bluuebunny/crossref_metadata_2025_split huggingface dataset:
DO PROVIDERS FAIL TO RECOGNIZE ANXIETY IN SOCIALLY VULNERABLE PATIENTS WITH INFLAMMATORY BOWEL DISEASE?
Authors: Sheehan Jessica , Jordan Ariel , Newman Kira , Eloubeidi Dala , Johnson Laura , Higgins Peter 
Published: January 2023

Abstract

INTRODUCTION
Social determinants of health (SDOH) are increasingly recognized for their role in perpetuating an inequitable healthcare system, particularly for those with chronic disease. Patients with inflammatory bowel disease (IBD) are likely subject to many of the same inequities, but data on SDOH and IBD outcomes are lacking. The social vulnerability index (SVI) is a publicly available tool from the Centers for Disease Control that provides neighborhood-level estimates of social need with higher values on a 0-1 scale indicating greater social vulnerability. The SVI has been used in other chronic diseases to determine which patients are at risk for poor outcomes, such as anxiety and depression. Utilizing census tract-level SVI data, we aimed to identify the relationship between SDOH and diagnoses of anxiety and depression in patients with IBD.

METHODS
We used a retrospective cohort of patients at a single IBD center between 01/01/2015 and 08/31/2022. Using the current address in the electronic medical record, we geocoded patients to individual census tracts and linked them to corresponding SVI and subscales (Figure 1). Controlling a priori for age, gender, race, ethnicity, marital status, English proficiency, religious affiliation, and tobacco use, we used multivariable logistic regression to examine the relationship between SVI and the diagnoses of depression and anxiety in patients with IBD.

RESULTS
Depression was increased but not significantly associated with higher total social vulnerability (OR 1.12, 95% CI 0.93-1.34, p=0.2). Depression was associated with higher scores on Socioeconomic Status (SES) (OR 1.36, 95% CI 1.05-1.76, p= 0.020) and Minority Status/Language (OR 1.22, 95% CI 1.03-1.44, p= 0.018). In contrast, anxiety was significantly associated with lower levels of social vulnerability (OR 0.77, 95% CI 0.64-0.92, p= 0.005) but associated with higher scores on Minority Status/Language (OR 1.36, 95% CI 1.16-1.60, p&lt;0.001). The remainder of SVI sub-scores either had no relationship with anxiety and depression or had a negative association with the outcome (Table 1).

CONCLUSIONS
Depression and anxiety were associated with living in socioeconomically disadvantaged and racially diverse neighborhoods; however, patients with higher total SVI and higher scores on the Household Composition were unexpectedly found to have reduced odds of developing anxiety. While these findings were initially surprising, we found them to be in line with current literature that suggests racial/ethnic minorities and low SES individuals are less likely to receive mental health diagnoses, yet suffer from these conditions at similar rates as their white and more affluent counterparts. Future research is needed to improve the mental health dialogue between providers and minority patients and ensure that minority and low SES patients are receiving equitable care.
COLITIS-ASSOCIATED COLON CANCER: EXPLORING THE DCLK1-S-MMP13-P53 AXIS
Authors: Yusuf Kafayat , Roy Badal , Umar Shahid 
Published: January 2023

Abstract
Chronic intestinal inflammation in patients with inflammatory bowel diseases (IBD) significantly increases the risk of colorectal cancer (CRC). Tuft cells in the intestine marked by doublecortin-like kinase-1 (DCLK1), are long-lived chemosensory cells with newly identified roles in colitis as epithelial ablation of DCLK1 worsens disease outcome. DCLK1 exists in long and short isoforms (DCLK1-L and DCLK1-S). Hypermethylation of DCLK1 alpha promoter encoding DCLK1-L particularly in CRC, allows switching to the DCLK1-S isoform that confers a more invasive tumor phenotype. In an infectious colitis model, we recently discovered that DCLK1-S is predominantly expressed in Ly6G+;MHCII- neutrophils that coincides with elevated levels of CXCL1/KC and MMP13 expression in the colon. In an unbiased molecular docking study, DCLK1’s kinase domain was found to interact with the catalytic domain of MMP13. MMP13 plays a crucial role in the modulation of extracellular matrix (ECM) degradation and cell-matrix interactions and wild type and mutant p53 differentially regulate MMP13 gene expression. Mutations in TP53 (tumor suppressor p53) are crucial for neoplasia initiation in IBD patients and are observed in 50-85% of colitis-associated colon cancers (CACCs). We further observed that p53 mutation status dictates DCLK1-S expression in colon cancer cells and in mice mutant for p53, expression of DCLK1-S and MMP13 correlated with neutrophilic inflammation and crypt hyperplasia. We will expand on these novel discoveries by employing high fidelity proteomic and phosphoproteomic studies and decipher how DCLK1-S-MMP13-p53 axes stimulate fibrosis, tumorigenesis, and tumor progression. These studies are expected to lead to therapeutic avenues to target CACCs.
METABOLOMICS ANALYSIS IDENTIFIED AN ORALLY ACTIVE METABOLITE FOR TREATING CROHN’S DISEASE-ASSOCIATED INTESTINAL FIBROSIS
Authors: Koon Hon Wai 
Published: January 2023

