bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE FUNCTION OF THE CYSTATHIONINE-GAMMA-LYASE/HYDROGEN SULFIDE AXIS IN THE PATHOGENESIS OF ULCERATIVE COLITIS
Authors: Toro Gabor , Szaniszlo Peter , Almenas Francisco Arroyo , Thanki Ketan , Maskey Manjit , Chao Celia , Hellmich Mark , Yochum Gregory , Pinchuk Iryna , Modis Katalin 
Published: January 2024

Abstract

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

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

CONCLUSION
These studies demonstrate that CSE regulates mucosal TNF-alpha signaling, pro- and anti-inflammatory responses as well as colonic epithelial repair. Adding the H2S donor GYY4137 reduces inflammation, suggesting the restoration of normal TNF-alpha signaling function.
Acknowledgments: KM is supported by the DoD Career Development Award (W81XWH2010641) and ACS Research Scholar Grant (RSG–21–027–01–CSM).
BACTERIAL SPHINGOLIPIDS EXACERBATE COLITIS BY INHIBITING ILC3-DERIVED IL-22 PRODUCTION
Authors: Bao Bin , Wang Youyuan , Boudreau Pavl , Song Xinyang , Wu Meng , Chen Xi , Patik Izabel , Tang Ying , Ouahed Jodie , Wu Chuan , Balskus Emily , Thiagarajah Jay , Liu Jian , Wessels Michael , Lencer Wayne , Kasper Dennis , An Dingding , Horwitz Bruce , Snapper Scott 
Published: January 2024

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

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

Abstract

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

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

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

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

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

Abstract
The development of real-time and non-invasive methods for monitoring gut health, signaling, and inflammatory status has the potential to transform the diagnosis, treatment, management, and drug development of numerous pathologies of the gut. Inflammatory bowel disease (IBD) represents one such area of large unmet clinical and pharmaceutical needs as it affects a large proportion of the population, has continued to increase in prevalence over time, and can have devastating consequences when not appropriately diagnosed and managed. Furthermore, there are a plethora of therapeutic options to which patients can show variable responses which means patients can undergo several cycles of costly therapy before finding an effective treatment regime for their disease.
Conventional methods in disease management and clinical trial measurements involve endoscopies, which are invasive, expensive, and constitute only single or limited set of timepoints that are not readily amenable to longitudinal studies. While stool or blood tests are also commonly used, they only measure a small number of biomarkers and do not provide the necessary sensitivity nor data-rich insight into disease pathology that is required to inform clinical decision making and ongoing drug development efforts.
Here, we have developed Exfoliome sequencing (Exfo-seq), an innovative non-invasive method to measure the gastrointestinal transcriptome directly from stool. Our approach makes use of the trace amounts of human RNA molecules (i.e., the exfoliome) that are present within stool due to natural turnover of intestinal cells. However, due to the massive amount of microbial and diet-derived contamination in the stool, the effort to capture human intestinal transcriptomic signals has remained limited to only a handful of genes. With a highly optimized signal capturing and amplifying method coupled with deep sequencing, we can simultaneously probe the mRNA levels of hundreds to upwards of several thousand genes from stool in a highly sensitive and quantitative manner. Exfo-seq can be performed to profile gut health, inflammatory state, disease pathway activity, and therapeutic response over time, and changes in gut cell populations, such as proliferation of immune cells during inflammation, can be inferred. Exfo-seq holds great potential as a non-invasive method to guide IBD diagnosis, treatment, long-term management and future drug development.
COMPARABLE CLINICAL OUTCOMES IN PEDIATRIC PATIENTS WITH CROHN’S DISEASE TREATED WITH ACCELERATED VS. STANDARD INFLIXIMAB DOSING DURING INDUCTION
Authors: Marshanski Tal , Fanous Eliana , Tal Noa , Weintraub Yael , Matar Manar , Shamir Raanan , Shouval Dror 
Published: January 2024

