bluuebunny/crossref_metadata_2025 huggingface dataset:
AUPHOS, A “FIRST-IN CLASS“ ORAL AGENT FOR CORRECTING METABOLIC DYSFUNCTION IN IBD
Authors: Wempe Lesley , Mohamed Rana , Warinner James , Goretsky Tatiana , Avdiushko Margarita , Kim Jong , Abomhya Ahmed , Lee Goo , Awuah Samuel , Barrett Terrence , Kapur Neeraj
Published: January 2022

BACKGROUND

Mucosal repair is the goal of medical therapy in IBD. Prospective inception cohort pediatric studies suggest that suppression of mitochondrial genes lead to unfavorable clinical outcomes in ulcerative colitis (UC) and Crohn’s disease (CD). We posit that the inability to restore epithelial mitochondrial respiration impairs ulcer healing in IBD. In the current study, we tested whether a novel compound (AuPhos) that improves mitochondrial function promotes ulcer healing in IBD.

METHODS

Biodistribution and pharmacokinectic (PK) studies were performed (6h, 12h, 24h) after single oral dose (25mg/kg) of AuPhos using C57/BL/6 (WT) mice. Mitochondrial uptake of AuPhos was determined by measuring gold content in normal colonocytes (NCM460) using graphite furnace atomic absorption spectroscopy. Oxygen consumption rate (OCR) in isolated crypt-IECs from AuPhos-fed WT mice were examined using high-resolution respirometry. The effect of AuPhos in colitis was tested in DSS (2%; 7d) WT (B6) mice. Disease activity index (DAI) (weight loss, diarrhea, and hematochezia), intestinal permeability (FITC-dextran), histological scoring and the frequency of fissioning crypts were determined throughout the 21d time course. Tissue mRNA levels for mitochondrial enzyme, cytokine, chemokine and intestinal stem cell (ISC) marker genes were assessed by RT-qPCR.

RESULTS

Biodistribution and PK studies revealed that higher levels of orally administered AuPhos in small intestine and colon tissue, with limited systemic absorption. AuPhos displayed a dose-dependent mitochondrial uptake in IEC where respirometry showed >30% increase in OCR after oral dosing in vivo. AuPhos treatment decreased DAI (**; p<0.01), histologic colitis scores D11-15 (*; p<0.05) and FITC-dextran permeability in DSS colitis mice. Notably, AuPhos increased fissioning crypt numbers near healing ulcers in DSS-colitis mice (**; p<0.01) while it reduced mRNA for pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IFN-γ, IP10). AuPhos induced mRNA for ISC markers [Lgr4 (*; p<0.05), Lgr5, Lrig1 (***; p<0.001)] and mitochondrial complexes [mtCO1 (**; p<0.01) and COX2 (***; p<0.001)]. These findings suggest that AuPhos-induced mitochondrial respiration drives transcriptomic regulation of IEC genes involved in colitis ulcer healing.

CONCLUSION

Our data suggests that AuPhos compound improves ulcer healing under acute colitis conditions by increasing mucosal OxPHOS metabolism. Specifically, we find that AuPhos increases mitochondrial respiration-induced crypt fissioning and ulcer healing associated with reduced mucosal inflammation and increased barrier integrity. Overall, AuPhos may be an important “first-in class” oral therapeutic for correcting the metabolic dysfunction central to IBD pathogenesis.
INTERLEUKIN-17 RECEPTOR SIGNALING TO PANETH CELLS HELPS MAINTAIN INTESTINAL INTEGRITY AFTER GAMMA RADIATION INDUCED INJURY
Authors: Kempen Cody , Gaudino Stephen , Bahadur Tej , Singh Ankita , Kumar Pawan
Published: January 2022

BACKGROUND

IL-17A/F signaling through the IL-17RA/RC receptor complex plays a vital role in immunity and inflammation. The expression of IL-17RA/RC by diverse intestinal epithelial cell types including Paneth cells and the observation that therapies neutralizing IL-17A or IL-17RA in Crohn’s disease (CD) patients induce adverse events suggest essential homeostatic functions of this cytokine. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in mediating small intestinal host defense under homeostatic conditions as well as after injury or infection, and their dysregulation constitutes a pathogenic factor for CD. The specific role of intestinal IL-17A signaling in Paneth cells to regulate host defense at steady state or after intestinal inflammation remains poorly understood. Thus, we hypothesize that intestinal IL-17A signaling, specifically in Paneth cells, plays an important role in regulating microbiota colonization as well as maintaining intestinal integrity after gamma radiation induced injury.

METHODS

To examine the importance of IL-17RA signaling to Paneth cells, we utilized total, entire gut epithelium (Il17rafl/fl;villin-cre) and Paneth cell-specific IL-17RA knockout mice (Il17rafl/fl;Defa6-cre+). We subjected these mice with gamma irradiation (1200 cGy) to study intestinal injury and regenerative responses. Mice were sacrificed 3/5 days post irradiation. Terminal ilium was collected from naïve or irradiated mice for immunofluorescence imaging, RT-PCR, RNA sequencing, and enteroid cultures.