Abstract

BACKGROUND
Intestinal fibrosis is a debilitating complication of Crohn’s disease (CD) patients. Surgical resection is used to treat intestinal strictures, but this approach may adversely affect the patients' quality of life. Based on the findings of our groups and others, we hypothesize that intestinal metabolites are associated with intestinal fibrosis. We aimed to discover novel anti-fibrogenic metabolites.

METHODS
We compared the intestinal metabolite profiles between non-IBD, stricturing CD, and non-stricturing CD patients in an inflammatory bowel disease (IBD) multi-omics database to identify CD stricture-related metabolites. We compared the fecal metabolite profiles between trinitrobenzene sulfonic acid (TNBS)-treated mice with and without anti-fibrogenic CSA13 treatment to identify mouse intestinal fibrosis-related metabolites.

RESULTS
Compared to non-stricturing CD patients and non-IBD patients, stricturing CD patients had reduced fecal levels of inosine. Compared to normal mice, TNBS-treated mice had reduced fecal levels of inosine. CSA13-exposed TNBS-treated mice had increased fecal inosine levels. Oral administration of inosine (10 mg/kg/day for 14 days) effectively reduced ileal fibrosis in fibrotic 40-week-old SAMP1/YitFc mice with 96-100% reduction of intestinal collagen mRNA expression and 87% reduction of overall ileal disease activity. Although inosine did not directly inhibit collagen expression in primary human ileal fibroblasts from stricturing CD patients (CD-HIF), it reduced collagen mRNA expression in fresh ileal tissues from stricturing CD patients. RNA-seq and proteomics identified that peroxiredoxin 2 (PRDX2) is negatively associated with intestinal strictures in CD patients. PRDX2 is a thiol-specific antioxidant gene that reduces peroxides to alcohols. Inosine increased the secretion of peroxiredoxin 2 (PRDX2) in primary human intestinal epithelial cells (HPEC). The inosine-mediated PRDX2 secretion was inhibited by the pretreatment of adenosine 2A receptor (A2AR) inhibitor ZM241385. PRDX2 reduced cell stress, induced cell stress-related protein (cyclooxygenase 2/COX-2), and inhibited collagen expression in the CD-HIF. Inhibition of COX2 by indomethacin reversed the anti-fibrogenic effect of PRDX2 in the CD-HIF. Inhibition of PRDX2 caused increased collagen expression in the CD-HIF. Lentiviral overexpression of Prdx2 ameliorated ileal fibrosis in the fibrotic SAMP1/YitFc mice. Fibrotic SAMP1/YitFc mice had reduced circulating free thiol, reflecting increased systemic oxidative stress. Inosine restored circulating free thiol levels in SAMP1/YitFc mice.

CONCLUSIONS
Inosine is an orally active anti-fibrogenic metabolite that promotes PRDX2 expression from intestinal epithelial cells. PRDX2 is a newly identified anti-fibrogenic protein, which may inhibit collagen expression by reducing cell stress.
SELECTION OF DIETARY FIBERS FOR GUT HEALTH BASED ON THEIR PHYSICOCHEMICAL PROPERTIES
Authors: Moncada Edward , Bulut Nuseybe , Li Shiyu , Hamaker Bruce , Reddivari Lavanya 
Published: January 2023

