARGETING IL-4 TO TREAT CROHN’S DISEASE ASSOCIATED INTESTINAL FIBROSIS IN SHIP DEFICIENT MICE
Authors: Safari K , Menzies S , Jung H , Sly L M 
Published: February 2022

Abstract

Background
Crohn’s disease (CD) is an immune-mediated disease characterized by chronic, relapsing, or progressive inflammation along the gastrointestinal tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Biological therapy is very effective at reducing inflammation in CD; however, biologics do not reduce the incidence of fibrosis or surgery in people with CD, suggesting that a distinct mechanism(s) may exist that drives intestinal fibrosis. Treatments for intestinal fibrosis are urgently needed as currently, no treatment exists that target intestinal fibrosis directly.
Mice deficient in the Src homology 2 domain-containing inositolphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation and fibrosis. Fibrosis is dependent on PI3Kp110δ activation, which leads to induction of the enzyme arginase I (argI). Genetic ablation or pharmacologic inhibition of PI3Kp110δ or inhibition of arginase activity blocked the development of intestinal fibrosis in SHIP-/- mice. Both IL-4 and IL-13 can activate PI3Kp110δ but intestinal pathology in SHIP-/- mice is characterized by high levels of IL-4. Thus, we hypothesize that SHIP-/- mice develop CD-like intestinal fibrosis due to increased IL-4 signalling.

Aims
Aim 1: To determine whether genetic ablation of IL-4 prevents ileal fibrosis in SHIP-/- mice

Aim 2
To determine whether inhibition of IL-4 activity can block or reverse ileal fibrosis in SHIP-/- mice

Methods
SHIP-/- mice were crossed with mice deficient in IL-4 (IL-4-/-) to generate wild type, SHIP+/+IL-4-/- SHIP-/-IL-4+/+, and SHIP-/-IL4-/- mice. Fibrosis was assessed in mice at 8 weeks of age. SHIP-/- mice (8-week-old) were treated with an anti-IL-4 antibody, IgG isotype control or PBS (injection control), for 2 weeks. Ileal fibrosis was assessed in SHIP-/- mice and compared to mice treated with anti-IL-4 antibody or controls. Measurements of ileal fibrosis include muscle thickening, and collagen accumulation by Masson’s trichrome staining.

Results
SHIP-/-IL4-/- mice do not have less ileal fibrosis than their SHIP-/- littermates. Inhibition of IL-4 signalling in SHIP-/- mice did not reduce ileal fibrosis.

Conclusions
Blocking IL-4 is not sufficient to block the development of ileal fibrosis in SHIP-/- mice. In future experiments, we will examine whether blocking IL-13, alone or in combination with IL-4, can ameliorate the development of intestinal fibrosis in SHIP-/- mice.

Funding Agencies
CIHR
A41 THE ROLE OF PGC-1α IN MURINE BONE MARROW DENDRITIC CELLS
Authors: Jaleel S , Lopes F 
Published: February 2022

Abstract

Background
The intestinal immune system tolerates food antigens and the commensal microbiota to prevent chronic inflammation. Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease, are characterized by the loss of tolerance towards the microbiota, leading to inflammation, which is characterized by the high production of cytokines such as TNF and the influx of macrophages and neutrophils to the gut. Tolerance is driven by tolerogenic dendritic cells (tolDCs). Currently, there is no cure for IBD and while available treatments may reduce symptoms, there are no pharmacological therapies that specifically seek to rescue tolerance. Inducing tolDCs in patients with IBD may be a promising therapy since it is a way to directly target the main cause of the disease. tolDCs have been defined by down-regulating TNF (pro-inflammatory cytokine), producing IL-10 (anti-inflammatory cytokine), and active oxidative phosphorylation (OXPHOS) in the mitochondria.

Aims
Given the tolDC characteristic of active OXPHOS, the objective of our project was to evaluate the role of PGC-1α, a major mediator of mitochondria biogenesis, in generating toDCs using murine bone marrow-derived dendritic cells (BMDC). Our hypothesis is that tolDCs would be (1) generated by pharmacological activation of PGC-1α by ZLN005, and (2) constrained by inhibition of PGC-1α by SR18292.

Methods
We treated BMDC cultures with ZLN005 (PGC-1α activator) or SR18292 (PGC-1α inhibitor), and LPS. We characterized the effect of PGC-1α manipulation on the metabolism of BMDCs by metabolomics and Seahorse XF Cell Mito Stress Test. In addition, we evaluated features of tolDCs, such as gene expression by qPCR, and cytokine production by ELISA.