Abstract

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

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

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

CONCLUSIONS
In a retrospective cohort, accelerated infliximab dosing during induction didn’t result in improved clinical outcomes up to 52 weeks.
INFLIXIMAB AND VEDOLIZUMAB HAVE SIMILAR CLINICAL AND SAFETY OUTCOMES AMONG BIOLOGIC-NAÏVE PATIENTS WITH MILD TO MODERATE PEDIATRIC INFLAMMATORY BOWEL DISEASE
Authors: Elknawy Essam , Rosen Michael , Colman Ruben , Goyal Alka 
Published: January 2024

Abstract

BACKGROUND
Infliximab (IFX) is the only FDA-approved intravenous therapy for the treatment of pediatric inflammatory bowel disease (IBD). The gut-selective anti-integrin vedolizumab (VDZ) has been increasingly used as second-line therapy. However, the comparative effectiveness of IFX vs. VDZ to treat biologic-naïve children with IBD is currently unknown.

AIMS
1. Compare the real-world effectiveness of IFX vs. VDZ in bio-naïve pediatric patients with IBD at 12 months. 2. Study the safety of IFX and VDZ in the pediatric population.

METHODS
A single-center retrospective cohort study was conducted at an academic children’s hospital between February 2015 and August 2023. We included bio-naive mild-moderate IBD patients, &lt;23 years old, who started IFX or VDZ as their first advanced therapy. Patients with a confirmed diagnosis of IBD based on Porto criteria with baseline and at least 6-month follow-up data were included. Exclusion criteria were designed to limit the study population to patients who would typically be eligible for vedolizumab treatment according to the current standard of care, including: prior biologic use; steroid-refractory acute-severe colitis; stricturing or penetrating Crohn’s disease (CD); or perianal disease; and extraintestinal manifestations. The primary outcome was steroid-free clinical remission (SFCR) at 12 months, defined by the PUCAI &lt;10 or ShPCDAI &lt;10 and off corticosteroids. Biochemical remission (BR) was defined as fecal calprotectin (FCP) &lt;250 μg/g. Descriptive statistics included the Chi-square and the Mann-Whitney U test.

RESULTS
Among the 100 included patients, 73 in IFX group vs. 27 in VDZ group, the mean age was 13 ± 4 years old, males were 68% (IFX) vs. 41% (VDZ) (P = 0.01). 49% had CD, 48% had UC, and 3% had unclassified IBD (IBDU). IFX- and VDZ-treated patients had similar Paris classifications. Baseline albumin levels (3.7 vs. 4.2 g/L, P&lt;0.01) and steroid use (58% vs. 74%, P = 0.13) were lower in IFX vs. VDZ-treated patients. 12-month SFCR was 72% (49/68) and 71% (15/21) in IFX- and VDZ-treated patients, respectively (NS). Among SFCR at 12 months, BR was 59.62% (IFX) vs. 76.47% (VDZ), P = 0.21. Adverse events were rated as mild to moderate and occurred rarely in 8.22% (6/73) of IFX patients and in 7.41% (2/27) of VDZ patients (P = 0.89). These included an infusion reaction (1 in each group), elevated liver enzymes (1 in each group), infection (1), folliculitis (1), eczema (1), , and psoriasis (1).

CONCLUSION
We found both IFX and VDZ to have similar effectiveness in achieving SFCR and BR at 12 months when used as first-line agents for patients with uncomplicated mild-moderately active IBD. Prospective, larger head-to-head studies are needed for further validation.

IFX group vs. VDZ group at the baseline.

IFX group vs. VDZ group for Steroid Free Clinical Remission Patients at 12 months.
THE DEVELOPMENT OF HUMAN PRIMARY CULTURE MODELS TO MODEL INFLAMMATORY SIGNALING IN CROHN’S DISEASE AND ULCERATIVE COLITIS
Authors: Thelin William 
Published: January 2024

