bluuebunny/crossref_metadata_2025 huggingface dataset:
STERILE NEUTROPHILIA INDUCED VIA CXCR4 ANTAGONISM MITIGATES COLONIC INFLAMMATION BY ENHANCING IMMUNOSUPPRESSIVE REGULATORY T CELLS IN MICE
Authors: Saha Piu , Yeoh Beng San , Vijay-Kumar Matam
Published: January 2024

Sterile neutrophilia (SN) is commonly associated with chronic diseases including inflammatory bowel diseases (IBD), but its defined role is largely unknown. Plerixafor (AMD3100) is a CXCR4 antagonist that promotes neutrophil egress from bone marrow resulting in SN. We first confirmed that C57BL6/J mice administered Plerixafor (10 mg/kg/bw, i.p.,) increased their circulating neutrophils by 50% within 2.5 h. Further, to study the role of SN in IBD, we induced chronic colitis by neutralizing IL-10 signaling via αIL-10R mAb (1.0 mg/mouse, i.p., 4 weekly injections) with or without weekly twice Plerixafor. Control mice were given isotype control mAb. As expected, αIL-10R+Plerixafor-treated mice had increased peripheral and splenic neutrophils. Further, these mice displayed remarkably reduced epithelial damage, hyperplasia, immune cell infiltration, and disease activity index when compared to αIL-10R+vehicle treated mice, which had typical colitis symptoms. To delineate the mechanism for such protection by Plerixafor, we profiled immune cells in circulation, spleen and lamina propria. In circulation αIL-10R+Plerixafor-treated mice had elevated CD3+CD4+ helper T cells (Th) but reduced CD3+CD8+ cytotoxic T (Tc) cells and CD3+CD4+FoxP3+ cells (Tregs) and CD3+CD4+RORγt+ cells (Th17) remained unchanged. While in the spleens of αIL-10R+Plerixafor-treated mice displayed significant increased Tregs, but decreased Th and Tc cells. Interestingly, markedly elevated Tregs, RORγt+ Tregs and tolerogenic IL-10+ Tregs was observed in lamina propria when compared to αIL-10R+ vehicle given mice. Interestingly, the proinflammatory IL-17+ Th cells were decreased in αIL-10R+Plerixafor-treated mice which showed mild colitis. Moreover, to further elucidate the role of Plerixafor in intestinal barrier function in colitic mice, we noticed treatment with Plerixafor increased the expression of occludin and claudins (1, 2), which are the principal transmembrane tight junctions (TJ) proteins; however Plerixafor treatment reduced the expression of zonula occludens (ZO), a peripheral membrane TJ protein. Collectively, our results demonstrate that SN could be an adaptive and beneficial immune response during chronic intestinal inflammation.
HIGH COPY NUMBER POLYMORPHISMS OF ALPHA DEFENSIN 1-3 ARE ASSOCIATED WITH THERAPEUTIC RESPONSIVENESS IN INFLAMMATORY BOWEL DISEASE
Authors: Kanmura Shuji , Morinaga Yuko , Maeda Nobuhisa , Tanaka Akihito , Komaki Yuga , Ido Akio
Published: January 2024

BACKGROUND AND PURPOSE

Prednisolone therapy is the first choice for the treatment of acute severe ulcerative colitis (ASUC), however, the refractory case is sometimes observed. Alpha defensin 1-3 (DEFA1A3) stored in neutrophils acts as an effector factor of innate immunity. It has been reported that the copy number variation of the DEFA1A3 gene is associated with the severity of ulcerative colitis (UC).

However, the impact of DEFA1A3 in response to treatment have not been fully investigated.

Therefore, we aimed to clarify the relationship between the number of DEFA1A3 copies and UC prednisolone treatment response.

SUBJECTS AND METHODS

Patients with UC who had attended our department and related facilities and had the number of DEFA1A3 copies measured were included between 2020 and 2022. The number of DEFA1A3 copies were measured using droplet digital PCR after DNA extraction from peripheral blood mononuclear cells. Mayo score was used to determine the response to prednisolone and severity of UC. ASUC was defined as presence of more than 6 bloody stools/d along with any one of the following: pulse rate> 90 bpm, temperature > 37.8 °C, hemoglobin < 10.5 g/dL, and/or CRP > 30mg/L. Clinical background and various parameters were extracted from medical record information.

RESULTS

The 47 ASUC patients were included in the study. The median DEFA1A3 copy number of the patients was 9, the median DEFA1A3 copy number in ASUC was higher than that in healthy subjects. The DEFA1A3 copy number was significantly higher in the non-remission group than in the remission group after treatment with prednisolone.There were no differences in other parameters such as CRP and WBC between the two groups.

CONCLUSION

DEFA1A3 copy number may be a predictive marker of prednisolone treatment response.
HAND GRIP STRENGTH IS ASSOCIATED WITH CLINICAL SYMPTOM BURDEN IN CROHN'S DISEASE
Authors: Thompson Ashley , Anderson Jenna , Stauffer Patrick , Peress Shira , Sofia M Anthony
Published: January 2024

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that may result in malnutrition and alteration of body composition, such as the development of sarcopenia. Sarcopenia is a known component of frailty, which is a driver of poor health outcomes and a significant independent predictor of mortality in patients with IBD. The purpose of this study was to determine whether grip strength, as a predictor of sarcopenia and frailty, is associated with clinical symptoms, endoscopic disease activity and disease-related disability in patients with IBD.

