bluuebunny/crossref_metadata_2025 huggingface dataset:
A MODEL TO STUDY INTESTINAL FIBROSIS IN IPSC-DERIVED HUMAN EPITHELIAL AND MESENCHYMAL CELLS FROM CROHN’S DISEASE PATIENTS
Authors: Valencia Christian Wong , Bay Olivia , Patel Shachi , Estrada Hannah , Casero David , Targan Stephan , Barrett Robert
Published: January 2024

INTRODUCTION

Intestinal fibrosis is a serious complication of Crohn's disease (CD) and is caused by the excess deposition of extracellular matrix (ECM) proteins. Numerous cell types, including intestinal epithelial and mesenchymal cells, are implicated in this but research efforts are impaired by a lack of in vitro models. To overcome this, we have previously developed a human model of intestinal fibrosis using iPSC-derived epithelial and mesenchymal cells generated from both control and CD patients. Using this model, we aimed to further characterize the transcriptomic signature associated with the fibrotic response as well as other functional hallmarks of fibrosis.

METHODS

iPSCs from 19 CD patients with (10) and without (9) fibrotic complications were directed to form HIOs. As iPSC-derived HIOs contain epithelial and mesenchymal cells, the organoids were dissociated to generate purified cultures of epithelial only-HIOs (eHIOs) and intestinal mesenchymal cells (MSCs). eHIO and MSC cultures were treated with TNFα and TGFβ, alone or in combination. We evaluated the transcriptomic profile of both cell types via RNA-seq and carried out additional studies via ELISA, ECM staining and scratch assay.

RESULTS

RNAseq analysis on the effects of cytokine induction in eHIOs lead to an enrichment in pathways associated with inflammation and regulation of the immune response. Furthermore, eHIOs from patients with fibrotic complications showed a significant upregulation of ORM1 regardless of culture conditions, which was subsequently confirmed at the protein level indicating an intrinsic difference between both patient groups. RNAseq analysis on MSC cultures found differentially expressed genes clustered in pathways associated with ECM production and remodeling, and cell migration and proliferation. Cell migration capacity of MSCs was assessed by measuring the reduction in scratch area and under basal conditions, MSCs from the fibrotic cohort had a lower rate of cell migration (40.81%) compared to the non-fibrotic cohort (20.97%); notably, the addition of TNFα appeared to accelerate the migration capacity of MSCs in both fibrotic (14.54%) and non-fibrotic (6.56%) samples. Finally, compared to untreated cultures, MSCs treated with TNFα/TGFβ exhibited a significant increase in ECM deposition (2.64- and 2.29-fold increase for non-fibrotic and fibrotic, respectively).

CONCLUSION

We have demonstrated the functionality of our model of intestinal fibrosis generated from iPSC-derived epithelial and mesenchymal cells from CD patients. Furthermore, we have identified both generalized and intrinsic differences in our cohort of patients with fibrotic complications. Future experiments on the role of ORM1 in intestinal fibrosis and its effects on mesenchymal cells could provide a deeper understanding of the events leading the development of intestinal fibrosis in CD patients.
CREEPING FAT-DERIVED FIBROBLASTS PARTICIPATE IN INTESTINAL FIBROSIS IN A NOVEL MOUSE MODEL OF INTESTINAL STRICTURES
Authors: Bauer-Rowe Khristian , Kim Alexia , Pham Benjamin , Griffin Michelle , Norton Jeffrey , Hyun Jeong , Longaker Michael
Published: January 2024

INTRODUCTION

An intestinal stricture is a common morbidity in Crohn's disease, but its pathogenesis is poorly understood. CF forms adjacent to strictures and is associated with stricture recurrence, but whether it promotes stricture formation is unclear. Adipocytes display remarkable plasticity, and adipocyte-derived fibroblasts (ADFs) play important roles in tissue wound healing and fibrosis. Here, we show that CF ADFs may promote intestinal stricture formation.

METHODS

We developed a novel mouse model of CF and intestinal fibrosis by creating anti-mesenteric colotomies. We then created colotomies in Adipoq-Cre; mTmG mice and harvested the mice at post-operative day (POD) 14. This system exclusively labels adipocytes and their derivatives GFP+, whereas all other cells are TdTomato+ (Figure 1A-B). We immunostained sham and colotomy bowel for mature adipocyte marker PLIN1. We quantified GFP+ lineage-negative ADFs (CD45-CD31-Terr119-EPCAM-ECadherin-) isolated from either sham or colotomy bowel at POD 14. We then isolated ADFs (GFP+) and non-ADFs (nADFs) (TdTomato+) by flow cytometry and performed single-cell RNA-seq (scRNA-seq) (Figure 1F).

RESULTS

The creation of a colotomy is sufficient to induce localized mesenteric adipose tissue (MAT) expansion around the colotomy site, consistent with CF formation (Figure 1C). We observed the presence of GFP+ cells with a fibroblast morphology that lost the expression of adipocyte markers and acquired the expression of fibroblast markers. (Figure 1D). Furthermore, we observed that GFP+ ADFs expanded in colotomy bowel compared to sham (Figure 1E). scRNA-seq of ADFs and nADFs revealed 5 major fibroblast clusters, including a Clu+ pro-fibrotic population and a Pi16+ progenitor population, which were enriched in bowel GFP+ ADFs (Figure 1G-H). Finally, quantification of gene expression revealed that GFP+ ADFs lacked mature adipocyte markers, expressed fibroblast markers, and were enriched for various ECM proteins.

