bluuebunny/crossref_metadata_2025_split huggingface dataset:
IRE1α-XBP1 CONTROLS GROUP 3 INNATE LYMPHOID CELLS IN INFLAMMATORY BOWEL DISEASE
Authors: Cao Siyan , Colonna Marco 
Published: January 2023

Abstract

BACKGROUNDS
Group 3 innate lymphoid cells (ILC3s) recently emerged as important regulators and potential drug targets for IBD. However, the response of ILC3s to environmental stimuli during intestinal inflammation remains elusive. IRE1α-XBP1 is the most conserved pathway of the endoplasmic reticulum stress response that plays an important role in intestinal homeostasis. IRE1α mediates the alternative splicing of Xbp1 mRNA to produce a potent transcription factor XBP1s. Our preliminary data suggested that IRE1-XBP1 is induced during the activation of intestinal ILC3s.

METHODS
We generated conditional knockout Ire1αflox/flox,Rorc-Cre (Ire1αΔRorc) mice with Ire1α deleted in ILC3s. Intestinal infections were induced by Citrobacter rodentium and Clostridium difficile. In the acute phase of C. rodentium and C. difficile infection, IL-22 secreted by ILC3s, but not adaptive immune cells, is crucial for the host defense. Dextran sodium sulfate (DSS) was given in drinking water to induce colitis. We recruited patients with active Crohn’s disease (CD) and collected ileal biopsies during routine colonoscopy before starting a new biologic therapy. Mucosal immune cells were isolated from tissue samples for analysis of ILC3s by flow cytometry.

RESULTS
In murine intestinal ILC3s, the activity of IRE1α-XBP1 follows a robust 24h circadian rhythm which parallels that of clock genes and cytokines including IL-22 and IL-17A. IRE1α-XBP1 in intestinal ILC3s is further activated in response to inflammation/infection in mice and in patients with IBD compared to healthy controls. The IRE1α-XBP1 activation in stimulated ILC3s requires mitochondrial reactive oxygen species. Using the Ire1αΔRorc mice, we demonstrate that IRE1α-XBP1 is critical for cytokine expression by ILC3s. XBP1s binds to the promoters of Il-22 and Il-17a in activated ILC3s. Ire1αΔRorc mice loss the rhythmic expression of Il-22 and Il-17a by ILC3s in the gut. Additionally, Ire1αΔRorc mice are highly vulnerable to C. rodentium and C. difficile infection as well as DSS-induced colitis (Figure 1). The Ire1αΔRorc mice exhibit reduced IL-22 and IL-17A in ILC3s and impaired epithelial barrier function with diminished expression of mucins and antimicrobial peptides. The susceptibilities of Ire1αΔRorc mice to infections and colitis are rescued by injection of recombinant IL-22. Importantly, the frequency of ILC3s expressing XBP1s in ileal mucosa from CD patients positively correlates with response to therapies (Figure 2).

CONCLUSIONS
IRE1α-XBP1 controls ILC3s by activating IL-22 and IL-17A that are crucial for intestinal barrier function. Loss of IRE1α-XBP1 in ILC3s impairs the optimal and rhythmic expression of protective cytokines and renders the mice more susceptible to intestinal infections and colitis. Moreover, XBP1s in mucosal ILC3s may become a useful marker to predict response to therapies in CD patients.
SINGLE CENTER EXPERIENCE WITH UPADACITINIB FOR REFRACTORY PEDIATRIC INFLAMMATORY BOWEL DISEASE
Authors: Bergstein Suzannah , Spencer Elizabeth 
Published: January 2023

Abstract

BACKGROUND
Upadactinib (UPA) was recently approved for ulcerative colitis (UC) for patients 18 and older, and there is promising data for its use in adult Crohn’s disease (CD). It is currently also approved for use in atopic dermatitis (AD) down to the age of 12, but doses used are lower than in inflammatory bowel disease (IBD). There is currently no data on its use for pediatric IBD; we present here a case series of patients ≤18 years on UPA.

METHODS
We identified ≤18yo patients who were started on UPA for the indication of IBD +/- AD and completed ≥58 days of therapy at a single, US center. Data, with relevant descriptive statistics, were gathered on demographics, disease subtype, Montreal classification, indication for UPA, time on UPA, number of biologic failures, tofacitinib use, concomitant biologic use, adverse events, and clinical and biomarker remission (8-16 week clinical remission: HBI &lt;5, pMS &lt;3; 2-6 month CRP normalization).