RESULTS

Our preliminary data from irradiated Il17ra-/- and Il17rafl/fl;villin-cre mice suggest that IL-17A signaling is important in maintaining intestinal barrier integrity. Specifically, these mice revealed increased microbial dissemination to liver and spleen compared to their respective control mice. Reduced expression of Lyz1 3 days post radiation in the terminal ileum of Il17ra-/- mice suggest impaired Paneth cell function. Cessation of Paneth cell specific IL-17RA signaling, also resulted in systemic bacterial dissemination 5 days post radiation. We also observed increased level of fecal Lcn2 in irradiated Il17rafl/fl;Defa6-cre+ mice. To understand Paneth cell-specific IL-17RA functions, we performed 16S microbial and RNA sequencing from ileum luminal contents and terminal ilea of naïve Il17rafl/fl;Defa6-cre+/- mice, respectively. While microbial 16s sequencing revealed no change to the overall microbial community, specific changes were observed at a select family level. Specifically, the level of Streptococcaceae was increased. RNA sequencing data showed no difference in Paneth cell antimicrobial peptides but did show reduced Caspase 4 expression in Il17rafl/fl;Defa6-cre+ mice. Collectively, our data revealed an important role of IL-17RA signaling in Paneth cell function at steady state and after injury.
THE ASSESSMENT OF MRE FINDINGS ACCORDING TO CDAI SCORE IN PATIENTS WITH CROHN’S DISEASE
Authors: Zbroja Monika , Kuczynska Maryla , Cyranka Weronika , Nowakowska Malgorzata , Grzegorczyk Magdalena , Siejka Karolina , Piekarska Monika
Published: January 2022

INTRODUCTION

Crohn’s disease (CD) is a chronic inflammatory bowel disease of the gastrointestinal tract. One of the diagnostic steps is to perform a magnetic resonance enterography (MRE). The purpose of the study was to compare MRE findings with clinical index of the disease activity - CDAI score, in order to verify the usefullness of magnetic resonance enterography.

SUBJECTS/METHODS

The study included 46 patients who underwent MRE according to a standard protocol, with dynamic contrast-enhanced sequences. All studies were performed in prone position, using mannitol as a positive oral contrast agent. The MRE severity grading was performed according to the consensus recommendations. CDAI score was assessed prior to examination by a specialist.

RESULTS

32 patients had multifocal lesions, 14 presented with unilocular lesions and 14 had a history of previous bowel resection. Penetrating disease was diagnosed in 15 subjects. The results indicate for good correlation between MRE and CDAI assessment in groups of patients with moderate and severe clinical symptoms. However, there is a significant discrepancy in MRE findings in the group of patients with mild disease activity according to CDAI. Out of 23 patients with clinically mild symptoms, 1 exhibited MRE characteristics of severe, 9 of moderate and 7 of mild inflammatory intestinal lesions.

CONCLUSION

There is good accordance between MRE and clinical findings in patients with prominent disease symptoms, indicating that MR enterography might be a promising modality in terms of lesion activity grading. Nonetheless, there exist a significant group of patients with mild disease symptoms, in whom MRE tends to show full spectrum of disease severity.
EFFECTIVENESS OF CROHN’S DISEASE EXCLUSION DIET FOR INDUCTION OF REMISSION IN CROHN’S DISEASE ADULT PATIENTS
Authors: Szczubelek Martyna , Pomorska Karolina , Korólczyk-Kowalczyk Monika , Lewandowski Konrad , Kaniewska Magdalena , Rydzewska Grazyna
Published: January 2022

INTRODUCTION

The Crohn’s disease exclusion diet (CDED) has a well-documented effectiveness in inducing remission in active Crohn’s disease (CD) in children. However, the data for adult population are limited. The aim of the study was to evaluate the effectiveness of the CDED with a supply of liquid formula Modulen (Nestlé) in inducing remission in CD adult patients.

MATERIALS AND METHODS

Between March 2020 and May 2021, an open label, non-randomized, single centre study was conducted in gastroenterology outpatient center. 32 patients with active CD (Crohn’s disease activity index CDAI >150 points) were treated with CDED with a supply of Modulen (Nestlé). The patients were seen at baseline, at week 6 and at week 12 of the study. During the visits anthropometric measurements, laboratory test, CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ) were performed. Data analysis was based on an intention-to-treat approach. Statistical analysis was carried out using R software, version 4.0.5. Normality of the distribution was validated using the Shapiro–Wilk test, skewness and kurtosis values and on visual assessment of histograms. Comparison between three measurements was conducted with ANOVA for repeated measures or a series of Wilcoxon signed-rank tests. The primary endpoint was the achievement of remission at week 12 (CDAI<150 points). The secondary endpoints were the inducement of a clinical response (a reduction in CDAI by 100 points or more), improved quality of life and an improvement in laboratory parameters and BMI.

RESULTS

32 participants were included in the study. The baseline CDAI was 253 points (175.50; 373.00) (from 151 to 562 points). Baseline calprotectin was at a median level of 393 μg/g (58.85; 969.00), ranging from 11.9 to 4 630 μg/g. A statistically significant drop in CDAI was observed after 6 weeks (p <0.001) and after 12 weeks (p <0.001) of dietary intervention as compared to baseline (Figure 1). IBDQ was significantly higher (p <0.001) at the first and second follow-up vs baseline. Calprotecin levels were significantly lower at the second follow-up vs baseline (p =0.021) (Figure 2). A clinical response was observed in 83.3% of the patients (CI95 [65.3%–94.4%]) after 6 weeks of treatment and in 85.7% of cases (CI95 [67.3%–96.0%]) after 12 weeks of treatment. A clinical remission was present after 6 weeks of treatment vs baseline in 76.7% of patients (CI95[57.7%–90.1]) and in 82.1% of participants (CI95[63.1%–93.9]) after 12 weeks of treatment vs baseline.