CONCLUSIONS

An anti-mesenteric model of intestinal strictures and CF in combination with immunostaining and scRNA-seq revealed that ADFs from CF infiltrate the bowel wall and expand at the site of fibrosis. ADFs exhibit fibroblast heterogeneity and are enriched for pro-fibrotic and stromal progenitor populations. Finally, ADFs produce collagen and fibronectin, suggesting that they may be pro-fibrotic. Altogether, these data highly suggest that CF contains pro-fibrotic stromal cells that infiltrate the stricture site to promote fibrosis.
EPITHELIAL MITOCHONDRIAL DYSFUNCTION IN CHRONIC POUCHITIS
Authors: Patel Parth H , Elsayed Mohamed , Hassan Syed Adeel , ElSaadani Mohamed A , Kasem Ahmad , Wempe Lesley , Bhogoju Sarayu , Goretsky Tatiana , Lee Goo , Barrett Terrence , Kapur Neeraj
Published: January 2024

BACKGROUND

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with refractory ulcerative colitis (UC). However, patients with IPAA are at risk of pouch-related disorders like “pouchitis” with an incidence rate range from 20-50%. The underlying etiopathogenesis of pouchitis has been unclear, which makes management and treatment of active pouchitis difficult. Mitochondrial (Mito) dysfunction is commonly associated with pathogenesis of inflammatory bowel diseases (IBD). We posit the reduced Mito function contributes to chronic pouchitis in IPAA patients. In this study we performed comparative analysis of Mito complex levels in pouchitis patients compared to normal controls.

METHODS

Biopsies collected from ileal pouches +/- inflammation (n=6), and normal (n=3) and inflamed ileum (CD Ileitis; n=3 mean SES=5.2) were preserved in Allprotect® or formalin. Total RNA was extracted, cDNA synthesized and analyzed by RT-qPCR for genes specific for Mito biogenesis and complexes, cytokines and cellular antioxidant machinery. Formalin-fixed tissues were processed for IHC staining of Mito complex-I (NDUFB6) and complex-IV (MTCO1).

RESULTS

Transcriptomic analysis of active pouchitis tissue showed significant (**p<0.01) reduction of Mito biogenesis genes (PGC1α: 69.5±13.9%, TFAM: 48.7±14.5%, NRF1:48.9±17.7%) compared to normal pouch. Similar mRNA analysis in CD-ileitis showed 90.6±15.2% reduction in PGC1α gene (**p<0.01) and more than 62% reduction in TFAM and NRF1 genes compared normal ileum. We also observed 21.6±9.8% reduction in Mito complex I (Ndufa1, Ndufa4, Ndufb2, Ndufb6), 33.6±8.7% reduction in complex-IV (Cox5a Cox6a1, Cox5e) and 38.8±11.8% reduction in complex-V (ATP5a, ATP5b, ATP5e) in chronic pouchitis compared to normal controls. In contrast, CD-ileitis showed 59.5±10.2% reduction in Mito complexes at mRNA level compared to normal ileum. Altogether, CD-ileitis showed 26.3% and 23.8% reduction in Mito complexes and biogenesis genes, respectively, compared to pouchitis. At protein level, tissues from chronic pouchitis showed significantly reduced expression of NDUFB6 and MTCO1 compared to normal controls. However, the decreased expression of NDUFB6 and MTCO1 was more pronounced in active CD-ileitis patients. Concertedly, suppression of Mito biogenesis and complex genes correlated with upregulation of pro-inflammatory cytokines (IL1β and IL-6) and concomitant reduction of anti-oxidant genes (Sod1, Sod2, Gpx, Prdx-2,3,4,6).

CONCLUSION

These data indicate decreased levels of Mito complexes in pouchitis, although reductions are less prominent in active CD. We postulate that Mito dysfunction plays a role in the pathogenesis of chronic pouchitis after IPAA surgery in IBD patients. Furthermore, we posit mitochondria-targeted therapy may deliver therapeutic benefits in refractory pouchitis.
GRANZYME A-PRODUCING CD4 T CELLS ARE DRIVERS OF IMMUNE CHECKPOINT BLOCKADE-INDUCED COLITIS
Authors: Park Sungtae , Wang Mengbo , Anderson Nicole , Kazemian Majid , Olson Matthew
Published: January 2024

Immune checkpoint blockade (ICB) (i.e. anti-CTLA4 and/or anti-PD-1) is a type of cancer immunotherapy that is broadly and effectively used across multiple cancer types. Despite this efficacy, ~60% of individuals of ICB recipients develop autoimmune-like inflammation in the skin, lungs and intestines. Of these barrier sites, an inflamed intestine is the most common form of severe disease that requires cessation of immunotherapy and potential tumor rebound. ICB-induced colitis therefore represents a significant health concern in an increasing population of cancer patients receiving this otherwise effective immunotherapy. Previous work has shown evidence of a dysregulated intestinal CD4 T cell response in ICB colitis patients, however, how CD4 T cells might contribute to disease has remained unclear. Here, we identify a unique subset of T helper (Th) 1-like CD4 T cells that express the serine protease granzyme A (GZMA) that are specifically elevated in ICB-induced colitis patients, suggesting a pathogenic role for GZMA-expressing Th cells in disease.

