bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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.
TH17 CELLS PROMOTE INTESTINAL FIBROSIS THROUGH THE PRODUCTION OF AMPHIREGULIN
Authors: Yang Wenjing , Yu Tianming , Yao Suxia , Pinchuk Irina , Cong Yingzi 
Published: January 2022

Abstract

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

Abstract

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&lt;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

Abstract

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

Abstract

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.
CHANGE IN URGENCY STATUS AMONG ULCERATIVE COLITIS PATIENTS: UNDERSTANDING THE IMPACT OF TREATMENT CHANGES FROM THE COREVITAS INFLAMMATORY BOWEL DISEASE REGISTRY
Authors: Wolf Douglas , Naegeli April , Moore Page , Janak Judson , Crabtree Margaux , Shan Mingyang , Hunter Theresa , Sontag Angelina , Cross Raymond 
Published: January 2022

Abstract

BACKGROUND
Stooling urgency (also known as urgency to defecate) is one of the most common symptoms among Ulcerative Colitis (UC) patients (pts). Understanding factors associated with changes in urgency status, such as the association between timing of treatment changes and subsequent onset or resolution of urgency symptoms, are essential in addressing unmet pts needs. Our aim was to explore treatment frequency and persistence among UC pts stratified by a change in urgency status from enrollment to the 6-month follow-up (6M) visit.

METHODS
Participants included UC pts in the CorEvitas Inflammatory Bowel Disease Registry between 5/3/17-9/1/20. Stooling urgency was defined as no urgency or urgency using the categories, none and hurry/immediate, from the Simple Clinical Colitis Activity Index (SCCAI). Urgency status groups were formed by urgency at enrollment and the 6M visit: no persistent urgency (NPU), i.e., no urgency at both visits; change from urgency to no urgency (UN); change from no urgency to urgency (NU); and persistent urgency at both visits (PU). Chi-square tests were conducted to compare treatment use and change between urgency status groups (NPU=reference group). Kaplan Meier curves and log-rank tests were used to assess time to first treatment change between urgency status groups.

RESULTS
The urgency status groups (n=400) included: 44% NPU (n=175), 21% UN (n=86), 14% NU (n=56), and 21% PU (n=83). A higher proportion of UN (47%, p=0.03) and PU (51%, p=0.01) pts received two or more treatments compared to NPU (33%) pts. Compared to NPU pts, pts in all three groups, UN (52% vs. 27%, p&lt; 0.001), NU (45% vs. 27%, p=0.02), and PU (53% vs. 27%, p&lt; 0.001) were more likely to change treatment between enrollment and the 6M visit. Similarly, a higher proportion of pts on a biologic at enrollment, UN (24% vs. 11%, p=0.01), NU (23% vs. 11%, p=0.03), and PU (35% vs 11%, p&lt; 0.001), changed treatment between enrollment and the 6M visit vs. NPU pts. The time to first treatment change was shorter for all other urgency status groups when compared to NPU pts (log-rank tests, all p&lt;0.02) (Figure 1). Among pts without urgency at enrollment, the time to first treatment change was shorter for NU vs. NPU pts (p=0.01) whereas it was similar for pts with urgency at enrollment, UN vs. PU pts (p=0.93) (Figure 1).

CONCLUSION
Among UC pts in a real-world setting, there were significant differences in change of treatment and time to treatment change between pts who experienced urgency either at their enrollment visit, 6M, or both, compared to those without urgency. Urgency at any time point is a symptom of great concern to UC pts, is a sign of inadequate therapy, and often is an indication to switch treatment therapy.
PATIENTS’ PERSPECTIVES, EXPERIENCES, AND CONCERNS WITH CROHN’S PERIANAL FISTULAE: INSIGHTS FROM SOCIAL MEDIA PLATFORMS
Authors: Khalil Carine , van Deen Welmoed , Dupuy Taylor , Syal Gaurav , Arnold Corey , Cazzetta Susan , Nazarey Pradeep , Spiegel Brennan 
Published: January 2022

Abstract

INTRODUCTION
Crohn’s perianal fistulae (CPF) impact the physical, emotional, and social wellbeing of patients. Despite the high biopsychosocial burden of CPF, limited data exist regarding how patients navigate challenges associated with this complication of CD and how they perceive treatments. Social media offers a rich opportunity to gain an in-depth understanding of the impact of CPF on patients’ daily lives outside of controlled environments. In this study, we used social media to examine patients’ experiences and concerns with CPF and assess its impact on their behavior and overall wellbeing.

METHODS
We used a mixed-method approach to examine 119,986 publicly available posts related to CPF from 10 US CD forums between 1/1/10-1/1/20. We randomly selected 700 posts for qualitative analysis using an inductive thematic approach. A latent Dirichlet allocation probabilistic topic model was applied to explore themes in an unsupervised manner within the collection of the 119,986 posts. Fifty topics were generated and manually reviewed to identify themes, which were compared to the themes identified in the qualitative data analysis.

RESULTS
We distinguished 4 main themes and several subthemes that were also identified in the qualitative thematic analysis. In 38% of the posts, patients used social media to seek peer-support and information about CPF symptoms, treatments, diet, experimental therapies, natural remedies, and patients’ apprehension regarding treatments. Moreover, 30% of the posts focused on discussions surrounding the biopsychosocial burden of CPF. Patients reported pain and constant discomfort, psychological effects including stress symptoms, distress, and fear, as well as social impact on work and intimate relationships. In 21% of the posts users discussed challenges associated with CPF treatments including financial challenges, unsuccessful procedures/treatments, recurrence of CPF post-treatment, and lack of information on CPF treatments. Lastly, 15% of the posts involved patients’ experiences with medications and surgeries such as efficacy of treatments, side effects experienced and complications. While the quantitative analysis revealed an additional subtheme related to financial challenges and local and topical care, the qualitative analysis revealed an additional subtheme related to patients’ apprehension to undergo treatments (Figure 1).

DISCUSSION
Social media analysis reveals a dynamic range of themes governing patients’ perspectives and experiences with CPF. The use of a mixed-methods approach generated complementary insights regarding patients’ need for information about CPF, the biopsychosocial burden of CPF, the different encountered challenges with treatment and the difficulty to navigate among available management options. These results highlight a gap in patient educational needs for CPF.