METHODS

This is a prospective cohort study performed at a single tertiary care center. Outpatient adults aged 18 to 89-years-old with a diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD), were consented and enrolled at the time of an outpatient colonoscopy. Study participants were asked to complete two paper surveys addressing clinical symptoms and IBD Disability Index. Grip strength measurements were obtained using a Jamar dynamometer and adjusted for age and sex by Z-score calculation.

RESULTS

There was a total of 74 patients, with a mean age of 47.06 years, 51.4% male and 48.6% female with a diagnosis of either UC (38%) or CD (62%). The mean disease duration was 15.7 years (0.5-50.7). Mean hand grip Z-score amongst all patients was lower in patients not in clinical remission compared to those in clinical remission (–0.160 vs 0.480, p = 0.025), though in subgroup analysis based on diagnosis, statical significance only maintained in the CD, but not the UC group (-0.230 vs 0.610, p=0.044; 0.020 vs 0.340, p=0.544 respectively). Mean hand grip Z-score was not associated with IBD Disability Index (–0.070 vs 0.250, p= 0.669) or endoscopic disease activity (UC 0.210 vs 0.070, p=0.513; CD –0.108 vs 0.274, p=0.638).

CONCLUSION

Low hand grip strength is associated with clinical disease activity in patients with CD but not UC. Our study does not suggest hand grip strength to be associated with IBD-related disability or endoscopic disease activity in either patients with UC or CD. Data on clinical outcomes at 6-months will be collected.

DISCUSSION

From the findings in our study, hand grip measurements alone may not be the best predictor of disease activity or related disability. There is a lack of validated diagnostic criteria for sarcopenia and frailty in the IBD population and additional diagnostic modalities may be required. While our study suggests that hand grip may be correlated with clinical disease activity in patients with CD, additional studies with a large population size and wider representation of disease severity, such as including hospitalized IBD populations, are needed to further validate these findings.
DEVELOPMENT OF CROHN'S DISEASE IN PATIENT PRESENTING WITH COMPLEX PERIANAL FISTULA TO A TERTIARY MEDICAL CARE CENTER
Authors: Sangmo Lodoe , Quraishi Baseer , Rajauria Palak , Ungaro Ryan , Wong Serre-Yu
Published: January 2024

BACKGROUND

Approximately 20% of patients with Crohn’s disease (CD) will develop a perianal fistula (PAF), most of which are complex fistulas1-4. Studies have shown that 4-5% of patients with CD present with perianal fistula without luminal disease, termed isolated perianal Crohn’s disease4,5,6. However, little is known about the natural history of isolated complex PAF (iPAF). We therefore aimed to evaluate the clinical course of patients who presented with iPAF including describing those who subsequently developed luminal CD.

METHODS

We performed a retrospective cohort study of patients seen within the Mount Sinai Health System (New York) with an ICD-10 diagnosis code for PAF between 7/22/2008 and 7/22/2022. Medical record review was conducted to identify patients with complex PAF who did not have evidence of luminal disease and had > 6 months of follow-up (Table 1). Luminal disease was defined as any evidence of ulcers, erosions, or strictures on endoscopic or video capsule exam or MRE with evidence of inflammation consistent with luminal CD. Demographics, comorbidities, imaging, endoscopy, surgeries, hospitalizations and medication data were collected. Descriptive and univariate analyses were performed. Complicated disease course was defined as a composite of any major CD-related surgery, PAF/IBD-related hospitalization or biologic use.

RESULTS

Among 887 patients with PAF, 62.2% (n=552) patients underwent luminal evaluation, of whom 80 patients (14.5%) were found to have no luminal disease (Table 1). Of these, 57 patients had >6 months of follow-up with 22.8% (n=13) going on to develop luminal disease. Luminal CD was diagnosed at a mean time of 4.2 (SD=3.8) years after iPAF presentation. Compared to patients who developed luminal CD, patients with solely iPAF were less likely to be <30 years old at PAF diagnosis (p=0.0225) or have concomitant autoimmune conditions (p=0.046) (Table 2). Patients with iPAF were less likely to have >2 fistulas (p=0.002) or have CD/PAF-related hospitalization (29.5% vs 61.5%, p =0.0356) compared to those who developed luminal CD (Table 2). Patients with iPAF were significantly less likely to have a complicated disease course than those who later developed luminal CD (2.3% vs 30.8%, p=0.007).

CONCLUSION

We observed that approximately 1 in 4 patients who presented with iPAF went on to develop luminal CD. Patients who went on to develop luminal CD were more likely to be <30 at PAF diagnosis, have concomitant autoimmune conditions and were more likely to have IBD-related adverse outcomes. The majority of patients with iPAF did not experience a complicated disease course and may represent a specific sub-phenotype of CD.
PREVALENCE OF FRAILTY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE. A PILOT STUDY
Authors: Ballart Maria Jesus , Grandon Francisca , Nieto Rodrigo , Alvarez Manuel
Published: January 2024

Frailty is a multidimensional syndrome that leads to greater vulnerability to stress, increasing the risk of adverse health outcomes. It is a dynamic process, with transitions between being robust, pre-fragile and fragile over time, suggesting that it is modifiable.

Inflammatory bowel disease (IBD) results in altered immune function with amplified inflammation. When severe, it manifests with features associated with frailty, such as weight loss, fatigue, and sarcopenia. The first studies on frailty in IBD were carried out in a surgical context. Subsequent studies have associated frailty with increased risk of mortality as an independent factor in IBD patients. Of the available evidence, all are retrospective -except one- and the majority measures frailty with associated ICD-10 diagnoses, which can underestimate its prevalence in younger patients.