As mouse models for ICB-induced colitis are virtually non-existent, we have profiled existing mouse models of intestinal inflammation for the presence of colonic GZMA-expressing CD4 T cells for more in-depth functional studies. Using this approach, we have identified the T cell transfer model of colitis as a model that mimics the GZMA CD4 T cell phenotype observed in human ICB colitis patients. Within this model, GZMA-expressing CD4 T cells arise early in the intestines after transfer and only minimally express other CD4 T helper (Th) cell lineage cytokines (i.e. IFN-γ or IL-17) indicating that these cells may represent a unique Th cell subtype that are associated with intestinal disease. Indeed, transfer of GZMA-deficient CD4 T cells into colitis-prone mice resulted in reduced intestinal inflammation and damage, despite efficient trafficking of these cells to the intestines. Mechanistically, CD4 T cell-derived GZMA promoted an exaggerated intestinal epithelial cell response to the microbiota, but was not required for immune-editing of the microbiota in this setting. Taken together, our data indicate that GZMA-producing Th cells are likely major contributors to ICB-induced colitis and may represent a valuable therapeutic target for limiting intestinal disease during ICB therapy.
IRE1A-XBP1 CONTROLS GROUP 2 INNATE LYMPHOID CELLS IN INTESTINAL INFLAMMATION AND FIBROSIS
Authors: Cao Siyan , Colonna Marco
Published: January 2024

BACKGROUNDS

Group 2 innate lymphoid cells (ILC2s) are increased in peripheral blood and intestinal samples from patients with ulcerative colitis or Crohn’s disease and murine models of IBD. ILC2s produce a large amount of type 2 cytokines including IL-5 and IL-13 and growth factor amphiregulin (AREG) that induce goblet cell hyperplasia and mitigate acute inflammation in the gut. On the other hand, prolonged or uncontrolled ILC2 activation may contribute to chronic inflammation and tissue fibrosis. However, the regulatory mechanisms and functional impact of ILC2s in IBD remains elusive. The IRE1a-XBP1 pathway orchestrates cellular stress response that plays a key role in intestinal inflammation.

METHODS

We generated conditional knockout Ire1aflo/floxIl5-Cre (Ire1aΔIl5) with Ire1a deleted in ILC2s. Rag-/-Ire1aΔIl5 mice were also generated to exclude possible contribution of T cells during chronic inflammation. Dextran sodium sulfate (DSS) was given in drinking water to induce acute/chronic colitis and intestinal fibrosis. We also collected colonic biopsies from healthy individuals and sort-purified ILC2s for flow cytometry analysis.

RESULTS

Mouse intestinal ILC2s express high level of Ire1a. The number of ILC2s increased in small intestine (SI) and colon of Ire1aΔIl5 mice compared to Il5-Cre controls. Additionally, SI and colonic Ire1aΔIl5 ILC2s produced more IL-5, IL-13, and AREG after ex vivo stimulation with IL-33 and IL-25. Upon DSS challenge, Ire1aΔIl5 mice exhibited milder signs of disease including weight loss, clinical scores as well as colon shortening and histology (Figure 1), which was accompanied by elevations in ILC2-derived cytokines and AREG as well as heightened goblet cell differentiation and mucin production. In response to 3 cycles of DSS, Rag-/-Ire1aΔIl5 mice developed worsened chronic colitis, fibrosis, and increased fibrosis markers including collagens and vimentin. Intraperitoneal injection of neutralizing antibody against IL-13 or AREG reversed the phenotype. In sort-purified human ILC2s, selective IRE1 inhibitor 4u8C enhanced production of IL-13, while selective IRE1 activator IXA4 suppressed IL-13 in response to IL-2, IL-7, and IL-33 ex vivo (Figure 2).

CONCLUSIONS

We demonstrate that IRE1a-XBP1 constrains cytokine production by intestinal ILC2s during inflammation. IRE1a deficiency in ILC2s protected against acute colitis with heightened type 2 cytokines and AREG; while loss of IRE1a exacerbated chronic colitis and fibrosis. We identified IRE1a as a potential therapeutic target for fibrostenotic CD.

Figure 1 Ire1aΔIl5 mice harbor elevated ILC2s (A) and produce increased IL-5, IL-13, and AREG by (B) SI and (C) colonic ILC2s ex vivo. (D-H) Ire1aΔIl5 mice are protected from acute DSS colitis. *P<0.001.

Figure 2 IRE1 modulators control IL-13 production by human ILC2s. **P<0.01.
NON-CASEATING GRANULOMAS ARE ASSOCIATED WITH STRICTURING CROHN’S DISEASE AND THEIR NUMBER AND SIZE ARE INCREASED IN THE MUSCULARIS PROPRIA OF STRICTURED COMPARED TO NON-STRICTURED INTESTINGAL SEGMENTS
Authors: Massey William , Li Jiannan , Goren Idan , Gordon Ilyssa , Rieder Florian
Published: January 2024

BACKGROUND

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that progressively leads to fibrosis-induced narrowing of the intestinal lumen, bowel obstruction, and need for surgery. CD exhibits transmural inflammation manifested by immune cell infiltrates composed of multiple immune cell types spanning the entire gut wall. Non-caseating granulomas are a typical hallmark of up to 60% of CD patients. Scarce evidence indicates an association of granulomas with post-operative recurrence suggesting a role of granulomas in disease pathogenesis. Strikingly, while evidence exists from other granulomatous diseases, granulomas have not been linked with stricturing CD.

METHODS

A total of 348 H&E stained sections from segments of small bowel CD surgical resection specimens were evaluated for non-caseating granulomas. Granulomas were defined by a trained inflammatory bowel disease pathologist as a cluster of ≥ 5 epithelioid histiocytes with or without the presence of multinucleated giant cells. CD segments were classified as non-involved (CDni), inflamed non-strictured (CDi), and strictured (CDs) to confirm whether histopathological presence of granulomas correlates with stricturing CD. Paired sets were available in 150 segments of 50 CD patients and analyzed further to determine whether granuloma number, location within the intestinal wall, or size of granulomas correlates with stricturing CD.

RESULTS

Granulomas were present in 20% of all CD tissue segments. 28% of CDs, 9% of CDi, and 5% of CDni segments were found to have granulomas and the fraction of segments containing granulomas was significantly higher in CDs compared to CDni and CDi (P<0.0001). The paired patient sections resembled the larger dataset with 16% of patients having granulomas in at least one of the three segments (16% of CDs, 8% of CDi, and 0% CDni). Further comparing the CDi and CDs sections in this subset of patients, we found that neither the total number nor the average size of granulomas were significantly different between CDs versus CDi tissue sections. Analysis of the layers of the intestinal wall revealed that the number (P<0.05) and average size (P<0.01) of granulomas were significantly increased in the muscularis propria of CDs versus CDi sections. There were no significant changes in number or average size in the mucosal or submucosal layers of the intestinal wall.