CONCLUSIONS

The CDED with a supply of liquid formula is an effective therapy for inducing remission in the adult CD population. However, a randomised trial is needed to obtain higher-level evidence.
MY SCD PROTOCOL - AN ONLINE, COMPREHENSIVE, REMOTELY-SUPERVISED PROTOCOL FOR IBD PATIENTS TO IMPLEMENT AN EFFECTIVE DIETARY INTERVENTION
Authors: Arjomand Ali , Caviness Rachelle
Published: January 2022

Many IBD patients are keen to modify their diet to better manage their disease. However, little or no dietary guidance is offered to IBD patients or is not comprehensive and lacks practical resources to implement and sustain the modification. Up to 70% of IBD patients self-prescribe dietary restrictions with demonstrated risk of nutrient deficiencies. There is currently no comprehensive IBD dietary intervention presented in a customizable, easy-to-follow protocol format. To meet this need, we developed and tested a full-featured online version of an effective IBD dietary intervention. METHOD: ‘My SCD Protocol’ is a comprehensive, customizable protocol based on the specific carbohydrate diet (SCD). The online, self-paced protocol provides educational resources, self-assessment tools, and step-by-step instructions to start and advance through SCD. Ingredients are presented in 4 ordered Stages (Elimination, Reintroduction, Maintenance, Expansion) to help methodically expand tolerable ingredients. Stage-specific curated recipes support implementation and offer variety and personalization. Patients self-report symptoms, meals, and progress using a HIPAA-compliant mobile app. Entries are accessible in real-time by the patient’s care team. The protocol currently holds 304 SCD ingredients and 164 recipes. Patients (n=87) referred to Modulla Health IBD Nutrition Clinic, or seeking support directly, implemented My SCD Protocol based on preference and ingredient tolerance. Symptoms were self-reported using the accompanying app. Interim results are reported here. RESULTS: Patients successfully accessed and personalized My SCD Protocol. Table 1 summarizes patient profiles. Table 2 presents self-reported symptom changes, showing improvements in all categories except urgency and appearance of mucus. Additional outcomes, including fecal calprotectin, will be reported. DISCUSSION: SCD has been shown to induce clinical response and biochemical remission in adult and pediatric IBD patients. SCD is either self-implemented by patients using a trial-and-error approach, or is dietitian-supervised, primarily using the ‘legal’ SCD ingredient list and little else. SCD was implemented in a clinical trial setting using a predefined, prescriptive meal model with little room to personalize diet (DINE-CD). My SCD Protocol is the first comprehensive protocol to help implement, personalize, and safely advance through SCD. Patients reliably accessed the educational videos, staged ingredients, matching recipe libraries, and logging tools using mobile and web tools. We show self-reported symptom improvements during the first 21 days of the protocol leading to longer-term adherence to diet modification. Care teams who recommend My SCD Protocol to patients can conveniently and continuously monitor patient progress in real-time and supervise patients throughout the intervention.
VALIDATION OF THE SIMPLIFIED ENDOSCOPIC MUCOSAL ASSESSMENT OF CROHN’S DISEASE (SEMA-CD) A NOVEL ENDPOINT TO ASSESS ENDOSCOPIC IMPROVEMENT WITH REAL WORLD DATA
Authors: Adler Jeremy , Colletti Richard , Noonan Lenore , Conklin Laurie , Lo Kim Hung , Xiao Yongling , Volger Sheri
Published: January 2022

BACKGROUND

To demonstrate treatment efficacy in Crohn’s disease (CD), regulatory authorities require that trials include an endoscopic remission endpoint. However, standardized endoscopic assessment of mucosal improvement, such as the simple endoscopic score of CD (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. A previous study demonstrated the Simplified Endoscopic Mucosal Assessment of CD (SEMA-CD) correlates strongly with SES-CD and that SEMA-CD is a score that can be easily used by clinicians in routine practice (Adler et al., 2021). The objective of this current study was to validate the SEMA-CD scored colonoscopy videos in additional populations and to examine the reliability of SEMA-CD over a range of mucosal disease severity in pediatric and adult participants and to evaluate sensitivity to change over time.

METHODS

We compared SEMA-CD and SES-CD scores in 110 patients with existing pre- and post-treatment colonoscopy videos from two ustekinumab clinical trials (UNISTAR, pediatric, n=36; SEAVUE, adult, n=74; Figure 1). Videos were separately scored with the SEMA-CD and SES-CD by different central readers, blinded to each other’s scores and to clinical history. Spearman’s rank correlation coefficient was used to evaluate correlation between scores, under different settings by study population (pediatric, adult), disease severity, and video quality. Inter- and intra-rater reliability were assessed with interclass correlation coefficient (ICC). Readers also rated ease of SEMA-CD scoring on a 7-point Likert scale.

RESULTS

SEMA-CD was highly correlated (rho [95% CI]) with the SES-CD, 0.89 (0.86, 0.92; Figure 2). Pre-to post-treatment changes in SEMA-CD scores compared with SES-CD scores were highly correlated 0.84 (0.77, 0.89). The positive relationship remained strong between scores when comparing total scores in pediatric 0.94 (0.90, 0.96) and adult 0.86 (0.80, 0.89) participants; across SES-CD disease severity categories (inactive, mild, moderate, severe; rho range 0.69-0.85); and in “optimal” 0.90 (0.86, 0.93) and “less than optimal” quality videos 0.88 (0.83, 0.91). Intra- and inter-reader reliability (ICC [95%CI]) were high, 0.93 (0.88, 0.96) and 0.89 (0.85, 0.91), respectively. SEMA-CD was rated as the same as, or easier than SES-CD 99.6% of the time.

CONCLUSION

This study demonstrated the SEMA-CD is feasible, reliable, reproducible, and sensitive to change in both adult and pediatric patients with CD. SEMA-CD should serve as an easy score for clinicians to record mucosal improvement and provide quality real world evidence for research using data from clinical registries.
ENDOSCOPIC STRICTUROTOMY – A NOVEL THERAPEUTIC MODALITY FOR IBD-RELATED STRICTURES: FIRST EUROPEAN EXPERIENCE
Authors: Lukas Martin , Kolar Martin , Vasatko Martin , Lukas Milan
Published: January 2022

INTRODUCTION

Both primary strictures and secondary anastomotic strictures are common complications in patients with inflammatory bowel diseases (IBD), especially Crohn’s disease (CD). Balloon dilation has been the gold standard in the endoscopic treatment of these strictures. Endoscopic stricturotomy (ESt, Figure 1) represents a promising novel approach, however, the data published on this method so far has been limited to a small sample and few sites.

