bluuebunny/crossref_metadata_2025_split huggingface dataset:
P021 Vitamin D receptor-dependent protective effect of moderate hypoxia in a mouse colitis model Running title: Hypoxia prevents mouse colitis through VDR
Authors: Wang Z , Hong Y , Hong L , Changzhi H , Jiaming Q 
Published: January 2022

Abstract

Background
Although physiological hypoxia is important for maintaining the intestinal barrier, its effect on the barrier during acute colitis and the underlying mechanisms are not fully understood. Here,we aim to explore the influence of hypoxia in dextran sulfate sodium (DSS)-induced colitis mice and the role of hypoxia-inducible factor (HIF) and vitamin D receptor (VDR) in the process

Methods
Colitis mice were subjected to hypoxia to detect colitis symptoms and intestinal barrier function changes. Finally, the mechanisms underlying the changes were explored in a colon cell line.

Results
First, compared with colitis mice without hypoxia stimulation, those with hypoxia stimulation showed significantly decreased pathological damage and improved permeability of the intestinal barrier. The expression of tight junction proteins (including occludin, claudin-1 and ZO-1), HIF-1α as well as VDR was up-regulated in colitis mice with hypoxia stimulation. However, in VDR gene knockout (VDR-KO) colitis mice, hypoxia treatment showed no protective effect, suggesting the VDR dependency of this effect. Second, we identified that although hypoxia stimulation could enhance the single-layer epithelial transmembrane electrical resistance in DLD-1 cells, these effects disappeared in VDR-knockdown cells. Furthermore, over-expression of HIF-1α in DLD-1 can increase the expression of VDR, then chromatin immunoprecipitation and luciferase assays confirmed that HIF-1α can bind to the promoter region of the VDR gene under hypoxia. Finally, compared with their wild-type siblings, VDR-KO mice showed reduced abundance of anaerobic bacteria and SCFA-producing bacteria.

Conclusion
Moderate hypoxia was protective against DSS-induced colitis, and VDR is instrumental in it. Furthermore, HIF-1α mediates the effect of hypoxia on the VDR signaling pathway. Moreover, intestinal flora may be an important link between hypoxia and VDR.
P022 Transcriptional biomarkers for vedolizumab therapy response in patients with moderate to severe Ulcerative Colitis
Authors: Arosa García L , Camba-Gómez M , Calviño-Suárez C , Bastón-Rey I , Ferreiro-Iglesias R , Porto M , Nieto-García L , Domínguez-Muñoz J E , Barreiro-de Acosta M , Conde-Aranda J 
Published: January 2022

Abstract

Background
Vedolizumab is one of the current treatments for patients with Inflammatory Bowel Disease (IBD). The efficacy and safety, together with its gut specificity, make this drug an appealing therapeutic option for IBD patients with moderate to severe disease. However, as observed for other biologic treatments, a significant proportion of patients do not have an initial response to vedolizumab treatment. Currently, there is a lack of reliable biomarkers for vedolizumab treatment response, although this would help to palliate the socioeconomic costs derived from this disease. For that reason, the primary aim of this study is to establish the basis for the search of transcriptional factors associated with vedolizumab treatment response.

Methods
For the realization of this study, we collected blood samples from responder and non-responder Ulcerative Colitis (UC) patients treated with vedolizumab. The clinical response was measured using the Partial Mayo Score. The frequencies of different immune system populations were analysed by flow cytometry. Moreover, we measured the transcriptional levels of several genes in peripheral blood mononuclear cells (PBMC) by RT-qPCR. These experimental procedures were performed at baseline (T0) and after 14 weeks of follow-up (T14).

Results
We enrolled nine patients with an average age of 46.25±11.71, of which seven were previously treated with anti-TNF therapy. Our results show a specific pattern in responder and non-responder patients in the percentages of different innate and adaptive immune cell populations at T0 versus T14. Similarly, we observed a significant reduction in the expression of some chemokines (i.e., CCL25) and pro-resolutive factors (i.e., ANNEXIN A1) at T14 versus T0 in PBMCs from vedolizumab responder patients, which was not observed in non-responder patients.