CONCLUSION

Together these data indicate that non-caseating granulomas are associated with stricturing CD and these granulomas are increased in number and size in the muscularis propria of strictured versus inflamed tissues from the same patient, but not other intestinal layers. This suggests a potential link between granulomas and the pathogenesis of stricturing CD.
UPREGULATION OF SERPINE1/PAI-1 INDUCED BY IL-33 CONTRIBUTES TO INTESTINAL FIBROSIS IN A CROHN’S DISEASE-LIKE ILEITIS MODEL
Authors: De Santis Stefania , Vidmar Kaylynn , Williams Joseph , Mattioli Benedetta , Chieppa Marcello , Del Pinto Rita , Pietropaoli Davide , Corridoni Daniele , Cominelli Fabio , De Salvo Carlo , Pizarro Theresa
Published: January 2024

IL-33 is a pleiotropic cytokine known to possess dichotomous roles during gut health and disease. We previously described that IL-33 promotes epithelial restitution/repair in otherwise healthy (C57BL/6) mice that have been challenged with dextran sodium sulphate (DSS) to induce acute colitis, with the end result of efficient resolution of inflammation. However, in SAMP1/YitFc (SAMP) mice that spontaneously develop Crohn’s disease (CD)-like ileitis, elevated IL-33 levels persist as disease progresses, perpetuating chronic gut inflammation and severe fibrosis. While IL-33 has been implicated in the development of inflammation-associated fibrosis, the precise mechanism(s) by which this occurs remains unclear. The aim of this study was to determine IL-33-dependent events leading to intestinal fibrosis in ileitis-prone SAMP mice. Our results show IHC co-localization of IL-33 with fibrotic lesions, specifically in cells morphologically-consistent with both macrophages and subepithelial myofibroblasts (SEMFs). Bulk RNA-Seq analysis of the human SEMF cell line, CCD-18Co, stimulated +/- IL-33 identifies one of the highest-expressing transcripts as SERPINE1, encoding for plasminogen activator inhibitor-1 (PAI-1), which has previously been reported as highly-enriched in IBD patients with active disease that do not respond to anti-TNF therapy. Analysis of publicly-available scRNA-Seq data confirms the increased expression of SERPINE1 in IBD patients that localizes to mesenchymal cell populations. Of note, robust upregulation of SERPINE1 is detected in activated fibroblasts from involved vs. non-involved areas of CD patients. Furthermore, spatial transcriptomics of SAMP ilea reveal a progressive and concomitant increase in both Il33 and Serpine1, with strong clusterization compared to healthy AKR controls, particularly during later time points when fibrosis is evident. Currently, results are pending on the treatment of SAMP mice with the PAI-1 inhibitor, MDI-2268, to determine its direct effect(s) on the development of inflammation-associated intestinal fibrosis. Taken together, these findings suggest IL-33-dependent regulation of Serpine1/PAI-1 that promotes intestinal fibrosis, commonly observed in CD patients, and may provide a novel target to treat IBD patients with fibrostenoic disease.
A CONSORTIA OF CLINICAL E. COLI STRAINS WITH DISTINCT IN-VITRO ADHERENT/INVASIVE PROPERTIES ESTABLISH THEIR OWN CO-COLONIZATION NICHE AND SHAPE THE INTESTINAL MICROBIOTA IN INFLAMMATION-SUSCEPTIBLE MICE
Authors: Li Chuang , Bleich Rachel , Sun Shan , Ahn Ju-Hyun , Dogan Belgin , Barlogio Cassandra , Broberg Christopher , Bulik-Sullivan Emily , Carroll Ian , Simpson Kenneth , Fodor Anthony , Arthur Janelle
Published: January 2024

Mucosal colonization with adherent-invasive Escherichia coli (AIEC) are believed to perpetuate intestinal inflammation and associated inflammatory bowel disease (IBD). However, it remains unclear if the 24-year-old AIEC in-vitro definition fully predicts mucosal colonization in-vivo. To fill this gap, germ-free inflammation-susceptible interleukin-10-deficient (Il10-/-) and inflammation-resistant WT mice were colonized with a consortia of AIEC and non-AIEC strains, then given a murine fecal transplant to provide niche competition. E. coli strains isolated from human intestinal tissue were each marked with a unique molecular barcode that permits identification and quantification by barcode-targeted sequencing. Our data reveal that specific AIEC and non-AIEC strains reproducibly colonize the intestinal mucosa of WT and Il10-/- mice. These E. coli expand in Il10-/- mice during inflammation and induce compositional dysbiosis to the microbiome in an inflammation-dependent manner based on histological analysis and 16S sequencing. Because select AIEC and non-AIEC strains colonize the mucosa, this suggests the in vitro AIEC definition may not fully predict in vivo colonization potential. Further comparison of seven E. coli genomes pinpointed unique genomic features contained only in highly colonizing strains (two AIEC and two non-AIEC). Those colonization-associated features may convey metabolic advantages (e.g., iron acquisition and carbohydrate consumption) to promote efficient mucosal colonization. Our findings establish the in-vivo mucosal colonizer, not necessarily AIEC, as a principal dysbiosis driver through crosstalk with host and associated microbes. Furthermore, we highlight the utility of high-throughput screens to decode the in-vivo colonization dynamics of patient-derived bacteria in murine models.
VALIDATION OF AN INFLIXIMAB POPULATION PHARMACOKINETIC MODEL FOR MAINTENANCE DOSING IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Singer Jason , Tong Dominic , Cumming Celine , Hughes Jasmine , Holmes Maya , Sferra Thomas , Moses Jonathan , Finkler Michael
Published: January 2024

INTRODUCTION

The use of infliximab has revolutionized the care of pediatric patients with inflammatory bowel disease (IBD); however, infliximab may lose efficacy over time during the maintenance phase and the use of therapeutic drug monitoring has been advocated to improve response rates. A population pharmacokinetic (popPK) model using infliximab concentrations, common clinical biomarkers, and demographic information to predict future infliximab concentrations would be clinically invaluable. Previous popPK models such as the Buurman [1] and Fasanmade [2] exist, but their utility, accuracy, and predictive values have not been clinically validated. This study aims to validate a reliable set of covariates for an infliximab popPK model that will predict maintenance drug concentrations and guide treatment decisions for children with IBD.