METHODS

All ESts performed in IBD patients between September 2018 and April 2021 in our tertiary IBD center were included. Data on demographics, disease characteristics, procedure details and outcomes were analyzed. Technical success was defined as an ability to pass the scope through the stricture following the procedure. Complications included perforation and immediate or delayed bleeding with the need of intervention or hospitalization.

RESULTS

In total, 92 procedures were performed in 67 patients (60 with Crohn’s disease, CD, and 7 with ulcerative colitis, UC) Among these 46.3% were males. Mean age was 43.9±12.5 years and mean disease duration was 14.6±9.7 years. Single ESt was done in 73.1% (49) of patients, while 26.9% (18) required multiple procedures. Most common location of stricture was surgical anastomosis site (82, 89.1%), while remaining 10 were located at anal canal (de novo stricture). Anastomotic strictures included ileo-colonic (64.1%), colo-colonic (9.8%), ileo-rectal (3.3%), and ileal pouch-anal (12.0%) anastomoses. Previous endoscopic balloon dilation (EBD) was attempted in 53.3% of the procedures, 27.2% of the analyzed procedures were preceded by earlier ESt. Technical success was achieved in 83 ESts (90.2%), complications occurred in four cases (all delayed bleeding, managed conservatively). After the mean follow-up time of 18.1±10.0 months, cumulative probability of reintervention (ESt, EBD or surgery) at 6 months was 30.2% (95% CI 15.6-46.2%), 40.3% (95% CI 25.5-54.6%) at 12 months and 48.8% (95% CI 34,0-62,1%) at 18 months (Figure 2). Time to reintervention was not significantly affected by previous intervention, age of the anastomosis, sex or age of the patients, concurrent therapy and specific ESt technique employed.

CONCLUSION

ESt is a novel endoscopic technique, which is both efficacious and safe to be performed in patients with IBD-related strictures.
NON-IMMUNE MEDIATED MUSCULOSKELETAL DISEASE IN CROHN’S DISEASE PATIENTS BEING EVALUATED FOR INFLAMMATORY SPONDYLOARTHRITIS - A PILOT STUDY
Authors: Schwartzman Monica , Longman Randy , Scherl Ellen , Schwartzman Sergio
Published: January 2022

BACKGROUND

Musculoskeletal (MSK) disease is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD). The emphasis in the published literature has been on the inflammatory arthritis associated with IBD, spondyloarthritis (SpA). There is a lack of data regarding common, non-inflammatory MSK diseases such as osteoarthritis and fibromyalgia. This distinction is important, as these two conditions have different prognoses, require different clinical approaches and management.

OBJECTIVE

To evaluate the prevalence of non-inflammatory MSK disease in a cohort of Crohn’s disease (CD) patients.

METHODS

This was a cross-sectional study of a validated CD cohort from a single center registry in New York City conducted from 9/2019 - 1/2021. Recruitment was limited due to the COVID-19 Pandemic. Patients were sent a four question MSK survey (Figure 1) addressing peripheral joint and back symptoms. Those who answered positively to any question were considered to have MSK symptoms. All patients underwent one study visit with a rheumatologist that included: 66/68 tender/swollen joint count (TJC/SJC), Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), Bath Ankylosing Spondylitis Metrology Index (BASMI), American College of Rheumatology fibromyalgia criteria, ESR and CRP. Disease activity was measured via a modified Ankylosing Spondylitis Disease Activity Score (ASDAS), Harvey Bradshaw Index (HBI), and Inflammatory Bowel Disease Questionnaire (IBD-Q).

RESULTS

26 CD patients participated. Median age was 45.6±17.7 years, 35% were male, median disease duration was 17.7±14.2 years and 73% were on immunomodulatory agents for CD. Median values (range) for the following physical exam and disease features were: TJC 10.8±13.2 (0-68), SJC 0.9±2.2 (0-66), SPARCC 2.8±3.1 (0-16), BASMI 1.5±1.0 (0-10, higher values: more motion limitation) ASDAS 1.5±0.9 (<1.3: inactive disease, >2.1: high disease activity), HBI 6.8±3.5 and IBD-Q 159±36. Median ESR and CRP were 18.9±22.2 mm/hr (normal 0-22) and 0.6±0.5 mg/dL (normal<0.7), respectively. 16/26 (62%) reported MSK symptoms. 7/16 (43.8%) had features of SpA, while 9/16 (56.3%) did not have evidence by history or exam of SpA and were therefore determined to have non-inflammatory MSK disease. 13/26 (50%) met fibromyalgia diagnostic criteria.

CONCLUSION

MSK conditions were very common in this pilot cohort. Though features of SpA were present in almost half of patients, non-inflammatory MSK disease was present in the majority of those with MSK symptoms. While both rheumatologists and gastroenterologists need to recognize the importance of SpA, it is additionally essential to understand that the most common MSK disease in IBD may be non-inflammatory, which has distinct implications for management. Future studies should examine the prevalence of these conditions in larger cohorts of IBD patients.
THE OPIOID EPIDEMIC: ASSESSING OUTCOMES OF OPIOID ABUSE IN CHRONIC INFLAMMATORY DISEASE (ULCERATIVE COLITIS VS CROHN’S DISEASE)
Authors: Dasu Neethi , Khalid Yaser , Blair Brian , Derosa Justin , McMahon Donald
Published: January 2022

BACKGROUND

The use of Opiates in patients with Inflammatory Bowel Disease (IBD) has been studied previously. However, to our knowledge, no studies have compared outcomes between patients with opioid abuse with ulcerative colitis (UC) versus patients with opioid abuse and concomitant Crohn’s disease (CD). Our study aims to investigate the impact on hospital mortality, hospital length of stay (LOS), and total charges between both patient groups.