There is no consensus in the literature on the best tool to measure frailty, however, this pilot study will objectively evaluate, using a risk score, the prevalence of this syndrome, which will allow, in the future, to carry out prospective studies that characterize frailty in IBD, understand the dynamic and longitudinal relationship between frailty and disease activity and, if appropriate, design and test interventions to alleviate this syndrome and its consequences in this population.

This was a descriptive study, with the objective to determine the prevalence of frailty in IBD patients in a teaching hospital in Chile. We also compared the characteristics of frail vs non-frail IBD patients.

Frailty was measured using SHARE-FI tool, which is a validated score to measure frailty in primary care, even in patients under 65 years of age.

64 patients were recruited, 28 had ulcerative colitis, 33 had Crohn’s disease and 3 had indeterminate colitis. 62.5% were female, with an average age of 42,3 ± 13,65 years. Average years since diagnosis were 11,6 ± 9,89.

The prevalence of frailty was 40,62%. No association was observed between the presence of frailty and the type of IBD, IBD activity indices, use of corticosteroids, use of biologic therapy, surgeries associated with IBD, IBD flare-ups with hospitalization within the last year, calprotectin levels, vitamin D levels. The odds of the presence of frailty in women are 4,2 times greater than in men, being women a possible risk factor for frailty. The frailty group had worse quality life measured with the IBD Questionnaire 9 (OR 0,86 [IC95% 0,79-0,94).

In conclusion, the prevalence of frailty in IBD was 40,62%. Contrary to what might be assumed, frailty turned out to be a condition independent of the type of IBD, time of evolution, activity and treatment, mostly associated with female sex and a worse quality of life. New studies are required to determine factors predisposing to frailty in IBD patients and prevent its appearance in order to improve their prognosis.
THE IMPACT OF OBESITY ON THE PREVALENCE AND SEVERITY OF PERIANAL COMPLICATIONS OF CROHN'S DISEASE
Authors: Youn Jennifer , Hsia Katie , Khadilkar Surya , Zeina Tanya , Rai Puja , Rastogi Akash , Adavelly Pranay , Hussani Sureya , Yanes Jason , Kotlier Jacob , Spence Samara , Levy Alexander , Friedman Sonia
Published: January 2024

INTRODUCTION

The incidence of obesity in patients with inflammatory bowel disease (IBD) is increasing and there is limited data on the effects of obesity on disease phenotype. Several studies have investigated the association of obesity with perianal fistulizing disease with conflicting results. In this study, we aim to examine the relationship between obesity and the prevalence and severity of perianal complications in patients with Crohn’s disease (CD).

METHODS

We conducted a cross-sectional study of CD patients treated at a tertiary care center from 2012 to 2022. Collected data included sex, race, smoking history, family history, maximum body mass index (BMI), and Montreal classification (Table 1). Obesity was defined as maximum BMI ≥30kg/m2 and further subdivided into 5 BMI categories (Table 2). The prevalence of perianal disease was defined by a history of perianal fistula. The severity of perianal disease was measured by four variables including history of perianal fistula surgery, number of perianal surgeries, history of fecal diversion, and median time to first anal surgery. Perianal fistula surgeries included abscess incision and drainage, seton placement, fistulectomy, and/or fistulotomy. Pearson’s chi-squared test was used to compare 2 categorical variables (non-obese vs obese). Exact Cochran-Armitage trend test was used to compare 5 BMI categorical variables. A 95% confidence interval was used with an alpha of 0.5. Values of p <0.05 was considered statistically significant. Data analysis was performed using Excel.

RESULTS

A total of 704 patients with CD were treated. In all, 68.9% were non-obese and 31.1% were obese. Furthermore, 2.8% were underweight, 36.5% normal weight, 29.5% overweight, 17.9% obese, and 13.2% severely obese. Non-obese patients were more likely to have a family history of IBD (p=0.043). Obese patients were more likely to have extraintestinal manifestations (p=0.004) and/or be former smokers (p=0.004). There was no significant association between obesity and prevalence of perianal fistula (p=0.719), history of perianal surgery (p=0.146), history of one or more perianal surgeries (p=0.220), history of fecal diversion (p=0.705) or median time to first perianal surgery (p=0.192) (Table 1). Increasing BMI category was not associated with the prevalence of perianal fistula (p=0.944), perianal surgery (p=0.583), more than one perianal surgery (p=0.114), fecal diversion (p=0.542) or median time to first perianal surgery (p=0.486) (Table 2).

DISCUSSION

In conclusion, there was no significant correlation between obesity and prevalence of perianal disease. Additionally, there was no significant correlation between obesity and severity of perianal disease. The overall impact of obesity on CD complications is still unknown and warrants further investigation.
REAL-WORLD LONG-TERM TREATMENT PERSISTENCE AMONG BIO-NAÏVE PATIENTS WITH CROHN’S DISEASE AND HISTORY OF FISTULA INITIATED ON USTEKINUMAB
Authors: Zhdanava Maryia , Kachroo Sumesh , Boonmak Porpong , Burbage Sabree , Shah Aditi , Jiang Zhuohan , Lefebvre Patrick , Kerner Caroline , Pilon Dominic
Published: January 2024

BACKGROUND

Fistula is a common complication of Crohn’s disease (CD). Treatment with certain biologics have been associated with fistula healing and closure, reduction of symptoms and need for surgical treatments. In clinical practice, biologic persistence and effectiveness are correlated. This study described long-term persistence among bio-naïve patients with CD and history of fistula who were initiated on ustekinumab (anti-interleukin 12/23 antibody).