METHODS

This retrospective study included 134 pediatric patients with 503 infliximab trough concentrations between 5 and 21 years of age, seen at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at UH Rainbow Babies and Children’s Hospital between January 1, 2008 and December 31, 2018. We recorded the patients' therapeutic infliximab trough concentrations and other clinical and demographic factors. In previous work, we refit published popPK models using induction phase data. Here, we refit our originally constructed one-compartment model based on induction phase data, the Cleveland Model, with maintenance phase data to yield the Cleveland Refit model. We then tested six different models: Buurman (B), Buurman Refit (BR), Fasanmade (F), Fasanmade Refit (FR), Cleveland (C), and Cleveland Refit (CR). Each model was evaluated on root mean square error (RMSE), mean percent error (MPE), and accuracy of the predicted infliximab concentration. We defined accuracy as the percentage of samples each model correctly predicted to be on the same side of 5 ug/mL, which is our clinical trough target.

RESULTS

On the first infliximab concentration following the induction phase, published models refit on induction phase data (BR, FR) have higher accuracy but also higher RMSE than published models. In contrast, the CR model was refit on maintenance phase data and has higher accuracy (71.1% vs 66.7%) and lower RMSE (6.8 vs 7.8 ug/mL) and MPE (-5% vs 10%) than the previous induction-only model.

CONCLUSIONS

The CR model improved upon the performance of the induction-only models tested on this cohort. This study suggests refit popPK models on a specific patient population work well for predicting maintenance phase infliximab concentrations, and may be useful for personalization of dose of frequency for pediatric patients with IBD. Further validation with external data in a multicenter, prospective study is needed.

References

1) https://doi.org/10.1111/apt.13299

2) https://doi.org/10.1016/j.clinthera.2011.06.002
PATIENT DECISION MAKING ABOUT UTILIZATION OF TREATMENT AND MANAGEMENT METHODS: TOWARD ENHANCED PROMOTION OF PREVENTIVE SELF-MANAGEMENT FOR ULCERATIVE COLITIS
Authors: DuBois Kelli , Blake Christine , Rudisill Caroline , Harrison Sayward , Hebert James
Published: January 2024

BACKGROUND

Living with Ulcerative Colitis (UC) is accompanied by physical and psychosocial burdens that significantly detract from quality of life. To accommodate, individuals employ multiple treatment and management methods to mitigate gastrointestinal (GI) disease symptoms, reduce pharmaceutical dependence, and respond to the daily challenges of living with UC. This study examines why and how patients choose to utilize treatment and management methods, with emphasis on patient perspectives and experiences.

METHODS

Adults living with UC for at least 5 years, who had experienced at least one disease flare, were recruited to participate in individual, semi-structured qualitative interviews (N=21). Verbatim transcripts were thematically analyzed using emergent coding with Nvivo12®.

RESULTS

Decision making about the use of treatment and management methods was shaped by participants’ sources of information, attitudes toward self-management, and personal motivations. Participants rarely expressed feelings of personal responsibility for the unpredictable course of illness. However, some believed that they could, to varying degrees, take charge of their UC experience. A few individuals described an active approach to managing their illness through self-adjusting treatment methods, health behavior change, and self-advocacy towards satisfaction with treatment options and enhanced patient-provider communication. The poor quality of life associated with the daily burden of living with UC emerged as a primary motive for exploration and utilization of treatment and management methods. Participants drew conclusions about diet’s impact on disease activity by observation of immediate GI symptoms. While most patients aimed to mitigate UC symptoms by taking medications, reducing stress, and avoiding perceived ‘trigger’ foods, participants reported primarily utilizing treatment and management methods as reactive responses to flares instead of as preventive measures against disease activity and disease progression.

DISCUSSION

Results provide insight into patient decision making and may inform individualized patient care, improve patient-provider communication, and guide interdisciplinary efforts to support self-management among patients with UC. Findings highlight a need for greater focus on promoting preventive self-management lifestyle behaviors to protect against disease activity and progressive impairment. This research supports the promotion of disease prevention and self-management both inside and outside of the clinical setting.
YOUTUBE AND INFLAMMATORY BOWEL DISEASE, A 10-YEAR UPDATE
Authors: Jain Varun , Gilman Christy Ann , Figueroa Esteban
Published: January 2024

INTRODUCTION

As the prevalence of inflammatory bowel disease (IBD) continues to rise, patients are turning to social media, notably YouTube®, for IBD information. This content has transformed since Mukewar et. al’s 2013 analysis of the top YouTube® videos about IBD. Furthermore, patient-desired information is now better understood, including 1) IBD treatment pros and cons, 2) self-advocacy, 3) IBD health tips, 4) IBD coping strategies, and 5) education on patient experiences. We analyzed YouTube® IBD videos to assess their informational quality and ability to address patient-desired attributes.

