bluuebunny/crossref_metadata_2025_split huggingface dataset:
P038 Microbial regulation of T-cell fate towards regulatory profiles during T-cell transfer induced colitis
Authors: Machicote A , Pelczar P , Nawrocki M , Fazio A , Liu B , Kopplin L , Wende M , Indenbirken D , Pabst O , Strowig T , Gagliani N , Huber S 
Published: May 2021

Abstract

Background
During Inflammatory Bowel Diseases (IBD), CD4+ effector T cells are main mediators of the tissue damage. Among them, Th17 cells strongly contribute to the inflammatory response. Interestingly, our lab previously showed that Th17 cells can convert into regulatory T cells, thereby controlling inflammation. However, the forces controlling the plasticity of T cells during IBD remain largely unknown. Our aim is to understand, how CD4+ T-cell plasticity can be modulated from a pro-inflammatory towards an anti-inflammatory profile during IBD. It is currently known that both Th17 and Foxp3 Treg cells can recognize microbiota-derived antigens and that changes in the microbiota are commonly observed in IBD. We hypothesize that the microbiota is a key candidate to modulate T-cell plasticity.

Methods
T-cell transfer mouse IBD model was performed by transferring CD4+ naïve T-cells into Rag1 -/- receptors. To study Th17 T-cell plasticity, we used as donors IL-17A Fate-mapping mice. These mice comprise of an IL-17ACRE/R26fl/fl YFP construct where the cells that previously expressed IL-17A turn into YFP+ cells. Ciprofloxacin and metronidazole, two antibiotics commonly given to IBD patients, were used to treat the mice. Stool microbiota composition was analysed longitudinally by 16S rRNA amplicon sequencing. Colitis development was evaluated by colonoscopy. CD4+ T cells were isolated from the colon and reporter expression was analysed by Flow Cytometry.

Results
After T-cell transfer colitis induction, ciprofloxacin and metronidazole treatment alleviated gut inflammation, as determined by weight loss (p=0.005), colitis score (p=0.004) and colon length (p=0.01). Antibiotic treatment increased the relative abundance of bacteria previously associated with beneficial IBD outcomes (e.g. Bifidobacterium). Interestingly, colonic CD4+ T-cells showed an increased conversion from Th17 towards a Foxp3+ Treg profile (Foxp3ExTh17) (p=0.03).

Conclusion
The conversion of CD4+ effector T cells into Treg cells is a promising approach to counteract inflammation in IBD patients. We showed that antibiotic treatment not only correlates with a relative expansion of beneficial bacteria, but perhaps most interesting, with an increased conversion of effector Th17 cells towards Foxp3+ Treg cells in the colon. Altogether, these data support the manipulation of the microbiota as a tool to revert intestinal inflammation in IBD patients.
P042 Diagnostic and prognostic value of soluble adhesion molecules in patients with ulcerative colitis
Authors: Tarasova G , Dobaeva N , Iakovlev A , Volkov A 
Published: May 2021

Abstract

Background
Experimental studies have shown that cell adhesion molecules contribute to the constant induction of pro-inflammatory cytokines (interleukin (6, 8, 10), necrosis factor of tumor-α), providing the chronicity of immune-mediated inflammation at ulcerative colitis (UC). Determination of the importance of molecules of integrin adhesion (sVCAM-1) and mucosal adressin (sMAdCAM-1) for evaluating the effectiveness of treatment of patients with UC.

Methods
119 patients with UC were examined: 17 (14.3%) with proctitis, 44 (37%) with left-sided localization, 58 (48.7%) with the total form. The comparison group consisted of 20 healthy volunteers. Determination of serum sVCAM and sMAdCAM was carried out by quantitative enzyme-linked immunosorbent assay (ELISA) based on a system for multiplex analysis using flow fluorimetry — Luminex MAGPIX (USA), ICAM-1 kit (Cusabio, USA). The indicators were assessed before the start of the basic therapy course, in accordance with national recommendations, and 12 weeks after its completion.

Results
In patients with left-sided and total UC, a 3.2 and 4.7-fold increase in sVCAM expression and a 2.8, 3.6-fold increase in sMAdCAM expression was recorded, averaging: 386.6 + 21.2 ng/ml, 623.4 + 11.1 ng/ml; 116.5 + 13.6 ng/ml, 193.8 + 15.2 ng/ml, respectively (p &lt;0.001). In the group with rectal lesions, there was a moderate increase in the expression of adhesion molecules: 157.1 + 11.3 ng/ml, 84.5 + 18.8 ng/ml, respectively (p&lt;0.07). Against the background of a 12-week treatment course, clinical and endoscopic remission was recorded in 84 (70.6%) patients. In the groups of patients with left-sided and total UC in the drug remission phase, there was a decrease in the expression of sVCAM (194.6 + 9.2 ng/ml, 236.7 + 14.1 ng/ml) and sMAdCAM (72.4 + 8.1 ng/ml, 98.2 + 9.7 ng/ml), respectively (p &lt;0.02). In cases with UC activity, increased levels of adhesion molecules persisted.