Abstract
Fiber under-consumption in the American population has been associated with a rise in several gastrointestinal diseases. In this study, we focused on Ulcerative Colitis (UC) which currently affects 1 million Americans needing effective preventive and treatment strategies. Short-chain fatty acid (SCFA) production by fiber fermentation is linked to an improved gut barrier function. However, physicochemical properties of fibers such as rate of fermentability, solubility, and structure complexity can influence SCFA levels and fiber tolerance by UC patients. The goal is to determine which fiber characteristics are associated with health benefits in UC patients.
Sixteen dietary fibers were selected based on different levels of solubility, rate of fermentation and structure complexity. Fibers were subjected to an in-vitro simulation of the upper gastrointestinal digestion before in-vitro fermentation using fecal samples from a healthy individual. Gas production, pH, and SCFA production were measured at different time points during the fermentation. Resistant Maltodextrins, Pectin, Inulin, and Wheat Bran were selected as high and low tolerable and efficient fibers for a second in-vitro fermentation using IBD patient fecal sample and an in-vivo study with IL 10-KO germ-free mice transplanted with fecal microbiome from a healthy individual. DNA was extracted from the in-vitro fecal samples and the 16S rRNA genes of the V3-V4 region were amplified to assess gut bacterial dysbiosis and modulation.
Results showed a relationship between fiber physicochemical properties and their roles in gut health. The fermentability rate is one of the major characteristics to be considered, since how fast fiber is fermented is correlated with gas production. SCFA and gas production levels differed significantly in in-vitro fermentation between healthy and IBD fecal samples within each fiber. Bacteria sequencing results showed that the α-and β-diversity were significantly different between IBD and healthy groups. Furthermore, α- diversity was not different between the donors within the fiber treatment, while β-diversity only differed among the fibers within the IBD donor. An increase in the relative abundance of bacteria from the Enterobacteriaceae family in the IBD group may explain the SCFA reduction and the role gut bacterial dysbiosis play in the utilization of these fibers and their potential health benefits. Initial data from the in-vivo study showed differential role of these fibers.
Understanding the connection between fiber properties, gut bacterial composition and fiber efficacy in the gut, can significantly aid in the design of clinical trials and future dietary recommendations. Positive impact of our findings will be evidence-based verification of fibers that are well tolerated by healthy individuals and UC patients for the prevention/protection of this disease.
DIFFERENTIAL ABUNDANCE OF THE FUNGAL MYCOBIOME IN PATIENTS WITH ULCERATIVE COLITIS
Authors: Hsia Katie , Kouhsari Laleh Montaser , Algarrahi Khalid , Fu May , Zhao Naisi , Chen Hannah , Michaud Dominique , Jangi Sushrut 
Published: January 2023

Abstract

BACKGROUND
The fungal mycobiome has been increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). Circulating antibodies to Saccharomyces antibodies are detected in 60-70% of Crohn’s disease and in 10-15% of patients with ulcerative colitis (UC). Specific fungal species, including Candida albicans, are increased in active IBD compared to healthy controls. Recently, UC patients with high fecal Candida prior to fecal microbial transplantation (FMT) were more likely to demonstrate robust treatment responses to transplant, with low Candida levels post-FMT predicting ameliorated inflammation in the recipient. Despite the accumulation of findings supporting the role of fungi in IBD, the mycobiome remains poorly characterized in UC. Few studies have examined changes in the UC mycobiome with respect to validated endoscopic indices or histologic parameters; furthermore, the effects of treatment exposure, including biologic medications, on fungal communities in UC are unknown.

AIMS
In this study, we aim to characterize the fungal mycobiome in UC patients with varying levels of endoscopic activity, endo-histologic activity, and treatment exposure.

METHODS
We performed a secondary analysis using the data extracted from the Crohn’s and Colitis Foundation’s Study of a Prospective Adult Research Cohort with IBD, which contains clinical, endoscopic, histologic, and metagenomic data. Using Internal Transcribed Spacer based deep sequencing of fungal rDNA from fecal samples, we classified sequences utilizing the UNITE fungal database and a fitted classifier. The R package DESeq2 was used to calculate the log-2 fold change of differential abundance.

RESULTS
We identified 504 unique fungal amplicon sequence variants across the cohort of 98 patients, belonging to phylum Ascomycota (71.5%), Basidiomycota (11%), Mucoromycota (0.16%), or unidentified (17.2%). Compared to endoscopic remission, patients with endoscopic activity (n=25) were enriched with Saccharomyces (4.31, p&lt; 5 x 10-5) and Candida (2.53, p&lt; 1 x 10-3). Similarly, compared to endo-histologic remission, patients with endo-histologic activity (n=19) were also enriched for Saccharomyces (2.71, p&lt;0.05) and Candida (2.07, p=0.05). Biologic exposure favored the growth of Candida (p-adj &lt; 1 x10-4). After adjusting for age, gender, and biologic exposure among patients with endoscopic activity, Saccharomyces (p-adj &lt; 5 x 10-12) and Candida (p-adj&lt; 1 x 10-8) remained enriched.