Conclusion
Our data suggest that the frequencies of certain immune populations are associated with the response to vedolizumab treatment. In the same way, we found that specific transcripts are modulated in response to this α4β7 integrin antibodies in PBMCs. Therefore, we found a solid system to search for vedolizumab therapy response markers using low invasive techniques.
P032 Host transcriptome signatures in human fecal-washes predict histological remission in IBD patients
Authors: Ungar B , Yavzori M , Fudim E , Picard O , Kopylov U , Eliakim R , Shouval D , Levin Y , Savidor A , Ben-Moshe S , Manco R , Dan S , Egozi A , Bahar Halpern K , Mayer C , Barshak I , Ben-Horin S , Itzkovitz S 
Published: January 2022

Abstract

Background
Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBD), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features. Our aim was to assess the utility of host transcriptomics of fecal wash samples of IBD patients compared to controls.

Methods
In this prospective cohort study, we obtained biopsies and fecal-wash samples from IBD patients and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching fecal-washes, and associated them with endoscopic and histological inflammation status. We also performed fecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes.

Results
We analyzed biopsies and fecal washes from 39 patients (19 IBD, 20 controls). Host fecal-transcriptome carried information that was distinct from biopsy RNAseq and fecal proteomics. Transcriptomics of fecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3*10–12). Fecal-transcriptome was significantly more powerful in identifying histological inflammation compared to transcriptome of intestinal biopsies (150 genes with area-under-the-curve &gt;0.9 in fecal samples versus 10 genes in biopsy RNAseq). Fecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells.

Figure 1 - Fecal-wash host transcriptome predicts histological inflammation. A) Study layout, B) Clustergram of fecal-wash host cell mRNA signatures, demonstrating that patients with histological inflammation (red) are clustered when measuring fecal wash transcriptome yet not biopsy transcriptomes. C-D) Principle Component Analysis demonstrating improved separation of inflamed patients based on fecal host transcriptomes. E, F) Expression of host genes in fecal washes has higher statistical power (Area under the Curve, AUC) in classifying histological inflammation compared to biopsies. D shows NFKBIA as an example, E shows the AUC of the 5% best classifying genes, F shows the overall AUC based on biopsies or washes. Gray areas have AUC&gt;0.9. G) UMAP of cells obtained from scRNAseq of mouse small intestine fecal washes.

Conclusion
Fecal wash host transcriptome is a powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscure using biopsy transctriptomics.
P035 An examination of resting state functional connectivity in patients with active Crohn’s disease
Authors: Thapaliya G , Eldeghaidy S , Radford S , Francis S , Moran G 
Published: January 2022

Abstract

Background
Crohn’s disease (CD) and its comorbidities may be associated with a specific intrinsic neural phenotype that can be measured using resting state functional connectivity (RSFC). RSFC alterations have been reported in CD in remission but have not been investigated in the active phase of the disease. Here, the primary aim was to study the effects of active CD on resting state networks (RSNs), hence identifying RSFC alterations specific to active CD status. A second aim was to investigate associations between disease duration and abdominal pain with RSFC in active CD.

Methods
25 active CD patients and 25 age-, BMI- and gender-matched healthy controls (HC) were recruited. Active disease was defined as CRP &gt; 5 mg/dl, or faecal calprotectin (FCP) &gt;250 μg/g or through ileocolonoscopy or MRE. RsfMRI datasets were acquired on a 3T Philips Achieva scanner, with data corrected for physiological noise and motion. ICA analysis was carried out using MELODIC (FSL software). A multi-session temporal concatenation was used to generate 30 independent component (IC) maps of RSNs. A dual regression analysis with variance normalization, using group IC maps from HC group as the network template, was performed. Differences in RSN between HCs and CD patients and associations with covariates of interest were assessed.