METHODS

Adults with CD and history of intestinal fistula initiated on ustekinumab (index date) between 9/23/2016 and 3/2/2022 were selected from the IQVIA PharMetrics® Plus database and followed for the maximum of 24 months. Patients were bio-naïve (i.e., no claim for CD-indicated biological agents) in the 12-month baseline period before the index date. Patients with other auto-immune diseases during the baseline period were excluded. Persistence on ustekinumab was defined as the absence of gaps between days of therapy supply of >120 days (i.e., over twice the duration of the US label maintenance cycle of 8 weeks or 60 days). Composite endpoints of being persistent while on monotherapy (no immunomodulators or biologics other than ustekinumab) and persistent while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) were also assessed. Persistence endpoints were assessed from the index date until the earliest of discontinuation (event), immunomodulator or non-index biologic use (event), corticosteroid use (event), 24 months follow-up or data end (censoring) using Kaplan-Meier analyses.

RESULTS

The sample included 445 patients (mean age: 42.8 years; 56.6% female; Fig. 1). Among these, 63.1% had CD involving the small intestine, and 59.6% had CD involving the large intestine. The most common type of fistula was anal fistula (36.0%). At 24 months after ustekinumab initiation, 64.2% of patients remained persistent (95% confidence interval [CI]: 55.8-71.4; Fig. 2a). Furthermore, 53.3% of patients were persistent while on monotherapy (95%CI: 45.1-60.7; Fig. 2b). Finally, 45.6% of patients were persistent while being corticosteroid-free (95%CI: 36.9-53.8; Fig. 2c).

CONCLUSIONS

This study quantified long-term persistence on ustekinumab among bio-naïve patients with CD and history of fistula. Over half of patients initiated on ustekinumab were persistent and persistent while on monotherapy 24 months after the treatment initiation. These findings support ustekinumab as a treatment option for long-term management of CD with history of fistula.

Figure 1 Selected baseline characteristics

Figure 2 (a) Persistent on ustekinumab, (b) persistent and on monotherapy, c) persistent and corticosteroid-free
DIFFERENCE IN HEALTHCARE OUTCOMES BETWEEN TEACHING AND NON-TEACHING HOSPITALS FOR PATIENTS ADMITTED WITH CROHN'S DISEASE
Authors: Salazar Miguel , Flocco Gianina , Al-Smadi Khaled , Saffouri George , Hammami Bader
Published: January 2024

BACKGROUND

The physician workforce at teaching hospitals differs compared to non-teaching hospitals, and data suggest that patient outcomes may also be dissimilar. Crohn’s disease (CD) is a costly disorder among hospitalized patients. Its complications often require endoscopic interventions, surgery, and advance levels of care, for which approaches are not standardized.

METHODS

We queried the National Inpatient Sample (NIS)[GS1] 2016-2019 using ICD10-PCS codes. Patients were subsequently divided based on the concomitant diagnosis of CD and subcategorized between teaching and non-teaching institutions. In-hospital mortality, total hospital cost, length of stay, and in-hospital complications were evaluated. Multivariate logistic regression analysis was conducted to adjust for confounders.

RESULTS

A total of 141,865 discharges with diagnosis of CD were identified, of which 108,735 (76.6%) were admitted to a teaching institution and 33,130 (23.4%) to a non-teaching institution. Those admitted to a teaching hospital were most likely to be black (10.0% vs 15.1%; P<0.01), Hispanic (4.4% vs 5.6%; P<0.01), have a Charlson score of ≥3 (27.1% vs 31.3%; P<0.01), belong to the highest income bracket (17.8% vs 24.7%; P<0.01), have private insurance (43.7% vs 51.3%; P<0.01), and be located in the northeastern U.S. (14.9% vs 23.8%; P<0.01). Those admitted to a teaching institution were more likely to have fistulizing disease (7.8% vs 15.6%; P<0.01), require parenteral nutrition (3.0% vs 6.1%; P<0.01), have severe malnutrition (4.8% vs 8.3%; P<0.01), undergo colonoscopy (10.4% vs 12.8%; P<0.01), and undergo bowel resection including large bowel (6.4% vs 11.4%; P<0.01) and small bowel (1.6% vs 2.4%; P<0.01), and were more likely to require conversion from laparoscopy to open laparotomy (0.8% vs 1.9%) during surgery.

On multivariate analysis, there was no significant difference in mortality [aOR 0.84; (P=0.59)] between teaching and nonteaching institutions. However, we found worse outcomes within teaching institutions such as a prolonged mean length of stay (4.5 days vs 5.6 days; P<0.01), more likely to need surgical bowel resection including small [aOR 1.39; (P<0.01)] and large [aOR 1.66; (P<0.01)], to develop venous thromboembolism [aOR 1.97; (P<0.01)], and to require conversion to open surgery during laparoscopy [aOR 2.3; (P<0.01), and ileus (aOR 1.18; (P<0.01)], they were less likely to require endotracheal intubation [aOR 0.63; (P=0.02)].