METHODS

Using the query “inflammatory bowel disease OR IBD,” we reviewed the top 50 English YouTube® IBD videos under 20 minutes. We gathered video metadata and assessed informational quality using the Patient Educational Video Score for Inflammatory Bowel Disease (PEVIS-IBD score) designed by Mukewar et al. with disease and treatment advancement updates. Possible scores ranged from 0 to 28. Patient-desired attribute count was noted per video. One-way ANOVA was done to test statistical significance.

RESULTS

49/50 videos remain accessible. 35% focus on Crohn’s Disease, 30% on Ulcerative Colitis, and 35% on both. Most videos were MD/RN education (17, 35%), patient stories (14, 29%), and hospital/physician-produced IBD explainers (11, 22%). Only 18 (37%) had YouTube® Health Source Accreditation.

MD/RN education videos ranked highest on PEVIS-IBD (13.47). Patient stories ranked lowest (7.57). 24/49 discussed at least one patient-desired attribute, with half of these covering three or more. MD/RN education videos did not address any attributes. Figure 1 shows detailed information about each category of video.

DISCUSSION

Our study shows a shift in IBD YouTube videos, with ⅓ of the top 50 videos being MD/RN education, a previously undescribed segment. Despite high PEVIS-IBD scores reflecting high-quality factual content, all of these videos lack patient-desired attributes, signaling a need for research to ascertain their value to patients.

Of the patient-centric videos (32, excluding MD/RN education), 75% discussed at least one desired attribute, with half discussing 3 or more. Patient story videos had the highest attribute count, but low PEVIS-IBD scores, highlighting an opportunity for videos that simultaneously feature patient stories and facts about IBD.

Only 37% of videos had YouTube® Health Source Accreditation, with videos from reputable organizations like the Crohn's and Colitis Foundation lacking this tag. Medical societies should be aware of this feature and ensure their channels are properly accredited.

Figure 1 Analysis of key video metadata by category.

Reference

Mukewar S, et al. YouTube and inflammatory bowel disease. J Crohns Colitis. 2013;7(5):392-402.
MICROBIAL REPRESENTATION ASSOCIATION WITH LEVEL OF SHORT CHAIN FATTY ACIDS IN SMALL BOWEL
Authors: Xu Linda , Yang Fan , Riethoven Jean-Jack , Izard Jacques
Published: January 2024

BACKGROUND

Small bowel microbiome and associated postbiotics understanding is still in its infancy.

In intestinal bowel disease treatment, surgical interventions leading to an ostomy are often the last resort. The ileostomates and the colostomates lack the whole or part of the colonic function, respectively. In these populations, fecal effluents represent aspects of the small bowel microbial communities and associated small molecules not available in traditional stool collections.

METHODS

We completed a cross-sectional collection of samples from participants with digestive resections were recruited including 26 ileostomates and 23 colostomates. Additionally, 22 individuals with unaltered digestive tracts were enrolled for a total of 71 participants. Stool were self-collected in transport and storage medium. Identification and quantitation of short chain fatty acids were performed using LC MS/MS equipped with a C18 reversed phase UHPLC column. Concentrations for acetic, propionic, butyric, isobutyric, valeric, 2-methylbutyric, isovaleric, and hexanoic acid were obtained. Analysis of covariance (ANCOVA) was used to evaluate the difference in the mean SCFA concentration across the groups. Microbial membership identification was performed using 16 rDNA sequencing for a subset of 59 samples. A table of amplicon sequence variants (ASV) counts per sample was derived using the dada2 R package. Kruskal-Wallis and Post-hoc test Dunn with Benjamini-Hochberg multiple test correction were used to compare the abundance of bacteria producing and utilizing specific short chain fatty acids between the three groups.

RESULTS

For the eight measured short chain fatty acids, all were significantly decreased in ileostomates compared to colostomates and control group (p < 0.001). We observed significant positive correlations between microbial metabolite producers and corresponding metabolites for propionic acid, butyric acid, isobutyric acid, and isovaleric acid. For example, at the level of the population, a positive correlation was found between the abundance of butyric acid microbial producers and the butyric acid level (R=0.5, p = 7.3e-05). Conversely, a significant negative correlation between levels of acetate producers and fecal acetic acid was found in the whole population.

CONCLUSION

The presence of a partial colon, in colostomate, did not drastically alter the detection of the different short chain fatty acids compared to the individuals with an intact colon. In contrast the absence of a colon was associated with a significant drop in level of detected postbiotics. These findings underline the biogeographical distribution of both the microbiome and small molecules along the digestive tract.
DIFFERENTIAL MORTALITY OUTCOMES AMONG DIFFERENT CLASSES OF DRUGS IN ELDERLY PATIENTS WITH ULCERATIVE COLITIS USING A MULTI-CENTER RESEARCH NETWORK
Authors: Chaaban Lara , Giorgianni Francesca , Melia Joanna
Published: January 2024

BACKGROUND

Several medical therapies exist for ulcerative colitis (UC) including 5-aminosalicylates (5-ASAs), immunomodulators (IMM), biologics and Janus Kinase (JAK) inhibitors that aim to induce and sustain both clinical and endoscopic remission of UC. Selection of treatment is dictated by disease severity and patient characteristics and preference. Long-term differences in mortality risk among these therapies is unknown. The aim of this study is to compare 10-year mortality among older adult UC patients exposed to different treatment regimens.

METHODS

Using TriNetX, a multicenter research database, elderly patients with UC who are 65 years or older were identified using ICD-10 code for ulcerative colitis(K51) on the Research Network, accessed on September 26th, 2023. Cohorts were subdivided according to exclusive different lines of therapy as shown in table 1: 5-ASAs, IMM, Biologics, and JAK inhibitors. Advanced therapy included the latter three classes of drugs whereas simple therapy included 5-ASA agents. Comparison of 10-year mortality profiles was done for advanced therapy and each different therapeutic class in reference to simple therapy (5-ASAs). Analyses were performed on a built-in statistical software on TriNetX.