Conclusion
The soluble adhesion molecules of sVCAM and sMAdCAM are modern markers of inflammation that can be used for assessing the effectiveness of course therapy of UC.
P055 Brain-Immune Axis Regulation is Responsive to Cognitive Behavioral and Mindfulness-Based Stress Reduction in Crohn’s Disease
Authors: Nemirovsky A , Ilan K , Lerner L , Cohen-Lavi L , Schwartz D , Goren G , Sergienko R , Greenberg D , Slonim-Nevo V , Sarid O , Friger M , Regev S , Odes S , Hertz T , Monsonego A 
Published: May 2021

Abstract

Background
Crohn’s disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the pituitary-hypophysis-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month period of Cognitive Behavioral and Mindfulness-Based Stress Reduction (COBMINDEX) impacts their inflammatory process.

Methods
Circulating inflammatory markers (IFN-α, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-18, IL-23, and IL-33) and a wide range of psychological parameters were measured before (T1) and after (T2) COBMINDEX in CD patients. Inflammatory parameters were also compared to age- and sex-matched healthy controls (HCs) at T1, and to wait-list CD patients (at T1 and T2) who were followed for 3 months but did not receive COMBINDEX. Psychological symptoms were assessed by two questionnaires: the Perceived Stress Scale PSS4, and the Brief Symptom Inventory of psychological distress with Global Severity Index GSI. Statistical significance was assessed using Spearman correlation.

Results
CD patients (N=100, mean age 33.6 ± 13 years, 69% female, Harvey-Bradshaw Index mean 31± 55) exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by higher serum levels of interleukin (IL)-6 (mean 4.084± 8.4) and IL-18 (mean 302.09± 286) shown in Figure 1. Notably, IL-18 levels correlated with a higher stress score and a lower wellbeing score in CD patients (Figure 2). COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 (0.32, p&lt;0.05) and INFα (0.36, p&lt;0.05) and correlated negatively with those of MCP-1 (-0.34, p&lt;0.05). Finally, baseline inflammatory markers of CD patients predicted COBMINDEX efficacy, as changes in HBI were negatively correlated with cytokines levels of IFNa (p=0.046), IFNg (p=0.03), IL-10 (p=0.002), IL-23 (p=0.025), IL33 (p=0.009) and IL12p70 (p=0.037) at T1 in the COBMINDEX group, but not in the wait-list group. In addition, basal levels of circulating cortisol at T1 negatively correlated with changes in GSI (-0.33, p&lt;0.05) between T1 and T2 in the COBMINDEX group, but not in the wait-list group.

Conclusion
Our results show that CD patients have a characteristic immunological profile that correlates with psychological stress and disease activity, and predicts COBMINDEX outcomes. We suggest that COBMINDEX induces stress resilience in CD patients, which not only impacts their well-being, but also their disease-associated inflammatory process.
P070 Efficacy of a novel non-covalent oral small molecule Nrf2 activator in a rat model of Inflammatory Bowel Disease
Authors: Murray C , Cooper N , Lucas C L , Manso A S , Ray N C , Worthington J , Fox J C 
Published: May 2021

Abstract

Background
Inflammatory Bowel Disease (IBD) is characterised by chronic inflammation and increased oxidative stress in the intestinal mucosa of patients. NF-E2-related factor 2 (Nrf2) plays a key role in the antioxidant response by regulating the transcription of antioxidant genes as well as reducing expression of inflammatory mediators. A role for the Nrf2 pathway in IBD has been demonstrated in rodent models previously but these studies have predominantly used compounds such as Dimethyl Fumarate that are covalent Nrf2 activators that have the potential for significant off-target activities. C4X Discovery has identified C4X_6746, a novel potent and selective non-covalent Nrf2 activator, that disrupts the interaction between Nrf2 and its repressor Keap1 and is being investigated as an oral treatment for inflammatory disorders.

Methods
Male Han Wistar rats were given 3% Dextran Sodium Sulphate (DSS) in drinking water for 8 days in order to induce colitis and were dosed once daily by oral gavage with vehicle, C4X_6746 (0.3, 3 or 30 mg/kg) or Cyclosporine A (CsA, 20 mg/kg). The Disease Activity Index (DAI) was assessed daily based on stool consistency, faecal blood and body weight. On study termination, the colon weight and length were measured, and additional endpoints assessed (colon macroscopic score, histology, colon markers of inflammation and antioxidant response).

Results
C4X_6746 caused a dose-dependent decrease in the DAI with 30 mg/kg showing similar efficacy to the reference comparator CsA. C4X_6746 (3 and 30 mg/kg) resulted in a statistically significant reduction in the colon weight:length ratio and the macroscopic score. The compound also reduced the DSS-induced histological changes including inflammatory cell infiltrate, epithelial damage and mucosal architecture changes. Analysis of the colon tissue showed that C4X_6746 reduced inflammation (MPO activity) and upregulated the antioxidant response (SOD activity, ratio of reduced:oxidised glutathione). Efficacy of C4X_6746 in the model correlated with the dose-dependent induction of NQO1 mRNA in the colon and blood as a biomarker for Nrf2 pathway activation.