METHODS

All patients aged 18 years and above with UC and CD as well as opiate abuse disorder, from 2016-2019 were identified from the US Nationwide Inpatient Sample (NIS). The NIS is a large, publicly available all-payer inpatient care database in the USA. The primary outcome evaluated was inpatient mortality. Multivariate regression analysis was used to estimate the odds ratios of in-hospital mortality, the average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics. STATA software was used for analysis.

RESULTS

Among 35,734 patients who had opioid abuse, 7,980 (22.3%) patients had UC and 27,949 (77.7%). The adjusted odds ratio (OR) for both inpatient mortality (OR 1.13, p=0.692) and hospital length of stay (LOS) (+0.62 days, p=0.09) for opioid abuse with UC compared to those with Crohn’s disease were not statistically significant. However, total hospital charges were $8,649 higher (p<0.018) in patients with UC. Independent positive predictor of increased mortality was older age (p<0.0001). Independent positive predictors of increased LOS and total hospital charges were the following: fistula formation (+10.1 days, +$118,312, p<0.001 for both), bowel obstruction (+2.5 days, p<0.006; +$16,685, p<0.036), hematochezia (+3.1 days, p<0.02; +$30,168, p<0.018), electrolyte abnormalities (+2.0 days, p<0.001; +$26,450, p<0.0001), colonoscopy (+2.5 days, p<0.001; +$19,102, p<0.005), bowel resection (+11.9 days, p<0.0001; +$131,750, p<0.0001). Total charges were also increased for white patients (+$13,236, p<0.016), black patients (+$28,070, p<0.008), Hispanic patients (+$25,970, p<0.0008).

CONCLUSION

Our study shows that there is no difference in mortality or LOS in patients with opioid abuse with UC versus those with CD. However, total charges are significantly higher for UC patients with opioid abuse. Also, elderly patients with UC are at increased risk for mortality. Opioid abuse in the IBD population is common, given that symptoms of disease activity often include pain. However, the abuse of opiates has led to an opioid crisis in the United States. It is interesting to note the disparity between patients with UC vs CD. This needs to be studied further in randomized trials to help mitigate adverse outcomes in this patient population.
PPI ADMINISTRATION CAUSES COLONIC TIGHT JUNCTION BARRIER DYSFUNCTION VIA INCREASE INENETROCOCCUS FECALIS
Authors: Nighot Meghali , Morris Nathan , Nighot Prashant , Clarke Kofi , Ma Thomas
Published: January 2022

BACKGROUND

Proton pump inhibitors (PPIs) are highly effective antagonists of gastric acid secretion and are widely used to treat a number of gastroesophageal disorders, including peptic ulcer disease, GERD, Barrett’s esophagus. PPI-induced elevation in intra-gastric pH and subsequent alterations of gastrointestinal physiology are known to cause undesired effects on the entire GI tract. Gastric acid suppression can change the composition of the intestinal microbiota causing intestinal dysbiosis and increased risk for intestinal inflammation. The intrinsic intestinal barrier is composed of a single layer of columnar epithelial cells and inter-epithelial tight junctions (TJ) residing at the apical-most region of the intercellular space. Defective intestinal TJ barrier is an important pathogenic factor for intestinal inflammation. The role of PPI on Intestinal TJ barrier is not known.

AIM

The aim of the present study was to study the effect of PPI on intestinal dysbiosis and mouse colonic TJ permeability.

METHODS

8 to 12-week-old male C57BL/6N mice were divided into two groups (Controls and PPI treatments (Omeprazole 20mg/kg B.W.) and were fed a nutritionally adequate feed for 30 days. Fecal samples were collected from both treated and untreated mice after 30 days. Fecal DNA was isolated using the Qiagen kit according to the manufactures Instructions. 16s amplicon DNA was sequenced by Genewiz (South Plainfield, NJ). Degenerate primers that amplify the V3-V4 region of bacterial rDNA genes were used (F341-806R pair).The amplicon pool sequenced on Illumina MiSeq generated paired-end 301 bp reads was multiplexed using Illumina’s fastq. At the end of the experiments, the colonic permeability was measured on Ussing chambers. Western blot (WB) and Immunofluorescence (IF) was used to study myosin light chain kinase (MLCK, a key regulator of TJ barrier) protein expression in mice colon.

RESULTS

The microbiome changes identified by 16S rRNA sequencing showed a significant increased proportion of Firmucutis in the fecal samples of PPI treated mice compared with untreated mice. Also, PPI group showed prominent increase in enterococcus spp which was identified as Enterococcus fecalis (EF). In Ussing chambers studies, PPI administration caused a decrease in transepithelial resistance (TER), and increase in urea and inulin flux when compared to untreated colonic tissues. Immunofluorescence and Western blot analysis showed that PPI administration also caused an increase in MLCK and phospho- MLC protein expression in mice colonic tissues. Also, PPI treatment caused increased focal sloughing of colonic surface epithelium with focal to diffuse lymphocytic infiltration in the colonic lamina propria in mice colon.