Results
We observed that activation of PGC-1α altered the metabolic profile of BMDC, and upregulates genes known to be expressed in tolDCs. However, this transcriptional upregulation was lost after LPS stimulation and did not alter TNF or IL-10 levels in BMDCs. PGC-1α inhibition, on other hand, decreased features of tolDCs, such as metabolic profile, transcriptional activation, and the levels of LPS-induced IL-10. Our data suggest that PGC-1α activation with ZLN005 does not increase the generation of tolDCs in vitro. However, inhibition of PGC-1α with SR18292 constrains tolDCs generation.

Conclusions
PGC-1α is important for the development of tolDCs in murine dendritic cells.

Funding Agencies
NSERC and FRQNT
A42 HETEROGENEITY IN EFFICACY AND SAFETY ENDPOINTS FOR PEDIATRIC CLINICAL TRIALS IN INFLAMMATORY BOWEL DISEASE: A NEED FOR HARMONIZATION
Authors: Crowley E , Turner D , Ma C , Nguyen T , McKay H , Schneider R , Silverberg A , Muise A , Feagan B , Griffiths A , Jairath V 
Published: February 2022

Abstract
NOT PUBLISHED AT AUTHOR’S REQUEST
Funding Agencies: None
A47 MICROBIAL FUNCTIONS AS BIOMARKERS OF PRO-INFLAMMATORY RESPONSE TO SELECT DIETARY FIBERS IN IBD
Authors: Armstrong H , Bording-Jorgensen M , Valcheva R , Zhang Z , Jovel J , Petrova A , Carroll M W , Huynh H Q , Dieleman L A , Wine E 
Published: February 2022

Abstract

Background
Dietary fibers are not digested in the bowel; they are fermented by microbes, typically promoting gut health. However, IBD patients experience sensitivity to consumption of fibers. Our previous findings offered the first mechanistic evidence demonstrating that unfermented dietary β-fructans (inulin and FOS) can induce pro-inflammatory cytokines in a subset of pediatric IBD colonic biopsies cultured ex vivo, and in the SYNERGY-1 (β-fructan) clinical study of adult remission UC patients. Incubating FOS with whole-microbiota intestinal washes from non-IBD or remission IBD patients improved fermentation and reduced pro-inflammatory responses, but not from patients with active disease. Fibre-induced immune responses correlated with microbe functions, luminal metabolites, and fibre avoidance.

Aims
Here we aimed to expand on our findings and define the role of microbial functions in mediating host response to β-fructans.

Methods
Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with FOS (5g/L), or fermentation supernatants (24hr anaerobic fermentation). Immune responses (cytokine secretion [ELISA/MSD] and expression [qPCR]) were assessed. Taxonomic classification of microbial fermentation cultures was conducted with Kraken2 and metabolic profiling by HUMAnN2. HPLC and gas chromatography volatile fatty acid (CG-VFA) analysis were used to identify concentrations of remaining fibre and SCFAs following anaerobic fermentation.

Results
7 microbial enzymes were identified to be predictive of cytokine (IL-1β, IL23, IL-5, IL-8, MIP-1α) secretion in ex vivo colonic biopsies from pediatric Crohn disease (CD; n=38), ulcerative colitis (UC; n=20), and non-IBD (n=21) patients, in response to β-fructans; their use as biomarkers of response was determined in patient stool from the SYNERGY-1 clinical study cohort. Fermentation of FOS by whole-microbe intestinal washes from only non-IBD or remission IBD patients reduced cytokine secretion, and our findings demonstrate that this was due to a combination of reduction of β-fructan present and production of a precise combination of anti-inflammatory SCFAs.

Conclusions
Our findings suggest that intolerance and avoidance of fibers in select IBD patients is associated with the inability to ferment these fibers, mediated by altered microbial functions (enzymes), leading to worsened inflammation. Data indicate that gut microbial function, not composition, predicts patient pro-inflammatory response to β-fructans, supporting our hypothesis that overall community function impacts fibre fermentation and affects associated pro-inflammatory effects. Our work highlights select disease state scenarios in which administration of fermentable fibers should be avoided and tailored dietary interventions considered.

Funding Agencies
CIHRWeston Foundation, Mitacs
A53 A NOVEL PH-SENSITIVE OPIOID ANALOGUE PROVIDES SUSTAINED ANALGESIA DURING COLONIC INFLAMMATION AND LACKS COMMON SIDE EFFECTS
Authors: Degro C E , Jiménez-Vargas N N , Tsang Q K , Yu Y , Stein C , Bunnett N W , Lomax A E , Reed D E , Vanner S 
Published: February 2022

Abstract

Background
Opioids provide effective pain relief during flares of inflammatory bowel disease but are limited by serious side effects. We showed that acute administration of a novel pH-sensitive opioid agonist, NFEPP, had potent analgesic effects in inflamed acidified colonic tissues without opioid typical side effects. However, the effects of repeated application of NFEPP during the course of an acute flare of colonic inflammation are unknown.