RESULTS

When comparing advanced therapy to simple amino-salicylate-based therapies, elderly patients demonstrated higher 10-year mortality with advanced therapy (13.5% vs 12.4%, OR=1.10, 95 % CI [1.13,1.29], p=0.017) as shown in table 2. When breaking down the classes of advanced therapies, immunomodulators had the highest risk of mortality as compared to simple therapy ( 19.1% vs 12.4%, 1.67 95%CI [1.52, 1.84], p<0.0001). However, biologic therapies had a lower mortality risk when compared to simple therapy (9.3% vs 12.4%, OR=0.73, 95% CI [0.64, 0.83], p<0.0001). Further data are needed to assess the mortality risk of JAK inhibitors as they were recently approved for ulcerative colitis and 10-year mortality risk could not be examined.

CONCLUSION

Among the different drug classes, immunomodulators were significantly associated with higher 10-year mortality risk compared to simple therapy whereas biologic therapies had the lowest mortality risk.

Table 1 Lines of Therapy

Table 2 Characteristics and Mortality Outcome of Patients on Different Lines of Therapy
SAFETY OF ANTI-TUMOR NECROSIS FACTOR AGENTS COMPARED TO USTEKINUMAB AND VEDOLIZUMAB IN ELDERLY PATIENTS WITH ULCERATIVE COLITIS
Authors: Chaaban Lara , Huang Jane , Melia Joanna
Published: January 2024

BACKGROUND

Common first-line treatments for ulcerative colitis (UC) currently include anti-tumor necrosis factor (anti-TNF) agents, ustekinumab (interleukin-12/interleukin-23 receptor antagonist), and vedolizumab (integrin antagonist). However, there are safety concerns when prescribing biologic therapies to elderly patients. While these medications have all demonstrated general efficacy and safety in UC, this study aims to examine the long-term comparative safety of anti-TNF agents with vedolizumab and ustekinumab in elderly patients with UC.

METHODS

The Research Network on TriNetX database was accessed on September 26, 2023, to identify patients at least 65 old who were diagnosed with UC: the first cohort included patients prescribed anti-TNF agents (included adalimumab, certolizumab pegol, golimumab, and infliximab) and the second cohort included patients prescribed either vedolizumab or ustekinumab. Primary outcomes included mortality, corticosteroid use, subsequent colectomy, colon cancer, infections, and all-cause hospitalizations within 10 years after matching for age, sex, and race. All analyses were performed in real-time using built-in statistical algorithms on TriNetX.

RESULTS

After matching cohorts, 1,075 elderly patients with UC patients were included in each cohort as shown in table 1. Patients who were prescribed anti-TNF therapy had a significantly increased 10-year risk of mortality (10.7%) compared to patients on either vedolizumab or ustekinumab therapy (5.77%) (OR 1.96, 95% CI [1.42, 2.7], p <0.0001). Corticosteroid use was higher in the anti-TNF cohort (40.6% vs 34.9%, p= 0.007). There were no significant differences between the two cohorts when comparing the need for colectomy (3.26% vs 2.23%, p = 0.15) or colorectal cancer occurrence (1.67% vs 2.05%, p=0.52) within 10 years. However, the anti-TNF cohort had a higher risk of all-cause hospitalization (32.5 % vs 22%, p=<0.0001), respiratory tract infections (18.4% vs 14.5%, p=0.015), and urinary tract infections (10.4% vs 7%, p=0.005).

CONCLUSION

In elderly patients with UC, ustekinumab or vedolizumab are safer treatment options compared to anti-TNF therapy.

Table 1 Demographics and Comparative 10-year Outcomes of Elderly Patients with UC.
REAL-WORLD RATE AND MAGNITUDE OF DOSE ESCALATION WITH BIOLOGICS IN PATIENTS WITH CROHN’S DISEASE
Authors: Gorritz Magdaliz , Tuly Rifat , Sun Kainan , Creveling Thomas , Moses Richard , Fisher Deborah , Bires Nicholas , Chan Wai Man Maria , Johnson Nate , Hull Michael , Upadhyay Navneet
Published: January 2024

INTRODUCTION

Advanced therapies (ATs), such as adalimumab (ADA), infliximab (INF), vedolizumab (VED), and ustekinumab (UST), referred to as biologics, are regularly used to treat moderate-to-severe Crohn’s disease (CD). Loss of response is a common problem with biologics in CD and one solution is to increase dose of biologics, affecting the cost of CD management. Assessing real-world dosing with biologics is important to inform the estimated treatment cost. The objective of this study was to assess the rate and magnitude of dose escalation with biologics in treatment of CD.

METHODS

This retrospective cohort study identified adult American patients in the IQVIA PharMetrics® Plus database who were diagnosed with CD and started an AT for CD between 01 Jan 2015 and 31 May 2021. Index date was the start date of a qualifying AT. Patients had ≥12 months of continuous pre- and post-index enrollment in a health plan, no claims for AT during the pre-index period, and no autoimmune diseases or indeterminate colitis. Rate and magnitude of dose escalation were assessed from the start of maintenance phase with AT until the end of follow-up period. Dose escalation was measured in first-line (1L) and second-line (2L) settings and defined as an increase in average dose ≥20% than expected dosing per FDA label during follow-up period after maintenance dose was reached. Dose escalations of ≥50% and ≥100% were also measured.