CONCLUSIONS

Institutional designs impact outcomes in CD, albeit no difference in mortality. In general, complication rates and resource utilization are higher in teaching centers when compared to non-teaching.
FROM ACADEMIA TO ANECDOTES: ASSESSING THE QUALITY OF ULCERATIVE COLITIS CONTENT ON YOUTUBE
Authors: Mohan Raj Mohan Ram , Joy Melvin , Magam Sai Greeshma , Natt Dilman , Magam Sai Reshma , Desai Jiten , Jiyani Rucha , Mustacchia Paul
Published: January 2024

INTRODUCTION

This study examines the varying impact of YouTube videos on Ulcerative Colitis (UC) from academic and private institutions. While academic channels offer evidence-based, scientifically vetted information, private sources may lack rigorous scrutiny and sometimes prioritize commercial or anecdotal content. With YouTube's massive user base, the absence of an editorial process can result in misinformation. This content quality and credibility discrepancy can significantly affect patient education and treatment outcomes for UC.

METHODS

We conducted a search on YouTube using the keywords "Ulcerative Colitis" and "UC IBD" to identify relevant videos. Exclusions were made for videos that were not in English, irrelevant, or lacked audio. We documented various video attributes such as views, likes, dislikes, comments, and the nature of the source (academic or private). The videos were then classified as reliable or unreliable based on the scientific accuracy of their content. We employed DISCERN, Global Quality Score (GQS), and the Patient Education Materials Assessment Tool (PEMAT) to evaluate video quality. The consistency among seven investigators in applying DISCERN, GQS, and PEMAT was measured using intraclass correlation.

RESULTS

We reviewed 21 YouTube videos that appeared in the search results, of which 11 (52.3%) were academic and 10 (47.6%) were private. Academic videos received higher DISCERN scores than private ones (317.5 vs. 23.64 5.07, p=0.018). The Global Quality Score was also higher for academic videos (3.9 vs. 2.2, p< 0.01), as was the PEMAT score (4.1 vs. 2.7, p= 0.022). Furthermore, academic videos were found to have a positive correlation with the number of likes (OR: 0.75, P< 0.001), subscribers (OR:0.68, P< 0.0001), and views (OR:1.52, P< 0.001).

CONCLUSION

Our study reveals significant quality discrepancies in YouTube videos on Ulcerative Colitis. Academic sources consistently outperformed private ones in accuracy and reliability, as indicated by higher DISCERN, Global Quality Score, and PEMAT ratings. The data also showed a positive correlation between academic sources and user engagement metrics like likes, subscribers, and views. These findings highlight the necessity of directing patients to academically-backed information to minimize the risk of misinformation.
HEALTH INSURANCE KNOWLEDGE AND HEALTH INSURANCE SELF-EFFICACY IN ADOLESCENTS AND YOUNG ADULTS WITH IBD
Authors: Huang Jeannie , Cruz Breanna Lopez , Rosales Daniela , Chuang Jonah , Cruz Rusvelda
Published: January 2024

BACKGROUND AND AIMS

In the United States, health insurance is a prerequisite for healthcare affordability. Adolescents and young adults with inflammatory bowel disease (AYA-IBD) often require costly therapies, and health insurance knowledge and health insurance self-efficacy are essential for a successful transition from pediatric to adult centered care. Nevertheless, little is known about AYA-IBD knowledge of and familiarity with health insurance.

METHODS

English-proficient AYA-IBD 15 years and older receiving care at an academic pediatric practice were invited to participate. Participants performed surveys on health insurance knowledge and health insurance self-efficacy. Descriptive statistics were performed to report survey results. Analyses of responses by demographic categories were performed using ANOVA analyses.

RESULTS

Fifty AYA-IBD completed the surveys. Thirty AYA-IBD were 15-17y and twenty were 18-22y. The majority of respondents were male (27), white (38), non-Hispanic (34), and had Crohn's disease (33). The median (interquartile range) disease duration was 33 (13, 61) months. Most had been on biologic or small molecule IBD therapy (46). All had health insurance: 32 had private insurance, 5 military insurance, and 13 government insurance. The majority (58%) of AYA-IBD answered less than half of the health insurance knowledge questions correctly (Table 1). Reported self-efficacy in choosing and using health insurance was slight to moderate (Table 2). Answers did not vary by demographic groupings.

CONCLUSIONS

AYA-IBD demonstrated suboptimal health insurance knowledge and slight to moderate health insurance self-efficacy. Our findings identify an important opportunity to provide much-needed health insurance education to help prepare AYA-IBD to manage the costs of medical care.

Table 1 AYA-IBD Health Insurance Knowledge Survey Responses

Table 2 Health Insurance Literacy Measure (Self-efficacy) Questions and Response Distributions
EVALUATION OF THE CLINICAL STAGE FXR AGONIST FXR314 IN HUMAN PRIMARY CELL 3D MODELS OF CROHN’S DISEASE AND ULCERATIVE COLITIS
Authors: Mon Aye , Gervacio Sherwin , Aidnik Haylee , Oxford Samantha , Rosette Caridad , Piu Fabrice
Published: January 2024

There is a critical need for novel approaches to treat inflammatory bowel disease (IBD) that extend beyond modulating the immune response. These innovative strategies should also focus on enhancing the integrity of the intestinal barrier and addressing fibrotic tissue development throughout the course of the disease, both critical components of IBD, to improve long term outcomes. Targeting the ligand-activated nuclear Farnesoid X Receptor (FXR) represents such an emerging opportunity.