Aims
To assess the analgesic and side effect profile resulting from repeated NFEPP applications during the course of acute colitis.

Methods
Acute colitis in C57BL/6 mice was induced via 2.5% dextran sulfate sodium dissolved in drinking water for 5 days. Mice were then randomly group assigned to either vehicle, fentanyl or NFEPP. Drugs and vehicle were administered sc. BID for 5 days (0.4 mg/kg), with a final injection on Day 6 (Day 1–6). Visceral nociception was evaluated by performing visceromotor responses (VMRs) to colorectal distension at different time points during colitis. Side effects were assessed using 1) a combination of oral contrast-enhanced abdominal CT-scans (before/after treatment) and defecation assessments to analyze gastrointestinal transit and isometric tension recordings to evaluate colon motility 2) pulse oximeter measurements to reveal cardiorespiratory effects. Inflammation was assessed by histological scoring, myeloperoxidase activity assay and tissue pH measurement of colon samples.

Results
NFEPP decreased VMRs to colorectal distension over the entire period of acute DSS colitis (Day 6: 40.54%, p&lt;0.001, reduction compared to baseline). However, strongest VMR inhibition was observed at Day 3 (66.7%, p&lt;0.05), concordant with the peak of inflammation (MPO: 3.5 U/mg tissue, p&lt;0.001; tissue Damage-Score: 3.0, p&lt;0.001; tissue pH: ΔpH= -0.28, p=0.001, all compared to healthy control). Treatment with NFEPP did not delay gastrointestinal transit (GIT, p=0.37, compared to baseline) nor fecal output (p=0.45, compared to vehicle) whereas fentanyl decreased transit (GIT: p&lt;0.05; fecal output: p&lt;0.05). Colonic contractile responses evoked by electrical field stimulation were reduced in fentanyl treated mice compared to NFEPP (10 Hz: p&lt;0.05). Fentanyl significantly reduced oxygen saturation (15 min: 85% SpO2, p&lt;0.01) and caused a sustained reduction in heart rate at Day 2 (60 min: Δ BPM -91.8 from baseline, p=0.001) whereas NFEPP did not affect oxygen saturation (p=0.95) and revealed minor, transient effects on heart rate (15 min: Δ BPM -75.6, p&lt;0.01) which recovered after 60 min.

Conclusions
Prolonged NFEPP administration effectively inhibits visceral nociception during acute colitis in a preclinical mouse model without altering gastrointestinal transit, colon motility and oxygen saturation.

Funding Agencies
CCC
A55 INTERLEUKIN-10 ELICITS CYTOPROTECTION VIA MITOCHONDRIAL SIGNAL TRANSDUCER AND ACTIVATORS OF TRANSCRIPTION 3 (MTSTAT3) TO PREVENT BACTERIAL PATHOBIONT EVOKED MITOCHONDRIAL FRAGMENTATION IN GUT EPITHELIA
Authors: NavaneethaKrishnan S , Wang A , Mckay D M 
Published: February 2022

Abstract

Background
Aberrant mitochondrial function is increasingly reported in inflammatory bowel disease (IBD). We recently reported that the IBD-associated pathobiont, adherent-invasive E. coli (AIEC) (strain LF82)-evoked epithelial mitochondrial fragmentation and mitochondrial depolarization. Remarkably, the transcription factor, signal transducer and activator of transcription (STAT)-3, can migrate to mitochondria (mtSTAT3) to regulate functions such as reactive oxygen species and ATP production. This non-canonical activity is dependent on STAT3 phosphorylation at serine727. IL-10 is an important regulator of enteric homeostasis that signals via STAT-3, however whether IL-10 affects mitochondrial dynamics is unknown.

Aims
To determine (1) if IL-10 preserves mitochondrial function in E. coli-LF82-infected epithelia through mtSTAT3, and if so, (2) to identify the mechanism by which mtSTAT3 restores mitochondrial functions.

Methods
The human colon-derived T84 epithelial cells or human organoids were exposed to E. coli LF82 (108 cfu/ml, 4h) ± co-treatment or an 18h pre-treatment with IL-10 (10 ng/ml). The effect of IL-10 on bacterial growth and its invasion of T84 cells were assessed by growth curve analysis and bacterial internalisation assays. We assessed mitochondrial network morphology using mito-tracker red and confocal microscopy, mitochondrial membrane potential with the fluorescent-dye TMRE and flow cytometry and fluorescence microscopy, and oxygen consumption rate (OCR) and ATP levels. STAT3 phosphorylation was analysed in whole cell protein extracts by western blot. Pharmacological inhibitors of JAK and Erk1/2 were used to examine the pathway of mtSTAT3 activation.