RESULTS
12 patients (Median age at UPA start: 16.5y, Interquartile Range [IQR]: 4; 67% female) completed 8 or more weeks (Median [IQR] days: 118 [80]) of UPA (Table 1). Two-thirds of patients had CD. A quarter of patients (25%) had concomitant AD. All patients were diagnosed &lt;17 years, with 67% patients diagnosed below or at the age of ten. The majority of patients (75%) had failed three or more biologics. UPA was used as monotherapy in 50% of patients. Four patients were exposed to and had a partial response to tofacitinib. The majority of patients (75%) had clinically active disease at UPA start. Most patients (83%) were induced with 45 mg, one patient was induced with 30mg, and one patient initiated 15mg as part of AD protocol, later increasing to 30mg. Out of the 12 total patients, 11/12 (92%) were in clinical remission between 8-16 weeks of therapy; in the subset of patients ≤17 years, 6/7 (86%) were in clinical remission. Nine patients had CRP levels measured 2-6 months after initiating UPA treatment; 8/9 (89%) of these patients achieved CRP normalization during this time. No serious adverse events occurred; one patient, who was on UPA monotherapy, developed recurrent styes that responded to hot compresses and antibiotic ointment. Joint involvement (sacroiliitis, arthritis, arthralgias) at the start of their treatment occurred in 3 patients; all of these patients had resolution of joint pain by 8 or more weeks. All patients had previously received vaccination for varicella; no patients were vaccinated for zoster, including the 5 who were 18 years of age.

CONCLUSION
No new safety signals were seen during induction dosing of UPA in teenage patients with IBD. In this very refractory group, nearly all patients achieved clinical & biomarker remission. Further study on the effectiveness and safety of UPA needs to be performed in pediatric patients.
AN ASSESSMENT OF HEALTHCARE PROFESSIONAL KNOWLEDGE REGARDING INVESTIGATIONAL STEM CELL THERAPIES FOR PATIENTS WITH CROHN’S PERIANAL FISTULA: A US MULTISPECIALITY EDUCATIONAL NEEDS SURVEY
Authors: Salinas Greg , Belcher Emily , Cazzetta Susan , Nazarey Pradeep , Stacy Sylvie 
Published: January 2023

Abstract

BACKGROUND
Crohn’s perianal fistulas (CPFs) are a common complication in patients with Crohn’s disease. Stem cell therapies are under investigation for the treatment of CPF; however, understanding amongst healthcare professionals (HCPs) is unknown and their educational needs have not been assessed. This study aimed to assess HCP familiarity with stem cells, their potential application in treating CPF and factors that may influence their use.

METHODS
An online educational needs survey was developed and distributed to HCPs, including gastroenterology and colorectal surgery specialists and primary care physicians (PCPs). Questions focused on the types of stem cells showing promise in treating CPF, their proposed mechanism(s) of action and familiarity with stem cell therapies. Factors influencing HCP treatment decisions regarding stem cell use in patients with CPF were also assessed. Results were reported using descriptive statistics.

RESULTS
Overall, 433 HCPs completed the survey, including: 151 PCPs; 127 gastroenterologists (GEs); 78 colorectal surgeons (CRSs); 63 GE nurse practitioners/physician assistants (NPs/PAs); and 14 CRS NPs/PAs. Uncertainty regarding the mechanism(s) of stem cell action for perianal fistula (PF) healing was reported in more than half of the surveyed PCPs and GE NPs/PAs (52% and 54%, respectively) and under half of the surveyed GEs, CRSs and CRS NPs/PAs (39%, 35% and 43%, respectively). Excluding GEs (42%), most HCPs (PCPs: 67%; CRS NP/NPAs: 64%; GE NP/NPAs: 60%; CRSs: 55%) were unsure about which stem cell types had shown promise in treating CPF. Regarding stem cell use in CPF, gastroenterology and colorectal surgery specialists considered clinical trial outcomes, particularly the success rate of PF healing and the safety profile of stem cells reported in clinical trials, as the most significant factors influencing decisions to use an approved stem cell therapy, with mean (standard deviation; SD) scores on a five-point scale of 4.2 (0.8) and 4.3 (0.7) for the success rate of PF healing and 4.1 (0.8) and 4.2 (0.8) for the safety profile, respectively. For PCPs, the success rate of PF healing reported in clinical trials and cost/insurance coverage were considered the most significant factors, with mean (SD) scores of 4.1 (0.8) and 4.0 (1.0), respectively.