Intestinal epithelial cells exhibit high expression of FXR which is pivotal for intestinal function by regulating the innate immune response, reducing bacterial translocation into the intestinal wall, preserving the integrity of the epithelial barrier, and potentially reducing fibrotic deposition. We have developed a human 3D co-culture model of multiple cell types derived from Crohn’s disease (CD) or ulcerative colitis patients (UC). These 3D-culture CD and UC models faithfully replicate various aspects of the IBD disease state, including differences in gene expression patterns relative to intestinal tissues from healthy donors, compromised epithelial barrier integrity (as measured by Fluorescein isothiocyanate-dextran and TEER assays) and disrupted fibrotic deposition (as determined via fibrosis biomarkers and quantitative collagen deposition).

FXR314 is an orally administered non-bile acid FXR agonist that has completed a Phase 2a clinical trial in NASH and is being considered as a novel therapeutic approach for IBD. We assessed the capacity of FXR314 to improve disease biomarkers in 3D models of human IBD. Specifically, its effects were characterized in five CD donors and three UC donors. Target engagement was demonstrated in all CD and UC donors tested through activation of FGF19, a well-accepted target of FXR activation. In CD donors, FXR314 broadly improved measures of epithelial barrier function in a subset of donors, and fibrotic markers in all five donors. In UC donors, FXR314 improved epithelial barrier function and fibrotic activity in all three donors. As anticipated, the effects seen across the different metrics were concentration dependent.

These primary multicellular 3D human IBD models (CD, UC) constitute a powerful tool to more accurately predict the relevance of specific targets and assess the efficacy of therapeutic candidates. Consequently, this could enhance the probability of success when conducting clinical trials. In this study, we demonstrated that the non-bile acid FXR agonist FXR314 improves multiple aspects of Crohn’s disease and ulcerative colitis in human donors, thereby strengthening its potential as a novel therapeutic approach for IBD.
THE FUNCTION OF THE CYSTATHIONINE-GAMMA-LYASE/HYDROGEN SULFIDE AXIS IN THE PATHOGENESIS OF ULCERATIVE COLITIS
Authors: Toro Gabor , Szaniszlo Peter , Almenas Francisco Arroyo , Thanki Ketan , Maskey Manjit , Chao Celia , Hellmich Mark , Yochum Gregory , Pinchuk Iryna , Modis Katalin
Published: January 2024

INTRODUCTION

Current combination therapies in ulcerative colitis (UC) target different inflammatory cascades, including tumor necrosis factor-alpha (TNF-alpha) signaling. However, most patients do not achieve long-term remission, suggesting that the molecular pathophysiology of UC is still poorly understood. Endogenously produced hydrogen sulfide (H2S) has emerged as a critical physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to epithelial injury. Inhibition of cystathionine-gamma-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. Our research group has strong evidence revealing that the CSE/H2S axis regulates TNF-alpha signaling in colonic epithelial cells. Therefore, we hypothesize that decreased CSE/H2S pathway activity in colonic mucosa cells leads to dysregulation of TNF-alpha signaling and uncontrolled inflammatory/immune responses with aberrant wound repair mechanisms contributing to the pathogenesis of UC.

RESULTS

We found a significant decrease in CSE mRNA and protein expression in colonic biopsies from patients with UC. Using a preclinical animal model of epithelium injury-induced chronic colitis (DSS), we confirmed a sustained downregulation of CSE, as well as upregulation of TNF-alpha and tumor necrosis receptor 2 expressions in colonic mucosa samples. Treatment with the slow-releasing H2S-donor GYY4137 significantly reduced the severity of DSS-induced inflammation and improved mucosal integrity and restitution responses. In epithelial cell and colonoid cultures, the inhibition of CSE-dependent H2S synthesis decreased the activation of extracellular-signal-regulated-kinase-1/2 (ERK1/2), increased IL-6 and TNF-alpha mRNA levels and suppressed basic and TNF-alpha–mediated colonocyte migration.

CONCLUSION

These studies demonstrate that CSE regulates mucosal TNF-alpha signaling, pro- and anti-inflammatory responses as well as colonic epithelial repair. Adding the H2S donor GYY4137 reduces inflammation, suggesting the restoration of normal TNF-alpha signaling function.

Acknowledgments: KM is supported by the DoD Career Development Award (W81XWH2010641) and ACS Research Scholar Grant (RSG–21–027–01–CSM).
BACTERIAL SPHINGOLIPIDS EXACERBATE COLITIS BY INHIBITING ILC3-DERIVED IL-22 PRODUCTION
Authors: Bao Bin , Wang Youyuan , Boudreau Pavl , Song Xinyang , Wu Meng , Chen Xi , Patik Izabel , Tang Ying , Ouahed Jodie , Wu Chuan , Balskus Emily , Thiagarajah Jay , Liu Jian , Wessels Michael , Lencer Wayne , Kasper Dennis , An Dingding , Horwitz Bruce , Snapper Scott
Published: January 2024

Commensal bacteria of the Bacteroidetes phylum are the primary producers of sphingolipids in the gut lumen. These lipids serve dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells (iNKT). Sphingolipid composition is significantly altered in fecal samples of patients with inflammatory bowel disease (IBD). However, the specific mechanisms by which bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remain unclear. In this study, we investigated the impact of bacterial sphingolipids on intestinal inflammation by mono-colonizing mice with Bacteroides fragilis strains that either express or lack sphingolipids during DSS-induced colitis. We discovered that B. fragilis sphingolipids exacerbate intestinal inflammation. Mice mono-colonized with B. fragilis lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin-22 (IL-22) by innate lymphoid cell type 3 (ILC3). Consistent with the inhibitory effect of sphingolipids on IL-22 production, mice colonized with B. fragilis lacking sphingolipids showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production following DSS treatment compared to those colonized with B. fragilis producing sphingolipids. Additionally, colitis severity in mice colonized with B. fragilis lacking sphingolipids was exacerbated upon IL-22 blockade. Furthermore, our study reveals that bacterial sphingolipids restrict epithelial IL-18 production following DSS treatment and interfere with IL-22 production by a subset of ILC3 cells expressing both the interleukin-18 receptor (IL-18R) and major histocompatibility complex class II (MHC II). These findings indicate that B. fragilis-derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL-18 expression, resulting in compromised production of IL-22 by ILC3 cells.