Abstract
Intestinal inflammation is a major pathological feature associated with gastrointestinal disorders such as Crohn’s disease and ulcerative colitis (UC). To unravel the complex mechanisms underlying these conditions and to develop effective therapeutic strategies, it is crucial to recapitulate intestinal inflammatory signaling using accurate and biologically relevant experimental systems. To establish primary cell-based models that reprise the inflammatory signaling in Crohn’s and UC, we developed the RepliGut platform. Briefly, we established a biobank of primary intestinal stem cells, derived from healthy full-length intestines from a range of donors of different sexes, ages, and ethnicities. From each donor, intestinal epithelial stem cells were isolated from each region of the small intestine and colon (duodenum, jejunum, ileum, ascending colon, transverse colon, and descending colon). The intestinal stem cells were passed to generate large and quality-controlled cell lots of “ready-to-use” vials which are cryopreserved and can be thawed directly onto 12- or 96-well Transwell inserts, generating the RepliGut platform. The RepliGut culture conditions allow for investigation into the physiology of intestinal epithelial cells as either proliferative stem or differentiated cell types and enable studies on focused regional differences in the intestinal tract, while the Transwell platform allows apical and basal media access that facilitates barrier function measures and convenient bi-lateral media sampling. Using this system, Crohn’s and UC-like inflammation can be produced via treatment with the most clinically and therapeutically validated cytokines associated with disease pathophysiology, TNF-α and IFN-γ. Circulating concentrations of both TNF-α and IFN-γ are observed to be elevated in patients with inflammatory bowel diseases and therapeutic antagonists including adalimumab (TNF-α) and JAK inhibitors such as tofacitinib (IFN-γ) represent the current standard of care. On the RepliGut platform, both TNF-α and IFN-γ produced a dose-dependent loss in epithelial barrier function, increased cytokine secretion, and caused cellular death, all of which were mitigated by adalimumab and tofacitinib, respectively. Moreover, at clinically relevant concentrations, combinations of TNF-α and IFN-γ produced synergistic inflammatory response on the intestinal epithelial cultures. In summary, the RepliGut platform provides a convenient and high-throughput platform that reproduces cytokine-induced intestinal inflammation for mechanistic studies and drug screening.
Monodromy Kernels for Strata of Translation Surfaces
Authors: Giannini Riccardo 
Published: January 2024

Abstract
The non-hyperelliptic connected components of the strata of translation surfaces are conjectured to be orbifold classifying spaces for some groups commensurable to some mapping class groups. The topological monodromy map of the non-hyperelliptic components projects naturally to the mapping class group of the underlying punctured surface and is an obvious candidate to test commensurability. In the present article, we prove that for the components $\mathcal {H}(3,1)$ and $\mathcal {H}^{nh}(4)$ in genus 3 the monodromy map fails to demonstrate the conjectured commensurability. In particular, building on the work of Wajnryb, we prove that the kernels of the monodromy maps for $\mathcal {H}(3,1)$ and $\mathcal {H}^{nh}(4)$ are large, as they contain a non-abelian free group of rank $2$.
Gardnerella Species and Their Association With Bacterial Vaginosis
Authors: Munch Matthew M , Strenk Susan M , Srinivasan Sujatha , Fiedler Tina L , Proll Sean , Fredricks David N 
Published: January 2024

Abstract

Background
Bacterial vaginosis (BV) is a condition marked by high vaginal bacterial diversity. Gardnerella vaginalis has been implicated in BV but is also detected in healthy women. The Gardnerella genus has been expanded to encompass 6 validly named species and several genomospecies. We hypothesized that particular Gardnerella species may be more associated with BV.

Methods
Quantitative polymerase chain reaction (PCR) assays were developed targeting the cpn60 gene of species groups including G. vaginalis, G. piotii/pickettii, G. swidsinskii/greenwoodii, and G. leopoldii. These assays were applied to vaginal swabs from individuals with (n = 101) and without BV (n = 150) attending a sexual health clinic in Seattle, Washington. Weekly swabs were collected from 42 participants for up to 12 weeks.

Results
Concentrations and prevalence of each Gardnerella species group were significantly higher in participants with BV; 91.1% of BV-positive participants had 3 or more Gardnerella species groups detected compared to 32.0% of BV-negative participants (P &lt; .0001). BV-negative participants with 3 or more species groups detected were more likely to develop BV within 100 days versus those with fewer (60.5% vs 3.7%, P &lt; .0001).

Conclusions
These results suggest that BV reflects a state of high Gardnerella species diversity. No Gardnerella species group was a specific marker for BV.