CONCLUSIONS
HCPs would benefit from more information and education on stem cell therapies for CPF, notably on the types of stems cells and mechanism(s) that lead to PF healing. Effective communication of stem cell clinical efficacy and safety data, alongside information on the cost/insurance coverage of stem cell therapy are all required to inform recommendations on the use of stem cells for treating patients with CPF.
MANAGEMENT STRATEGIES FOR OBESITY VARY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Dave Sonya , Beniwal-Patel Poonam 
Published: January 2023

Abstract

INTRODUCTION
Obesity among patients with inflammatory bowel disease (IBD) is increasing with prevalence of 15-40%. Studies have shown that obesity may have poor prognostic implications on IBD treatment and outcomes. There is lack of data focused on the management of obesity in IBD patients. This study’s primary aim was to evaluate whether patients with obesity and IBD have similar rates of obesity management compared to non-IBD obese patients with and without nonalcoholic fatty liver disease (NAFLD).

METHODS
This is a single-center retrospective study of 400 obese (body mass index &gt; 30 kg/m2) adult patients seen in a primary care clinic between March 2019 and August 2021. Four cohorts, each with 100 patients, were studied. The 4-level cohort analysis included patients with ulcerative colitis and obesity (UC-O), Crohn’s disease and obesity (CD-O), NAFLD and obesity (NAFLD-O), and a control group of patients with obesity only. The 3-level cohort analysis combined UC-O and CD-O and compared this cohort to the NAFLD-O and obesity-only cohorts. Obesity management data collected included: if obesity was documented (OD) in the medical record’s problem list, dietician referral, pharmacologic therapy, and bariatric surgery referral. One-way ANOVA was used to compare numeric variables and chi-squared was used for categorical variables. Logistic regression models were used for primary outcomes.

RESULTS
Baseline characteristics of BMI, age, gender, and race were similar among patients in the 4-level and 3-level cohort analyses (Tables 1 and 2). Across both analyses, NAFLD-O patients had the highest prevalence of OD (79% p&lt;0.001) and 2.61 higher odds of OD than the control (p =0.003). NAFLD-O patients also had the highest prevalence of dietician referrals (69%, p=0.01). CD-O patients had the highest prevalence of pharmacologic intervention (17%, p=0.01). UC-O patients were less likely to be referred to a dietician (OR=0.55, p=0.03) while CD-O patients were more likely to have pharmacologic management (OR=3.21, p=0.02). Secondary outcomes of comparisons of IBD-specific variables between UC-O and CD-O revealed significant differences as well (Table 3).

DISCUSSION
This is the first study investigating differences in treatments offered for obesity in IBD. With emerging evidence that obesity likely plays a role in IBD pathogenesis, timely identification and treatment is crucial. Significant differences in management of IBD patients with obesity highlight the need for increased awareness among healthcare providers. Our findings that CD-O patients had a higher rate of corticosteroid, immunomodulator, anti-TNF, anti-interleukin use, and IBD surgery compared to UC-O patients suggests that obesity may contribute to the pathogenesis of CD more so than UC. Further studies are needed to determine which obesity therapies are most effective in the IBD population.
THE INTERPLAY OF IBD AND DEPRESSION IN INPATIENT LENGTH OF STAY, COST, AND COMPLICATIONS
Authors: Dong Rachel , Chang Patrick , Zhang Bing 
Published: January 2023

Abstract

BACKGROUND
Many patients with inflammatory bowel disease (IBD) also have symptoms of depression. Both IBD and depression are associated with high healthcare utilization. In this cross-sectional study of population-based data, we sought to better characterize the impact of comorbid depression on hospitalizations of IBD patients.

METHODS
We used the 2016-2018 National Inpatient Sample (NIS) from the United States Department of Health and Human Services to identify hospitalizations with IBD and depression using ICD-10 codes. ICD-10 codes also identified confirmed complications of IBD, such as rectal bleed, fistula, abscess, or intestinal obstruction. Hospitalizations for suicidal intent were excluded from our analysis. Health outcomes including length of stay (LOS), total cost, and complications of IBD were compared between IBD patients with and without depression. Patients with confirmed discharges were captured and survival curves were compared for time to discharge. Statistical analysis was performed using STATA, including two-sample t-testing and logistic regression (significance, p&lt;0.01).

RESULTS
Over three years, 129,011 hospitalizations for IBD were isolated. Of these, 2,124 hospitalizations (1.65%) were recognized to have both IBD and depression. Lengths of hospitalization for IBD patients with depression were longer than those without (mean LOS [95% CI]: 7.52 [7.06-7.98] vs. 5.28 [5.24-5.32], p&lt;0.001) (Figure 1). Despite this, total cost of hospitalizations for IBD patients with depression was lower compared to IBD patients without depression ($mean [95% CI]: $47,841 [43,720-51,963] vs. $53,544 [53,023-54,065], p=0.008). Additionally, odds of hospitalization with IBD complication were lower in admissions coded for IBD with depression compared to without (OR [95% CI]: 0.52 [0.45, 0.61], p&lt;0.001). On sub-analysis, hospitalizations of IBD patients with depression in partial or full remission had lower length of stay than hospitalizations of IBD with ongoing depression (mean LOS [95% CI]: 4.84 [3.90-5.79] vs. 7.52 [7.06-7.98], p&lt;0.001) (Figure 2).