Results
IL-10 affected neither E. coli-LF82 growth nor invasion of T84 epithelia, but substantially reduced the AIEC-induced mitochondrial fragmentation in T84 cells and organoids. IL-10 preservation of the mitochondrial network was accompanied by increased mitochondrial membrane potential, OCR, and ATP levels in E. coli-LF82 infected T84 cells. IL-10 + E. coli-LF82-treated epithelia displayed increased phospho-S727 STAT3 that was reduced by inhibition of Erk1/2 but not JAK activity.

Conclusions
Mitochondria are a potential drug target in IBD, and the E. coli-LF82 pathobiont can be added to a growing list of microbial pathogens that evoke epithelial mitochondrial dysfunction. We have uncovered that IL-10 can stabilize mitochondrial function in E. coli-LF82 infected cells, possibly through mtSTAT-3. Our results underscore the role of IL-10/STAT3 signaling in preserving mitochondrial functions that could result in mitochondria-targeted therapeutics in IBD and other bacteria-driven enteropathies.

Funding Agencies
CIHRAIHS
A62 PROTEASE-ACTIVATED RECEPTOR-2 ACTIVATION ENHANCES EPITHELIAL WOUND HEALING THROUGH SRC PATHWAY-DEPENDENT CELL MIGRATION
Authors: Lucena Périco L , MacNaughton W 
Published: February 2022

Abstract

Background
Protease-activated receptors (PARs) and their activating enzymes play a role in inflammatory bowel disease (IBD) pathogenesis, but the specific roles of PAR2 in disease initiation and progression remain unclear. Interestingly, PAR2 activation has both pro-proliferative and pro-migratory effects and could be involved with restoration of the epithelial barrier following injury. We previously showed that the PAR2 activation increase the epithelial wound healing through ERK, PI3K and JNK pathways. However, the role of Src kinase, which is also activated by PAR2, is not known.

Aims
We hypothesized that PAR-2 activation induces a wound healing response in intestinal epithelial cells through Src activity.

Methods
Circular wounds were made in T84 colonic epithelial cells monolayers. Wounded monolayers were treated with the PAR2 activating peptide, 2-furoyl-LIGRLO (2fLI, 5 μM), or the inactive control reverse-sequence peptide, 2-furoyl-OLRGIL (2fO, 5 μM), and live cell imaging was used to record wound closure over a 12 or 24-hr period. The specificity of PAR2 was assessed with a PAR2 inhibitor (GB88). Proliferation and cytotoxicity were measured using EdU and TUNEL assays. The mechanism of action was evaluated using inhibitors of FAK (PF57328 and FAK14) and Src (PP2) and western blot (WB) was used to confirm the protein levels [p-FAK (Y397; Y576/577) and p-Src (Y416)]. For immunofluorescence, images of E-cadherin and F-actin or p-FAK were taken to capture the entire wound border and surrounding cells.

Results
PAR2 activation by 2fLI promoted wound closure compared to 2fO or vehicle control at the 12 and 24 hr timepoints ( p&lt;0.05). PAR2’s ability to enhance wound closure was blocked with the PAR2 inhibitor, GB88 ( p&lt;0.01). PAR2 activation had no effect on proliferation at the wound-edge and did not cause apoptosis, but enhanced lamellipodia/filopodia formation ( p&lt;0.001), indicating that PAR2 might program the cells toward a migratory phenotype rather than a proliferative phenotype. When we investigated the mechanisms of action, PAR2 activation did not induce focal adhesion kinase (FAK) expression in T84 cells and inhibition of FAK by selective inhibitors (PF573288 and FAK14) did not alter PAR2-induced wound healing. The immunofluorescence for p-FAK (Y397) and WB (Y937 and Y576/577) confirmed these results. However, the Src tyrosine kinase inhibitor (PP2, p&lt;0.0001) inhibited PAR2-induced wound healing. PAR2 activation increased Src phosphorylation (Y416, p&lt;0.05).

Conclusions
PAR2 activation drives wound healing in part via Src tyrosine kinase activity, but independently of FAK activity. These findings provide a further mechanism whereby PAR2 can participate in the resolution of intestinal wounds in gastrointestinal inflammatory diseases.

Funding Agencies
CAG, CIHR