CONCLUSION

Our results suggest that the PPI causes overgrowth of a pathobiont EF associated increase in mouse colonic TJ barrier permeability.
INTERLEUKIN 21-INDUCED METABOLIC REPROGRAMMING DRIVES CD4 T CELL INFLAMMATORY RESPONSE DURING INTESTINAL INFLAMMATION
Authors: Bamidele Adebowale , Sagstetter Mary , Hirsova Petra , Ramos Guilherme Piovezani , Klatt Emily , Westphal Maria , Faubion William
Published: January 2022

BACKGROUND

Significant proportion of inflammatory bowel disease (IBD) patients continue to respond inconsistently to therapies, underscoring disease complexity and the need for efficacious treatment. Interleukin 21 (IL-21), which is known to support T helper (Th) cell function, is highly expressed within inflamed tissues of IBD patients compared to healthy controls. Also, inflammatory regulatory T cells (Tregs) have been linked to refractory human IBD, and the complete induction of IBD in mice has been shown to require IL-21. Given that healthy Tregs are critical for self-tolerance and prevention of IBD, we investigated the metabolic role of IL-21 in instigating Treg dysfunction and the therapeutic ramifications of targeting metabolic pathways during IBD.

METHODS

Human Tregs as well as relevant control Th cells were generated from naïve CD4+ T cells isolated from healthy blood donors. Microarray analysis was utilized for targeted transcriptional profiling. Immune phenotyping was assessed by fluorescence-activated cell sorting. Metabolic phenotyping of cells was assessed by Seahorse flux analysis and mass spectrometry-based targeted metabolomics. Colitis was induced in Rag1-/- (T and B cell deficient) mice by adoptive transfer of pathogenic naïve CD4+ T cells.

RESULTS

Acute IL-21 stimulation of human Tregs induced glycolysis and fluctuations in mitochondrial respiration (i.e. oxidative phosphorylation – OXPHOS), as assessed by Seahorse flux analysis. In agreement, microarray analysis, validated by qPCR, revealed IL-21-induced alterations in the expression of genes associated with glycolysis and OXPHOS metabolism. Prolonged IL-21 stimulation rendered Tregs susceptible to inflammatory response, as evidenced by the production of inflammatory Th cytokines such as interferon γ, tumor necrosis factor, IL-17A, and IL-17F. Exploring the mechanisms underlying IL-21-induced effects, we observed reduced expression of inactive glycogen synthase kinase 3 (GSK3) β, a protein known to prevent pyruvate entry into the mitochondria. This reduction in inactive GSK3β in response to IL-21 was accompanied by high abundance of intracellular pyruvate and lactate, as assessed by targeted metabolomics. Importantly, GSK3 inhibition or exogenous membrane-permeable methyl pyruvate abrogated IL-21-induced metabolic rewiring and Treg inflammatory response. Moreover, GSK3 inhibition diminished the metabolic and inflammatory function of Th cells. Lastly, GSK3 inhibition prevented pathogenic CD4+ T cell-induced colitis in mice, as evidenced by reduced Disease Activity Index, Mouse Colon Histology Index, and serum inflammatory cytokines.

CONCLUSIONS

IL-21 potently engages human Tregs in a metabolic state that subsequently augments an inflammatory phenotype. Therefore, desensitizing CD4+ T cells to detrimental cues, such as IL-21, may augment Treg function during human IBD.
EICOSATETRAYNOIC ACID REGULATES MITOCHONDRIAL AND EXTRA-CELLULAR MATRIX GENE EXPRESSION AND TISSUE STIFFNESS IN A HUMAN INTESTINAL ORGANOID MODEL OF ILEAL CROHN’S DISEASE
Authors: Jurickova Ingrid , Huron Alex , Angerman Elizabeth , Bonkowski Erin , Jegga Anil , Haberman Yael , Denson Lee
Published: January 2022

BACKGROUND

Mutations in the DUOX2 intestinal epithelial cell NADPH oxidase are associated with risk for Crohn’s Disease (CD), and may influence wound healing and the development of strictures. Patients who develop strictures exhibit reduced expression of genes encoding mitochondrial sub-units, and increased expression of genes encoding extra-cellular matrix proteins, in the ileum at diagnosis. We conducted a perturbagen bioinformatics analysis which predicted that the cyclooxygenase and lipoxygenase inhibitor eicosatetraynoic-acid (ETYA) would reverse the ileal gene signature associated with stricture development. In the current study we tested effects of ETYA in a human intestinal organoid model (HIO) system.

METHODS

HIO were derived from wild type (WT) and DUOX2 mutant (DUOX2var) induced pluripotent stem cells (iPSCs) prepared from CD patients. WT and DUOX2var HIO were examined under basal conditions, and following exposure to ETYA for 72 hours or 12 days. Superoxide production in EPCAM+ epithelial cells and CD90+ stromal cells was measured by flow cytometry. RNA was prepared and expression of mitochondrial and extra-cellular matrix genes linked to strictures in patients was determined using RNA sequencing and a TaqMan Low Density Array (TLDA) card. HIO tissue stiffness was measured using atomic force microscopy (AFM).

RESULTS

ETYA reduced superoxide production by HIO EPCAM+ epithelial cells only in WT organoids; no effect was observed in DUOX2var HIO. This was specific, as no effect of ETYA upon superoxide production was detected in CD90+ stromal cells. Under basal conditions, RNA sequencing demonstrated that WT HIO expressed core mitochondrial and extra-cellular matrix genes and enriched biologic functions implicated in CD strictures. Expression of extra-cellular matrix and wound healing genes was increased in DUOX2var HIO under basal conditions. ETYA up-regulated expression of the COX5B, POLG2, and SLC25A27 mitochondrial genes associated with lower rates of strictures, while reducing expression of the ACTA2, VIM, and COL1A1 extra-cellular matrix genes associated with higher rates of strictures, independent of DUOX2 genotype. WT and DUOX2var HIO exhibited tissue stiffness comparable to normal human ileum under basal conditions; this was significantly reduced by ETYA exposure only in DUOX2var HIO.