CONCLUSION
These data demonstrate that endoscopic and histologic inflammation in UC is associated with expansion of Saccharomyces and Candida compared to remission, even after controlling for exposure to biologic exposure. These findings are recapitulated during endo-histologic activity. The role of these fungal taxa as potential biomarkers and targets for personalized approaches to therapeutics in UC should be evaluated.
INNATE TL1A SIGNALING PROMOTES INTESTINAL NEUTROPHIL ACTIVATION AND COLITIS ASSOCIATED CANCER
Authors: Pires Silvia , Yang Wei , Longman Randy 
Published: January 2023

Abstract
Intestinal inflammation associated with chronic inflammatory bowel disease (IBD) increases the risk of developing colitis-associated cancer (CAC), but the cellular mechanisms driving CAC are not well defined. Polymorphisms in TNFSF15 (called TNF-like cytokine 1a or TL1A) are highly associated with IBD and the aim of this work is to evaluate a potential mechanistic role of TL1A in regulating CAC. Data from the human atlas protein database revealed that TL1A protein is present in 50% of colorectal cancer tissue samples and that high expression of TNFSF15 correlated with reduced survival. To test the functional role for TL1A in tumorigenesis, we used the well-established AOM/DSS model of CAC in mice deficient for the TL1A receptor (called death receptor 3 or DR3) and mice deficient for myeloid derived TL1A (CD11C cre+TNFSF15fl/fl). We found that both DR3-deficient mice and myeloid derived TL1A deficient mice had a significant reduction in tumor number compared to heterozygous littermate controls. To evaluate the contribution of innate lymphocytes, we used DR3-deficient mice on a RAG-deficient background in our AOM/DSS model. Even in the absence of B and T cells, DR3-deficient mice still showed significant reduction in tumor burden, suggesting innate lymphoid cell (ILC) contribution. DR3-deficient mice also revealed a significant reduction in neutrophil infiltration. Neutrophil depletion with α-Ly6G similarly resulted in a significant reduction of tumor numbers in our CAC model in a DR3 dependent manner. To test the direct regulation of neutrophils by ILCs, we establish a co-culture model. TL1A activated ILCs triggered neutrophil activation (CD177) and maturation (CD11B) which required GM-CSF. In vivo activation with a DR3 agonist confirmed intestinal ILC3 production of GM-CSF but also impacted bone marrow granulopoiesis by expanding both mature neutrophils and granulocyte-macrophage progenitors (GMPs).
CONCLUSION: Our data reveals a new link between intestinal ILC production of GM-CSF and neutrophil activation that promotes CAC and bone marrow granulopoiesis.
REPOGRAMING OF THE INTESTINAL IMMUNE CELL COMPARTMENT DEFINES THE RESPONSE TO AUTOLOGOUS STEM CELL TRANSPLANTATION IN CROHNS DISEASE
Authors: Guisado Daniela , Talware Sayali , Singh Shishir , Gold Stephanie , Mansi Moutasem , Fozilov Elbek , Etra Aaron , Cho Judy , Cohen Louis 
Published: January 2023

Abstract

INTRODUCTION
For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission.(1, 2) Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease state using hematopoietic stem cells. As such, the study of how the immune system responds to auto-SCT will provide unique insight into CD pathogenesis and treatment. To date, no studies in any cohort have defined the mucosal and peripheral immune response to auto-SCT. Here we report initial studies of high dimensional immune phenotyping of patients with CD during auto-SCT.