CONCLUSIONS
While IBD patients with depression demonstrated lengthier hospitalizations compared to IBD patients without depression, the higher inpatient cost and complications from the latter group may reflect diagnostic, procedural, or surgical management of active disease. While major limitations of this administrative database include identification of hospitalizations instead of individual patients, as well as possibly underreporting or lower recognition of depression during hospitalization, our findings suggest that management of comorbid depression may reduce the length of stay in hospitalized patients with IBD.
THE RELATIONSHIP BETWEEN SELF-REPORTED SLEEP, WRIST ACTIGRAPHY, AND SYMPTOMS AMONG ADULTS WITH INFLAMMATORY BOWEL DISEASE (IBD)
Authors: Winders Samantha , Yoo Linda , Clark-Snustad Kindra , Jacobs Jeffrey , Barahimi Mitra , Heitkemper Margaret , Lee Scott D , Kamp Kendra 
Published: January 2023

Abstract

BACKGROUND
Recently, there has been a growing recognition of the bidirectional link between sleep and inflammation. Several studies have reported the prevalence of sleep disturbances in those with Inflammatory Bowel Disease (IBD) and found poor sleep has the potential to increase the risk of disease relapse. Additionally, sleep loss may adversely affect cognitive performance, mental health, metabolism, and pain perception. While previous research has indicated potential associations between sleep and symptoms commonly reported in IBD, few studies use objective measures of sleep. Wrist actigraphy can objectively and non-invasively measure sleep-wake cycles and has been found feasible for use in the IBD population. This study aimed to examine the relationship between self-reported sleep, wrist actigraphy, and symptoms among adults with IBD.

METHODS
Participants with IBD (ages 18-55) completed demographic and sleep questionnaires, a 28-day symptom diary, and wore a wrist actigraph for up to 15 days. Sleep questionnaires were the Pittsburgh Sleep Quality Index (PSQI), Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance, and PROMIS sleep-related impairment. Participants rated symptoms on a 4-point Likert scale, including gastrointestinal-related symptoms such as abdominal pain, diarrhea, bloating, constipation, fatigue, and extraintestinal symptoms, including anxiety, depression, and stress. Data analysis included descriptive statistics and Pearson correlations.

RESULTS
Twenty-five participants (Crohn’s Disease=18; Ulcerative Colitis=7) were included. The mean age was 33.5 (SD 8.3) years of age, 60% were female, 92% were White, 88% were non-Hispanic or Latino, and 36% had active endoscopic disease. Most (64%) participants had poor quality sleep (PSQI global ≥ 5). In contrast, the averages for onset latency, efficiency, wake after sleep onset (WASO), and total sleep time were all within normal values at 17.4 min (SD 26.7), 84.2% (SD 7.5), 48.7 min (SD 27.3), and 435.8 min (69.2), respectively. PROMIS sleep disturbance was significantly correlated with abdominal pain (r=0.56), bloating (r=0.43), constipation (r=0.46), fatigue (r=0.50), and stress (r=0.42). PROMIS sleep-related impairment was significantly correlated with bloating (r=0.47), constipation (r=0.50), fatigue (r=0.60), depression (r=0.42), and stress (r=0.46). Onset latency was significantly correlated with anxiety (r=0.41) and stress (r=0.42). Sleep time was significantly correlated with fatigue (r=0.42).

CONCLUSION
This study highlights sleep disturbances are prevalent in those with IBD and significantly correlated with both GI and extraintestinal symptoms. Future work is needed to explore these relationships further and the potential benefit of sleep interventions in this population.
TRENDS AND RELATED FACTORS OF QUALITY OF LIFE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Kim Sihyun , Yoon Hyuk , Jun Yu Kyung 
Published: January 2023

Abstract

INTRODUCTION
Inflammatory bowel disease(IBD) affects health-related quality of life(HRQoL). The short inflammatory bowel disease questionnaire(SIBDQ), measuring physical, social, and emotional status(score 10-70, poor to good HRQoL), is known to be well correlated to HRQoL of IBD patients.