CONCLUSIONS

ETYA regulates mitochondrial and extra-cellular matrix genes implicated in stricture formation in an HIO model system. DUOX2var HIO exhibit increased extra-cellular matrix gene expression under basal conditions, which is reduced by ETYA exposure in conjunction with a reduction in tissue stiffness. Collectively, these data confirm that HIO provide a relevant model system to study mechanisms regulating stricture formation in CD, including screening of small molecules prioritized by perturbagen bioinformatics analysis.
TH17 CELLS PROMOTE INTESTINAL FIBROSIS THROUGH THE PRODUCTION OF AMPHIREGULIN
Authors: Yang Wenjing , Yu Tianming , Yao Suxia , Pinchuk Irina , Cong Yingzi
Published: January 2022

BACKGROUND & AIMS

Intestinal fibrosis is a major serious complication of Crohn’s disease (CD). Gut microbiota-reactive Th17 cells have been established as crucial in the pathogenesis of CD, however, how Th17 cells induce fibrosis is still not completely understood.

METHODS

Wild-type Th1 cells and Th17 cells, or amphiregulin (Areg)-/- Th17 cells, were transferred into Tcrbxd-/- mice to induce colitis and intestinal fibrosis. CD4+ T cell expression of Areg was determined by qRT-PCR and ELISA. Intestinal fibroblasts were isolated from normal and CD patients and used to determine the effects of Areg on cell proliferation and migration in vitro. Video microscopy and single-cell tracking were used to assess cell migration kinetically. Areg expression was compared in peripheral blood CD4+ T cells, intestinal biopsy tissues, and lamina propria lymphocyte (LPL) from healthy controls and CD patients with or without intestinal fibrosis.

RESULTS

When transferred into TCRβ/δ-/- mice, although Th1 and Th17 cells induced intestinal inflammation at similar levels, Th17 cells induced more severe intestinal fibrosis than Th1 cells. RNA-seq analysis showed higher levels of AREG expression in Th17 cells compared to Th1 cells, which was further confirmed by qRT-PCR. Transfer of Areg-/- Th17 cells induced less severe fibrosis in TCRβ/δ-/- mice compared with WT Th17 cells. IL-6 but not IL-23 promoted Areg expression in Th17 cells in a time and dose-dependent manner. Treatment with Th17 signature cytokine IL-21, but not IL-17, upregulated T cell expression of Areg. Consistently, IL-21R-/- T cells produced lower levels of Areg. Mechanically, STAT3 mediates Areg expression in Th17 cells, in that IL-6 promoted STAT3 activation, and IL-6 did not induce AREG expression in STAT3-/- T cells. Areg expression was lower in STAT3-/- T cells compared with WT T cells under Th17 conditions. Treatment with RORgt inhibitor, which inhibits Th17 differentiation, suppressed Th17 cell Areg expression, indicating that higher Areg expression requires fully Th17 differentiation. Areg promoted human intestinal fibroblast proliferation and motility, which was mediated by activation of mTOR, and mTOR inhibitors inhibited Areg-induced human intestinal fibroblast proliferation and motility. Finally, Areg expression is increased in peripheral blood CD4+ T cells, intestinal biopsy tissues, and lamina propria lymphocytes of CD patients with fibrosis.

CONCLUSION

Collectively, these findings reveal that Th17-derived Areg promotes fibrotic responses in both experimental colitis and human CD patients. Thereby, Areg could serve as a potential therapeutic target for fibrosis in CD.
COMPARING THE GUT METABOLOMIC PROFILES IN HISPANIC AND NON-HISPANIC PEDIATRIC ULCERATIVE COLITIS PATIENTS
Authors: Hosseini Parastou Khalessi , Michail Sonia
Published: January 2022

BACKGROUND

Diagnosis of ulcerative colitis (UC), a subgroup of inflammatory bowel disease (IBD), is frequently overlooked among the Hispanic population. Although previously thought to impact predominantly white populations, epidemiological studies have shown an increased incidence of UC among Hispanics. Other studies have also noted variations in disease phenotype when comparing Hispanic UC patients to non-Hispanic patients. These variations could be linked to differences in the gut microbiome and shifts in the metabolomic profile. This study aims to compare the profiles of Hispanic UC patients to those of non-Hispanic whites.

METHODS

Participants aged 7-21 with mild to moderate UC were enrolled at Children’s Hospital of Los Angeles. Eighteen Hispanic and forty non-Hispanic patients were included in this analysis. Metabolite profiling yielded 230 known metabolites. Independent sample T-tests were used to identify significant differences (p<0.05) in metabolites between Hispanic and non-Hispanic UC samples. The average for each metabolite was calculated in Hispanic, non-Hispanic, and healthy patients. Averages were then compared and used to define metabolites as enhanced or diminished.

RESULTS

66 metabolites were found to be significantly different between Hispanic and non-Hispanic UC patients. When comparing the profiles of Hispanic to that of non-Hispanic patients, 2 metabolites were enhanced and 64 were diminished. The two enhanced metabolites included 1-monostearin and 1-monopalmitin. Figure 1 depicts the top 10 most diminished metabolites in Hispanic patients compared to non-Hispanic patients. These 10 metabolites were amino acids, amino acid degradation products, and one polyol compound.