Work Model
TNF IS REQUIRED FOR SPONTANEOUS INNATE COLITIS IN MICE LACKING ADAPTIVE IMMUNITY
Authors: Huerta Alvaro Torres , Boger-May Antonia , Ruley-Haase Katelyn , Reed Theodore , Rajashekara Arpitha Mysore , Hiller Morgan , Mayer Lauren , Boone David
Published: January 2024

BACKGROUND

Colitis involves excessive inflammation driven by the reciprocal interaction of innate and adaptive immune cells. To better understand how innate immunity contributes to colitis, we developed a spontaneous innate model of colitis that is highly penetrant, early onset, and driven by microbes. TNF is a cytokine produced predominantly by T cells but also by innate and non-immune cells and contributes to IBD in many patients. We therefore examined the role of TNF in innate immune mediated colitis.

METHODOLOGY

We developed a 100% penetrant mouse model of colitis by crossing villin transgenic expression of tnfaip3 (villin-tnfaip3) to rag1 null mice (rag1-/-), designated as TRAG mice (villin-tnfaip3 x rag1-/-). TRAG mice are characterized by inflammation of the colon in the absence of T and B cells. We crossed TRAG mice with tnfa-/- mice (tnfa-/- x TRAG) to elucidate the role of TNF in this model. The histopathological score of disease was evaluated by H&E, and the innate immune populations characterized by multi-color flow cytometry. Apoptosis, necrosis, and cell death were evaluated histologically by localizing cleaved caspase-3, phosho-MLKL and TUNEL positive cells. Secretion of cytokines from intestinal tissue in culture was quantified by ELISA.

RESULTS

TRAG mice develop early-onset colitis that is driven by microbes but is not transmissible to rag1-/- littermates. TRAG mice showed histological signs of colitis and a high infiltration of leukocytes in the intestinal mucosa without concurrent systemic inflammation. This colitis was not observed in tnfa-/- x TRAG mice. TRAG mice exhibited a pro-inflammatory cytokine signature with elevated secretion of IL1a and IL1b but not IL-18 or IL-33, which was not observed in mucosa from tnfa-/- x TRAG mice. LPLs from TRAG colons indicated TNF production by inflammatory monocytes, monocytes, and neutrophils. Monocytes and macrophages from the TRAG mouse mucosa, but not the tnfa-/- x TRAG mucosa, showed an M1 profile defined by elevated iNOS and decreased arginase. Increased crypt cell death was evident in TRAG colons, and this was significantly diminished in the crypts of tnfa-/- x TRAG colons. Early aggressive treatment of TRAG mice with anti-TNF antibody, but not anti-IL1a antibody, prevented colitis in TRAG mice.

CONCLUSIONS

TNF drives innate colitis featuring increased infiltration of mucosal leukocytes, increased secretion of IL1a and IL1b, skewing of macrophages to an M1 profile, and increased cell death in colonic crypts. Even in the absence of T cell derived cytokines, including TNF, innate sources of TNF are sufficient to drive colitis and early use of anti-TNF therapy is effective against this innate form of colitis. We are currently investigating the signals and forms of cell death that are driven by TNF in this model.
INFLAMMATION-TRIGGERED CLAUDIN-23 DOWNREGULATION IMPACTS INTESTINAL EPITHELIAL BARRIER FUNCTION
Authors: Raya-Sandino Arturo , Lozada-Soto Kristen , Garcia-Hernandez Vicky , Parkos Charles , Nusrat Asma
Published: January 2024

Intestinal epithelium maintains gut homeostasis by protecting the underlying tissue compartments from harmful contents. Although it is suggested that epithelial barrier function compromise contributes to the pathogenesis of inflammatory bowel disease (IBD), the underlying mechanisms are not well understood. Claudins (CLDN) are tight junctions (TJ) proteins that determine epithelial barrier properties during homeostasis and whose expression is altered in IBD, thereby contributing to a leaky barrier. We recently identified the expression of an atypical CLDN family member, CLDN23, in the regulation of homeostatic intestinal epithelial barrier function. Analysis of the human colonic crypt-luminal axis revealed increased CLDN23 expression in differentiated intestinal epithelial cells (IEC) facing the lumen compared to the proliferative crypt-base IECs. Complementary cell biologic approaches using IEC-specific Cldn23 knockout mice (Cldn23ERΔIEC) and human colon cell lines revealed that CLDN23 strengthens epithelial barrier function. Mechanistically, CLDN23 promoted redistribution of barrier-forming CLDN3 and CLDN4 from the lateral membrane to the TJ through cis- and trans-interactions, resulting in narrowed CLDN3 and CLDN4 pore diameters. Since inflammation compromises the epithelial barrier and contributes to disease pathogenesis in IBD, we first examined CLDN23 expression in colonic mucosal tissue from IBD individuals. Immunofluorescence and RNA scope labeling revealed that CLDN23 expression was significantly decreased in colonic epithelial cells of IBD individuals. Furthermore, reduced CLDN23 expression was also detected in primary colonic epithelial cells (colonoids) from mice treated with pro-inflammatory cytokines TNFα and IFNγ compared to untreated colonoids. Barrier function assays of control Cldn23f/f and Cldn23ERΔIEC mice-derived colonoids treated with TNFα and IFNγ identified decreased transepithelial electrical resistance in colonoids lacking CLDN23 and treated with these pro-inflammatory cytokines. These findings suggest a protective role for CLDN23 in regulating barrier function under homeostatic and inflammatory conditions.
STOOL-BASED EXFOLIOME RNA PROFILING ENABLES NON-INVASIVE GUT DISEASE DIAGNOSIS AND MONITORING
Authors: Huang Yiming , Sun Yiwei , Wang Harris
Published: January 2024