RESULTS

The study identified 7,353 CD patients starting an AT (1L setting) (median age, 38 years; 51.4% female; median follow-up, 28.5 [18.6-43.0] months), and 1,608 (21.9%) patients who received treatment with AT in a 2L setting. More patients reached maintenance dose in a 1L setting (89.4% [INF] to 93.8% [ADA]) than in a 2L setting (77.4% [INF] to 90.3% [UST]). The rate of dose escalation in patients who reached maintenance dose was 21.1% [ADA], 19.2% [IFX], 29.3% [VED], 49.5% [UST] in a 1L setting, vs 23.8% [ADA], 21.9% [IFX], 25.1% [VED], 52.0% [UST], respectively, in a 2L setting (Figure 1). The frequency of dose escalation ≥50% varied for different therapies, 13.8% [ADA], 6.1% [IFX], 19.1% [VED], and 40.0% [UST] in a 1L setting vs 15.3% [ADA], 9.0% [IFX], 17.6% [VED], and 42.3% [UST] in a 2L setting (Figure 2). Dose escalation ≥100% was uncommon with both 1L therapies (0.6% [ADA] to 10.1% [VED]) and 2L therapies (0% [ADA] to 7.7% [VED]).

CONCLUSIONS

A meaningful percentage of Crohn’s disease patients treated with adalimumab, infliximab, vedolizumab, or ustekinumab had dose escalation regardless of line of treatment. Understanding the impact of these utilization patterns may inform real-world cost management.

Figure 1 Rate of dose escalation with advanced therapies in Crohn’s disease

Figure 2 Magnitude of dose escalation with advanced therapies in Crohn’s disease
Host Transcriptional Meta-signatures Reveal Diagnostic Biomarkers for Plasmodium falciparum Malaria
Authors: Silva Nágila Isleide , Souza Pedro Felipe Loyola , Silva Bárbara Fernandes , Fonseca Simone Gonçalves , Gardinassi Luiz Gustavo
Published: January 2024

Background

Transcriptomics has been used to evaluate immune responses during malaria in diverse cohorts worldwide. However, the high heterogeneity of cohorts and poor generalization of transcriptional signatures reported in each study limit their potential clinical applications.

Methods

We compiled 28 public data sets containing 1556 whole-blood or peripheral blood mononuclear cell transcriptome samples. We estimated effect sizes with Hedge's g value and the DerSimonian-Laird random-effects model for meta-analyses of uncomplicated malaria. Random forest models identified gene signatures that discriminate malaria from bacterial infections or malaria severity. Parasitological, hematological, immunological, and metabolomics data were used for validation.

Results

We identified 3 gene signatures: the uncomplicated Malaria Meta-Signature, which discriminates Plasmodium falciparum malaria from uninfected controls; the Malaria or Bacteria Signature, which distinguishes malaria from sepsis and enteric fever; and the cerebral Malaria Meta-Signature, which characterizes individuals with cerebral malaria. These signatures correlate with clinical hallmark features of malaria. Blood transcription modules indicate immune regulation by glucocorticoids, whereas cell development and adhesion are associated with cerebral malaria.

Conclusions

Transcriptional meta-signatures reflecting immune cell responses provide potential biomarkers for translational innovation and suggest critical roles for metabolic regulators of inflammation during malaria.
Trading Sovereignty for Self-Determination
Authors: Beall Katherine M
Published: January 2024

Weak or dependent states, especially those with histories of colonial and imperial domination, have traditionally been among the strongest advocates for strict institutionalization and observance of the norm of non-interference. These states are vulnerable to international pressure, and they have sought to limit this pressure by “jealously” guarding their sovereignty. Yet, after decades of advocating for strict non-interference, many have begun to delegate extensive interventionist authority to their regional organizations. What explains this change? I explore this question in the case of the decision by Latin American leaders to compromise on non-interference by delegating authority to enforce human rights to the Organization of American States. I argue that they were motivated by attempts to maintain self-determination and resist the imposition of authority. In making this argument, I extend the definition of self-determination to incorporate self-determination over international rules. I show that existing explanations for this development that emphasize norm diffusion or democratization cannot account for important dynamics. These findings offer evidence that the expansion of regionalism in the Global South has been, in part, a subtle strategy to mitigate the undesirable effects of hierarchy and to create an international system based on respect for self-determination.
A novel glycine-rich peptide fromZophobas atratus, coleoptericin B, targets bacterial membrane and protects againstKlebsiella pneumoniae-induced mastitis in mice
Authors: Wang Xue , Li Shuxian , Du Mengze , Liu Ning , Shan Qiang , Zou Yunjing , Wang Jiufeng , Zhu Yaohong
Published: January 2024

Objectives

The growing occurrence of bacterial resistance has spawned the development of novel antimicrobial agents. Antimicrobial peptides, a class of small molecules with antimicrobial activity, have been regarded as the ideal alternatives to antibiotics.

Methods

In this study, we amplified a new type of Zophobas atratus coleoptericin (denoted coleoptericin B) through rapid amplification of cDNA ends (RACE) PCR and expressed recombinant Z. atratus coleoptericin B (rZA-col B) by prokaryotic expression. Subsequently, we evaluated the antimicrobial effect and biocompatibility of rZA-col B in vivo, investigated its antimicrobial mechanism, and assessed its therapeutic effect in a murine model of mastitis caused by MDR Klebsiella pneumoniae.

Results

The in vivo studies demonstrated that rZA-col B possesses broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative bacteria. It exhibited less than 1.5% haemolysis and 10% cytotoxicity, even at a concentration of 128 μM. Additionally, rZA-col B had a minimal risk of inducing drug resistance. Furthermore, rZA-col B could disrupt the integrity of bacterial membranes, induce membrane permeabilization and ultimately lead to bacterial death. Importantly, rZA-col B also alleviated mastitis caused by MDR K. pneumoniae in a murine model by enhancing bacterial clearance, reducing neutrophil infiltration, decreasing TNF-α and IL-1β expression, and protecting the mammary barrier.

Conclusions

rZA-col B may be a promising antibacterial agent to combat MDR bacterial infection.