Results
RSNs comprising the visual, cerebellar, frontal parietal and frontal RSN, default mode network (DMN), salience, temporal and dorsal attention RSN were identified. Enhancement of activity and increase connectivity in the medial visual RSN (orbital frontal cortex), in the frontal parietal network (occipital fusiform gyrus, thalamus, caudate, posterior cingulate cortex, postcentral gyrus) were observed in CD relative to HC. Further, decreased activity was seen in the salience network (cerebellum, postcentral gyrus), cerebellar network (occipital fusiform gyrus, cerebellum) and the DMN (parahippocampal gyrus, cerebellum) in CD relative to HC. Greater abdominal pain scores were associated with lower connectivity in the precuneus in the medial visual RSN, in the parietal operculum in the salience RSN, as well as reduced connectivity in the cerebellum in the frontal RSN. Finally, greater disease duration was associated with greater connectivity in the visual RSN in the middle temporal gyrus and planum temporale.

Conclusion
Alterations in RSFC between active CD and HC in RSNs implicated in cognition, attention, emotion and pain may reflect neuroplasticity in response to chronic systemic inflammation, abdominal pain, disease duration and severity. Identification of a neural phenotype specific to active CD status, may help guide intervention constituting a neurobehavioural precision medicine approach to treatment.
P048 Bridging the Gap Between Body and Soul: A Pilot Study Examining Inflammation and Depression / Anxiety in Inflammatory Bowel Disease Patients
Authors: . Mekori - Domachevsky E , Avinir A , Dar S , Haj O , Ben - Horin S , Gothelf D , Kopylov U , Taler M 
Published: January 2022

Abstract

Background
Inflammatory bowel diseases (IBD) have a varied phenotype, among which are increased rates of emotional difficultiesthat were proven to worsen patients’ prognosis. Common to IBD and depression / anxiety is the postulated role of inflammation in their pathogenesis. The aim of this study was to examine whether inflammation per se is linked to depressive and anxious symptoms is a cohort of IBD patients (and is not merely an emotional response to a medical condition).

Methods
Fifty patients with Crohn’s disease (CD) and 30 with ulcerative colitis (UC) were recruited at the gastroenterology department, Sheba Medical Center. They completed a set of questionaries that measured depressive symptoms (BDI), state and trait anxiety symptoms (STAI), stress levels (PSS), IBD quality of life (IBDQ) and sleep quality (PSQI). After which blood samples were drawn and analyzed for C – reactive protein (CRP) and complete blood count. In addition, the ratios between several leukocyte sub-population (that were previously proven to be correlated with IBD as well as depression / anxiety) were calculated, and medical data was obtained from patients’ records. Finally, backwards linear regression was used to determine which factors are associated with the depressive and anxious symptoms.

Results
For the Crohn’s group, predictive factors for depressive symptoms were gender (β = -0.17, p = 0.034), systemic symptoms (β = -0.59, p &lt; 0.001), anxiety levels (β = 0.33, p &lt; 0.001) and platelets to lymphocytes ratio (β = -0.33, p = 0.001). Predictive factors for anxiety were anxiety as a trait (β = 0.89, p &lt; 0.001) and monocytes to lymphocytes ratio (β = 0.20, p = 0.010).
For the UC group, predictive factors for depressive symptoms were emotional functioning (β = -0.77, p &lt; 0.001), systemic symptoms (β = 0.53, p = 0.025) and sleep quality (β = 0.52, p = 0.005). As for anxiety, predictive factors were gender (β = 0.21, p = 0.039), anxiety as a trait (β = 0.59, p &lt; 0.001), depressive symptoms (β = 0.38, p = 0.004) and neutrophil to lymphocytes ratio (β = 0.25, p = 0.017). Intriguingly, CRP only had a single marginal contribution to depressive symptoms in the UC group (β = 0.20, p = 0.098).