The development of real-time and non-invasive methods for monitoring gut health, signaling, and inflammatory status has the potential to transform the diagnosis, treatment, management, and drug development of numerous pathologies of the gut. Inflammatory bowel disease (IBD) represents one such area of large unmet clinical and pharmaceutical needs as it affects a large proportion of the population, has continued to increase in prevalence over time, and can have devastating consequences when not appropriately diagnosed and managed. Furthermore, there are a plethora of therapeutic options to which patients can show variable responses which means patients can undergo several cycles of costly therapy before finding an effective treatment regime for their disease.

Conventional methods in disease management and clinical trial measurements involve endoscopies, which are invasive, expensive, and constitute only single or limited set of timepoints that are not readily amenable to longitudinal studies. While stool or blood tests are also commonly used, they only measure a small number of biomarkers and do not provide the necessary sensitivity nor data-rich insight into disease pathology that is required to inform clinical decision making and ongoing drug development efforts.

Here, we have developed Exfoliome sequencing (Exfo-seq), an innovative non-invasive method to measure the gastrointestinal transcriptome directly from stool. Our approach makes use of the trace amounts of human RNA molecules (i.e., the exfoliome) that are present within stool due to natural turnover of intestinal cells. However, due to the massive amount of microbial and diet-derived contamination in the stool, the effort to capture human intestinal transcriptomic signals has remained limited to only a handful of genes. With a highly optimized signal capturing and amplifying method coupled with deep sequencing, we can simultaneously probe the mRNA levels of hundreds to upwards of several thousand genes from stool in a highly sensitive and quantitative manner. Exfo-seq can be performed to profile gut health, inflammatory state, disease pathway activity, and therapeutic response over time, and changes in gut cell populations, such as proliferation of immune cells during inflammation, can be inferred. Exfo-seq holds great potential as a non-invasive method to guide IBD diagnosis, treatment, long-term management and future drug development.
COMPARABLE CLINICAL OUTCOMES IN PEDIATRIC PATIENTS WITH CROHN’S DISEASE TREATED WITH ACCELERATED VS. STANDARD INFLIXIMAB DOSING DURING INDUCTION
Authors: Marshanski Tal , Fanous Eliana , Tal Noa , Weintraub Yael , Matar Manar , Shamir Raanan , Shouval Dror
Published: January 2024

BACKGROUND

Accelerated infliximab administration during induction is used extensively in pediatric patients with Crohn’s disease (CD), though the overall effect of this approach on patients’ outcomes in several studies has been questionable. We aimed to assess in a real-life cohort whether accelerated infliximab administration during induction resulted in improved clinical outcomes in pediatric CD.

METHODS

This single-center retrospective study included patients aged<18 years diagnosed with CD between 2016-2021 that were treated with infliximab. We compared outcomes of patients treated with standard-dosing (0,2,6,14, up to 8mg/kg) vs. accelerated-dosing. Primary outcome with steroid-free clinical remission by week 52.

RESULTS

Sixty-eight patients were included, of whom 7 discontinued infliximab prior to week 14, due to infusion reactions or primary non-response resulting in surgery. 25 received standard-dosing, and 36 accelerated-dosing, including 19 patients that received >8mg/kg infliximab at 1st infusion. Comparison of both groups at time of infliximab initiation showed similar demographic features, Paris classification, prior rates of medication failure and rates of current immunomodulator use. Importantly, the baseline median pCDAI (23.0 [12.5-26.5] vs. 18.8 [13.1-26.9]), CRP (1.5 [0.3-5.5] vs. 1.4 [0.4-3.4] and calprotectin (782 [66-3840] vs. 1060 [576-2900]) values were comparable in the standard- and accelerated-dosing groups, respectively. Patients in the accelerated-dosing group achieved a higher trough infliximab level by end of induction (10.3±6.6 vs. 3.3±3.4, P<0.001), and more patients were above the target trough infliximab level (78.1% vs. 21.8%, P<0.001). However, the median PCDAI and inflammatory markers at week 14, 26 and 52 were comparable between groups. Moreover, the rates of patients above the desired trough levels were also comparable at week 52 (71.4% vs. 70.6% in the accelerated vs. standard-dosing group). Finally, rates of treatment discontinuation were also similar among groups.

CONCLUSIONS

In a retrospective cohort, accelerated infliximab dosing during induction didn’t result in improved clinical outcomes up to 52 weeks.