AIM/METHODS
We aimed to evaluate factors that impact IBD patients' HRQoL. This prospective study included a cohort of patients with ulcerative colitis(UC) and Crohn’s disease(CD). IBD patients completed a SIBDQ questionnaire at enrollment and 20% of those patients completed a second SIBDQ questionnaire at follow-up. Data were analyzed using multiple linear regression analysis and Pearson’s correlation.

RESULTS
A total of 1,058 patients with IBD(UC 68%, CD 32%) were included. A SIBDQ score was median 52(IQR: 44-58). The first and follow-up SIBDQ score were not significantly different between UC and CD patients (p=0.243 and p=0.893, respectively). The distributions of SIBDQ change were as follows: decrease over 10%: 28%, -10% &lt; change &lt; 10%: 29%, increase over 10%: 43%. In UC patients, significant factors that negatively associated with SIBDQ score, were physician’s global assessment(r=-3.562, p&lt;0.001), corticosteroids use(r=-5.478, p&lt;0.001), fecal calprotectin level(r=-2.313, p=0.008), presence of joint symptoms(r=-2.925, p=0.017). In CD patients, significant factors that negatively associated with SIBDQ score, were Crohn's disease activity index score(r=-0.035, p=0.009), level of abdominal pain(r=-3.400, p=0.013) and presence of skin symptoms(r=-3.842, p=0.016). Factors that associated with SIBDQ score in both UC and CD patients were stool frequency(r=-2.913, p&lt;0.001 in UC patients; r=-2.347, p=0.014 in CD patients).

CONCLUSION
SIBDQ questionnaire shows that IBD patients' HRQoL was mainly affected by the patient-reported outcome. However, it was also influenced by biochemical markers and extraintestinal symptoms depending on the specific type of IBD.
EICOSATETRAYNOIC ACID REGULATES PRO-FIBROTIC PATHWAYS IN AN INDUCED PLURIPOTENT STEM CELL DERIVED MACROPHAGE:HUMAN INTESTINAL ORGANOID MODEL OF ILEAL CROHN’S DISEASE
Authors: Dreskin Benjamin , Jurickova Ingrid , Angerman Elizabeth , Bonkowski Erin , Denson Lee 
Published: January 2023

Abstract

INTRODUCTION
Biologics targeting TNF are the mainstay of therapy for children with Crohn’s Disease (CD). However, a subset of patients do not respond, progressing to intestinal fibrosis requiring surgical resection. Prior studies have defined an ileal gene expression module linked to future strictures, and identified small molecules which may reverse this gene signature and suppress fibroblast activation. In the current study we developed a pre-clinical model system and tested a lead candidate, eicosatetraynoic acid (ETYA), a Peroxisome Proliferator-Activated Receptor (PPAR) agonist and arachidonic acid metabolism inhibitor.

METHODS
Peripheral blood samples were collected from pediatric CD patients and induced pluripotent stem cell (iPSC) lines were generated. iPSC were differentiated into human intestinal organoids (HIOs) and macrophage-like cells. Macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without eicosatetraynoic acid (ETYA) pre-treatment. Flow cytometry and cytospin characterized macrophage activation markers and morphology. Co-culture populations were harvested, and RNA and conditioned media were isolated for downstream analysis. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to quantify measures of inflammation and fibrosis, and to test whether introduction of ETYA abated any of these inflammatory or fibrotic changes.

RESULTS
iPSC-derived macrophages exhibited morphology similar to primary macrophages, and expressed inflammatory macrophage cell surface markers including CD68 (Fig. 1A). LPS-stimulated iPSC-derived macrophages expressed a global pattern of gene expression by RNA sequencing enriched in CD ileal inflammatory macrophages (ToppCell Atlas, p=4.397E-117), and produced cytokines and chemokines implicated in refractory disease (Fig. 1B). Co-culture of LPS-primed macrophages with HIO led to up-regulation of the fibroblast activation genes ACTA2 and COL1A1 (Fig. 2). Under these conditions, HIO collagen content measured by sirius red staining and polarized light microscopy was increased (Fig. 2). ETYA pre-treatment prevented these pro-fibrotic effects of LPS-primed macrophages upon HIO gene expression and collagen content. However, LPS induction of macrophage IL1B, TNF, and OSM production was not suppressed by ETYA, suggesting an alternative mechanism of action upon HIO fibroblast activation and collagen content in the co-culture system.

CONCLUSIONS
ETYA inhibits effects of LPS-primed macrophages upon HIO pro-fibrotic gene expression and collagen production. This was not associated with an effect of ETYA upon macrophage inflammatory cytokine production. Future studies will test alternate pathways including PPAR activation and arachidonic acid metabolism which may mediate this response.