Conclusion
Our results suggest that after controlling for demographics, disease activity, medication type and psychological factors inflammation by itself does play a role in the evolution of depression and anxiety in IBD patients. Furthermore, as the leukocytes’ ratios but not CRP had significant predictive values, we postulate that an imbalance between the innate and adaptive arms of the immune system mediates these phenomena, rather than an unspecified immune activation.
P049 The treatment effect of tonsil-derived mesenchymal stem cells (T-MSCs) via regulating programmed death-1/programmed death ligand-1 (PD-1/PD-L1) in ulcerative colitis
Authors: Song E M , Joo Y H , Park Y , Choe A R , Tae C H , Moon C M , Kim S E , Jung H K , Shim K N , Jung S A 
Published: January 2022

Abstract

Background
The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has not been fully evaluated in inflammatory bowel disease. We evaluated the level of PD-1/PD-L1 in the mucosa of patients with ulcerative colitis and revealed the role of PD-1/PD-L1 in the immunomodulatory mechanism of tonsil-derived mesenchymal stem cells (T-MSCs).

Methods
We used chronic murine colitis model induced by dextran sodium sulfate (DSS). We measured the PD-1 and PD-L1 levels in inflamed colonic tissues before and after the treatment with T-MSC. We also measured the levels of PD-1 and PD-L1 in the colonic tissues from patients with ulcerative colitis and compared with those from normal controls.

Results
In chronic colitis model, the level of PD-L1 was decreased than normal controls (fold change) (1.0 vs. 0.46±0.08, P=0.05). However, the level of PD-1 was increased than normal controls (1.0 vs. 6.84±8.16, P=0.142). After treatment with T-MSC which showed significant improvement in body weight, disease activity index and colon length, the levels of PD-1 and PD-L1 were recovered; PD-L1 was significantly increased (1.04±0.77 vs. 0.46±0.08, P=0.031) and the level of PD-1 was decreased (3.63±1.94 vs. 6.84±8.16, P=0.537). When measuring the level of PD-1 and PD-L1 in both soluble medium and cell lysate of T-MSC, we found that the PD-1 and PD-L1 were expressed in both forms (182.63 pg/ml in soluble medium and 11.85 pg/protein(ug) in cell lysate after 7 days of differentiation period). In the analysis using human colonic tissues, a significantly increase in the levels of PD-1 and PD-L1 was observed in the colonic mucosa of patients with UC compared with normal controls (PD-1: 2.09±3.95 vs. 7.93±14.21, P=0.034 and PD-L1: 2.24±2.91 vs. 10.08±18.13, P=0.044).

Conclusion
The altered expression of PD-1 and PD-L1 in colonic mucosa may a possible mechanism of ulcerative colitis and T-MSC-derived PD-L1 could repress the colitis.
P056 Local nanocarrier delivery of JAK1 siRNA for IBD treatment: an in vivo mouse model
Authors: Garrido Trigo A , Veny M , Dotti I , Esteller M , Sulpice E , Jary D , Clément F , Gidrol X , Navarro F , Salas A 
Published: January 2022

Abstract

Background
Janus Kinases (JAK), including JAK1, JAK2, JAK3 and TYK2, have garnered increasing interest as therapeutic targets for several chronic inflammatory diseases such as inflammatory bowel disease (IBD). Although oral small molecule JAK inhibitors are being used in the clinics as an effective treatment for moderate-to-severe ulcerative colitis, nonethelessthey can lead to severe systemic immunosuppression, which is associated with an increased risk of infections. Our project aimed to develop a nanomedicine that induced JAK1 mRNA degradation within the intestinal mucosa with little systemic distribution.

Methods
The NEWDEAL project (H2020) developed both potent small interfering RNAs (siRNA) specific for JAK1 (siJAK1) or TNF (siTNF), and lipid nanoparticles (CL40) as nano-vectors. Their biodistribution in a mice colitis model was analyzed using labeled AF488-siJAK1 complexed to CL40 and given intrarectally (IR) for 3 consecutive days. In vivo cellular uptake was determined by FACS analysis. To induce colitis, C57/Bl6 mice received 2.5% dextrate sulfate sodium (DSS) in drinking water for 5 days. To determine efficacy of siRNAs, mice started DSS on day 0 and received IR administrations of siRNAs alone or complexed with CL40 nanoparticles on days -3, -2, -1, 1, 3, 5 and 7. On day 9, mice were sacrificed and disease activity index (DAI), histological score, fecal inflammatory markers and qPCR of targeted genes were analyzed.