DISCUSSION

This study found a significant difference in the metabolomic profiles of Hispanic UC patients compared to non-Hispanics. This difference could suggest a relationship between ethnicity and the gut’s metabolomic profile. Most notably, Hispanic patients were found to have diminished levels of nearly all significantly different metabolites when compared to non-Hispanic patients. This includes protective fatty acids, amino acids, and amino acid degradation byproducts. Increased deficits of protective anti-inflammatory mediators can be linked to increased risk of severe disease among Hispanic UC patients. These findings support the need for therapeutics targeting specific metabolite deficiencies within Hispanic UC patients.
RELATIONSHIP BETWEEN SELF-REPORTED SLEEP AND DISEASE ACTIVITY DIFFERS BASED ON ENDOSCOPIC OR CLINICAL DISEASE ACTIVITY MEASURES
Authors: Kamp Kendra , Clark-Snustad Kindra , Yoo Linda , Buchanan Diana , Jacobs Jeffrey , Barahimi Mitra , Heitkemper Margaret , Lee Scott D
Published: January 2022

BACKGROUND

Patients with inflammatory bowel disease (IBD) report more sleep disturbances than healthy controls. Self-reported sleep disturbances have been associated with active clinical disease. Few studies have examined the relationship between self-reported sleep and endoscopic disease activity, and IBD sleep studies have yet to consider the discrepancies that exist between clinical and endoscopic disease measures. The purpose of this pilot study was to examine self-reported sleep based on endoscopic and clinical disease activity among patients with IBD.

METHODS

Patients with IBD were recruited from a single medical center. Patients ages 18-55 with a scheduled endoscopy were included. Patients completed informed consent, wore a wrist actigraph for 10 days, and answered baseline demographic, clinical disease activity, and sleep questionnaires including Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance, PROMIS sleep-related impairment, and the Pittsburg Sleep Quality Index (PSQI). For both the PROMIS and PSQI, higher scores indicate greater sleep/wake disturbances. Endoscopic disease activity (Mayo or Simple Endoscopic Score) within three months was obtained from the medical record.

RESULTS

The study included 27 participants with a mean age of 33.3 (SD: 8.2) years and a disease duration of 11 (SD: 7.2) years. The sample predominantly had Crohn’s disease (75%) and 61% were female. Sixty-three percent of the total sample were classified as poor sleepers based on the PSQI. When comparing self-reported sleep based on clinical disease activity, patients with active clinical disease had higher self-reported sleep disturbance (57.3 vs. 49.7, D=1.28) and sleep-related impairment (58.1 vs. 52.8, D=0.51) compared to those with inactive clinical disease. However, self-reported sleep and endoscopic disease activity had the opposite interpretation. Only 40% of patients with active endoscopic disease were poor sleepers compared to 76.5% of patients with inactive endoscopic disease. Patients with active endoscopic disease had lower self-reported sleep disturbance (49.2 vs 52.6, D=-0.53) and sleep-related impairment (49.7 vs. 56.6, D=-0.71) compared to those with inactive endoscopic disease.

CONCLUSION

The relationship between self-reported sleep and disease activity differs based on the measure of disease activity. Our findings of self-reported sleep disturbances and active clinical disease are similar to previous studies. However, when examining the relationship based on endoscopic disease activity, patients with active endoscopic disease had less self-reported sleep disturbance than patients with inactive endoscopic disease. Further research is needed to better characterize the relationship between sleep and disease activity, and determine the underlying mechanisms related to poor sleep in the IBD population.
IMPROVING THE VACCINATION RATES FOR IMMUNOSUPPRESSED PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Cheng Tony , Kreitman Kyle , Stowe Carissa , Waters Bradford , Baidoo Leonard
Published: January 2022

BACKGROUND

Immunosuppressive therapy (IS) has altered the course of Inflammatory Bowel Disease (IBD). IBD patients are at considerable risk of developing vaccine-preventable illness and are even more susceptible when on treatment. Many of these patients fail to receive appropriate vaccinations for influenza, pneumonia, hepatitis B, Shingles and recently COVID. Our aim was to develop a quality improvement intervention to increase recommended vaccinations in IBD patients on IS.

METHODS

A retrospective chart analysis was completed at the Memphis Veteran Affairs Gastroenterology Practice. 55 patients were found to be on immunosuppressive therapy with a biologic and/or immunomodulator. Once identified, these patient’s vaccination records were reviewed to see if they were up to date on recommended vaccinations for influenza, pneumonia, hepatitis B, COVID, and Shingles. Patients who were not up to date on their vaccinations were called by a provider (Resident, Fellow, or Nurse Practitioner), and were offered a nurse visit to be given the appropriate vaccinations. After a 6-month intervention period, the data on the 55 patients was recollected and analyzed.

RESULTS

Of the patients analyzed, 63% (n=35) had Crohn’s disease and 37% (n=20) had Ulcerative Colitis. The most common biologic medication the patients were on was adalimumab (n=24), and the most common immunomodulator was azathioprine (n=17). Prior to the intervention, 22% had received the shingles vaccine, 20% had received the COVID-19 vaccine, 78% had received the hepatitis B vaccine, 69% had received the flu vaccine, 62% had received the pneumococcal 23 vaccine, and 72% had received the pneumococcal 13 vaccine. After the intervention, 65% had received the shingles vaccine, 65% had received the COVID-19 vaccine, 87% had received the hepatitis B vaccine, 85% had received the flu vaccine, 78% had received the pneumococcal 23 vaccine, and 84% had received the pneumococcal 13 vaccine.

CONCLUSION

Patients on immunosuppressive therapy remain vulnerable to vaccine-preventable illnesses such as Shingles, Pneumococcal Pneumonia, Influenza, Hepatitis B, and COVID-19. Our quality improvement intervention increased overall vaccination adherence. This project was a proof of concept and in the future, we hope to integrate a warning system into our practice to alert providers when these patients are due for their appropriate vaccinations. It is also a practice that can be adopted by other healthcare providers who treat patients with IS and biologics to improve vaccination uptake.