METHODS
Patients with CD were enrolled in a Phase IIa study of auto-SCT (NCT03219359). 14 patients were transplanted (2018-2022). Paired blood and intestinal samples were taken prior to transplant and 6 months post-transplant. Fresh leukocytes were isolated and analyzed by mass cytometry (CyTOF). Supervised clustering of immune cell populations using canonical markers was performed in parallel with unsupervised clustering by FlowSOM.(3)

RESULTS
After 6 months post-transplant,12/13 patients had an endoscopic response (↓SES-CD by 50%) and 10/13 patients were in endoscopic remission (SES-CD&lt;4). Supervised clustering of major immune cell subsets demonstrated distinct site-specific responses to transplant in myeloid and lymphoid cell populations (Fig 1). Naïve CD4+ and CD8+ T cells universally decrease in number at 6 months post-transplant whereas all other B and T cell populations have discordant changes in the blood and intestine, especially naïve and transitional CD27- B cell populations which significantly increase in blood and decrease in the intestine. CD14+ populations are universally increased in number post-transplant with a specific increase in CD14+ CD206+ macrophages in the intestine. Unsupervised clustering of blood and intestinal immune cells resolve 100 cell clusters that correlate with canonical immune cell markers (Fig 2). Unsupervised analysis further highlights a significant increase in multiple intestinal CD14+CD206+ immune cell populations reflecting newly arrived and/or differentiating and mature monocyte derived macrophages. Principal component and hierarchical clustering analyses of immune cell clusters suggest a reprograming of the intestinal immune compartment post-transplant whereas changes in circulating immune cells populations fail to separate the pre and post-transplant states.

CONCLUSION
We demonstrate for the first time differences in the intestinal and peripheral immune response to auto-SCT. These studies highlight the changes in intestinal immune cell networks that define the transplant response perhaps through CD14+ cells.
NEW ONSET OF INFLAMMATORY BOWEL DISEASE IN A PATIENT WITH EOSINOPHILIC ESOPHAGITIS: 10-YEAR CONSTELLATION OF AUTOIMMUNE GASTROINTESTINAL DISORDERS
Authors: Guzman Adalberto , Ibarra Maria , Mishagina Irina , Ravichander Benjamin , Sangha Lillian 
Published: January 2023

Abstract

INTRODUCTION
Inflammatory bowel disease (IBD) is well known for concurrent immune-mediated disorders such as eosinophilic esophagitis, psoriasis, and rheumatoid arthritis.(1) For the past two decades, we are seeing an increased occurrence of eosinophilic esophagitis (EoE) in long standing IBD patients (2) (3) (4), but the question has arisen as to new onset IBD in chronic EoE patients. One study that involved 4814 patients demonstrated that the prevalence of eosinophilic esophagitis in IBD was 5 times higher compared to general population and EoE in IBD is 2 times higher than expected.(5) Multiple factors have been identified that may trigger the exact inflammatory response in IBD and EoE patients. Both diseases are associated with an exaggerated response to interleukins, especially IL-13 sharing cytokines and helper T cell mediated pathophysiology that is linked to disruption of the gastrointestinal tract barrier. (6) (7)

CASE DESCRIPTION
A 25-year-old healthy male presented back in 2012 with a history of three months of worsening dysphagia that resulted in 15-lb weight loss. Upper endoscopy showed esophagus with small caliber lumen, linear furrows, and thin concentric rings with microscopic evidence of eosinophilic esophagitis. Over the years he developed multiple episodes of persistent dysphagia, several endoscopies demonstrated pangastritis and duodenitis with a new pyloric and duodenal bulb stricture. Due to his remitting-relapsing course despite long-term medical treatment, patient underwent additional workup including an abdominal CT and upper endoscopy that showed worsening of the pyloric stricture that improved after balloon dilation. In 2020, the patient developed diarrhea, rectal bleeding, generalized abdominal pain and 21 lb weight loss despite medical treatment. Colonoscopy showed multiple erosions in the ileum and rectum not seen on previous studies. The biopsy indicated ulcerated mucosa with necrosis in the ileum and rectal area with mixed inflammatory infiltration with the presence of a non-caseating granuloma consistent with Chron’s disease.

DISCUSSION
It is unclear which disease manifest first or if it is a clustering and co-occurrence of diseases. The fact that both diseases share the same pathogenetic mechanism with overexpression of mucosal interleukin-13 (IL-13) causing loss of functionality of the gastrointestinal barrier could explain symptoms observed on both. Many studies demonstrated that IBD was diagnosed before EoE in almost 2/3 of the cases. The association of EoE-IBD is found significantly more in males and occurs at a younger age compared to IBD alone. Further studies will be needed in order to confirm the co-occurrence of diseases because of the increased risk of IBD-related complications and higher chance of requiring systemic corticosteroids and anti-TNF therapy in patients who have coexisting EoE-IBD.