Results
Colonic phagocytic cells - such as macrophages, neutrophils and monocytes - are the main targets cells of the siRNA-CL40 nanocomplexes following IR administration. A small percentage of cells in the draining lymph nodes captured siRNA CL40 nanocomplexes, remaining almost undetectable in spleen. This suggests a localized effect of the siRNA nanocomplexes after IR administration. While siJAK1-alone effectively reduced JAK1 mRNA expression in the distal colon, it did not improve intestinal inflammation induced by administering DSS. siTNF-CL40 treatment, though not siTNF-alone, significantly decreased intestinal inflammation in the DSS colitis model of treated mice, revealing significant protection from weight loss, lower histological scores, and reduced production of fecal lipocalin.

Conclusion
In summary, these results show that despite effectively reducing JAK1 mRNA expression, siJAK1 administration does not ameliorate colitis in a DSS mice model. However, we showed that a locally delivered siTNF-nanocomplex has the capacity to improve clinical, macroscopic and histological symptoms as well as fecal biomarkers in DSS colitic mice. We conclude not only that siRNA-CL40 target delivery is a good therapeutic strategy, but also that siTNF-CL40 is effective in locally treating intestinal inflammation.
P057 Mucosal microbiota adapts to ATF6-induced alterations in host lipid metabolism with prognostic value in colorectal cancer
Authors: Bierwirth S , Sorbie A , Coleman O , Reuß E , Weber P , Köhler N , Kacprowski T , Dunkel A , Pauling J , Ecker J , Baumbach J , Rosenstiel P , Steiger K , Wirbel J , Zeller G , Janssen K P , Haller D 
Published: January 2022

Abstract

Background
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. The endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) is a clinically relevant pre-cancerous marker in CRC and colitis-associated CRC. We established the interrelated role of the microbiota and ATF6 signalling as a novel tumor-promoting mechanism in our transgenic mouse model of spontaneous microbiota-dependent ATF6-driven CRC (nATF6IEC).

Methods
To elucidate the transcriptional program initiated by acute and chronic ATF6 signalling, mRNA sequencing analyses of murine colonic intestinal epithelial cells were performed 4 days or 5 weeks after induction of ATF6, respectively. Germfree (GF) mice served to dissect microbiota contribution to the transcriptional response. CRC patient datasets (TCGA) were used to estimate ATF6 activity and validate ATF6-driven signatures. To investigate the impact of ATF6 signalling on metabolites, untargeted metabolomics of faeces and targeted lipidomics of tissue were performed. Mucosal microbiota was spatially characterised by 16S rRNA profiling at mm resolution along the colonic longitudinal axis. Based on 16S rRNA data, Phylogenetic Investigation of Communities Reconstruction of Unobserved States (PICRUSt2) was used to infer microbiota lipid-specific functional content.

Results
We identified an ATF6-UPR core of 368 differentially expressed genes fully activated by acute ATF6 signalling. Functional analysis using KEGG pathways showed that chronic ATF6 signalling predominantly alters UPR-related and metabolic pathways, with 22% of metabolic pathway genes classified as lipid metabolism. GF mice confirmed that the microbiota enhances ATF6-induced metabolic changes. Kaplan-Meier analyses significantly associate our microbiota-dependent ATF6-driven and lipid-specific ATF6-driven gene signatures with decreased disease-free survival in CRC patients since primary therapy. Moreover, ATF6 activity correlates with the presence of CRC-associated bacteria in TCGA samples. Tumor-susceptible mice show alterations in lipid metabolites, particularly long-chain fatty acids (FA) and elongation of saturated FA. PICRUSt2 revealed bacterial lipid detoxification mechanisms, with an increased total abundance of oleate hydratase-positive species.

Conclusion
Chronic ATF6-signalling alters host lipid metabolism and the lipid milieu in tumor-developing nATF6IEC mice. ATF6-driven microbiota changes are concomitant with bacterial lipid detoxification mechanisms in the tumor niche. We postulate that chronic ATF6 signalling represents a clinically relevant pathologic response that alters the intestinal lipid milieu and thus selects for a tumor-promoting microbiota.