Conclusion
The efficacy of C4X_6746 in the rat DSS model supports development of non-covalent oral Nrf2 activators to significantly reduce oxidative tissue damage and chronic inflammation in IBD.
P087 The role of bile acids in mediating fibrosis in inflammatory bowel disease
Authors: Hazel K , McGinley N , O’Toole A , Keely S 
Published: May 2021

Abstract

Background
Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract that affects approximately 15,000 people in Ireland. 10% of these patients will develop fibrostenosing disease, usually requiring surgery. There are currently no antifibrotic medications in use for the treatment of fibrostenosing CD.
Bile acids (BAs), produced in the liver and classically known for their roles in facilitating fat absorption from the diet, have previously been shown to have the capacity to regulate fibroblast activation and to exert protective effects against both hepatic fibrosis and intestinal inflammation. Therefore, altered mucosal fibroblast function in response to luminal BAs may be an important factor in the pathogenesis of fibrostenosing Crohn’s disease.
Our aim is to determine if treatment of fibroblasts under pro-fibrotic conditions with naturally occurring BAs decreases markers associated with fibrosis.

Methods
NIH/3T3, a murine fibroblast cell line, were treated with TGF-ß (5 ng/ml) to induce their activation and transition to myofibroblasts in the absence or presence of varying concentrations of the naturally-occurring BAs, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) over 24 hours. qPCR was employed to determine expression of alpha-smooth muscle actin (aSMA), an important marker for ECM deposition and fibrosis.

Results
Treatment of fibroblasts with DCA within the range of normal physiological concentrations (50 to 200 µM) induced a significant inhibition of TGF-ß-induced aSMA expression. At a concentration of 100 µM, DCA reduced TGF-ß-induced responses by 50%, compared to cells treated with TGF-ß-alone (RQ=2.17; RQ=4.58, respectively) (n=6) (p=0.0031) (Figure 1). Similarly, treatment with UDCA at supraphysiological concentrations (500 µM) decreased aSMA expression following TGF-ß stimulation (RQ=1.75; RQ=3.69, respectively) (n=5) (Figure 2). Treatment with conjugated BAs TDCA and TUDCA suggest an intracellular mechanism of action by DCA and UDCA. INT-777, the specific agonist of the TGR5 bile acid receptor, also reduced TGF-ß-induced aSMA expression, suggesting this receptor may be involved in mediating the effects of naturally-occurring BAs.
Figure 1:

Figure 2:

Conclusion
We have shown that treatment of fibroblasts under pro-fibrotic conditions with the BAs, DCA and UDCA, results in a significant decrease in aSMA expression. These data suggest that BAs represent a promising target for the development of new anti-fibrotic agents to treat/prevent fibrostenosing CD.
P089 IFNγ-macrophages could mediate EMT in Crohn’s disease
Authors: Marín-Aracil J , Barrachina M D , Bauset C , Cosin-Roger J , Coll S , Calatayud S , Antonio L S , Ortiz-Masiá D 
Published: May 2021

Abstract

Background
Macrophages contribute to fibrosis by releasing different mediators and the pattern of secretion may vary depending on the surrounding environment. We previously described that the mRNA expression of IFNγ was significantly higher in intestinal samples from CD patients. The aim of the present study is to analyze the role of IFNγ-treated macrophages in epithelial mesenchymal transition (EMT).

Methods
The mRNA and protein expression of IFN in surgical resections from Crohn′s disease. U937 were differentiated to macrophages and then treated with IFNγ (2 ng/ml) for 4 days, the mRNA expression of macrophages markers were determined by RT-PCR. IFNγ-U937 were coculture with HT29 cells for 2 days and the expression of EMT markers in HT29 cells were analyzed by RT-PCR and WB. Results are expressed as mean±SEM (n≥5). Statistical analysis was performed by ANOVA + Newman-Keuls.

Results
The mRNA and protein expression of IFNγ were significantly higher in intestinal samples from B2 CD patients (11.4±1.6 fold induction and 3.5±0.3 pg/mg, respectively) and B3 CD patients (14.2±1.8 fold induction and 3.1±0.1 pg/mg, respectively) than in controls (1,0±0,1 fold induction and 0.8±0,1 pg/mg, respectively). U937 cells treated with IFNγ increased significantly the mRNA expression of CD16 (1.9±0.2* vs vehicle) and CD86 (1.6±0.1* vs vehicle). IFNγ-U937 cocultured with HT29 increased significantly the mRNA and protein expression of EMT markers in HT29 cells (Vimentin: 3.0±0.5* vs vehicle-HT29; αSMA: 24.4±8.3* vs vehicle-HT29; SNAIL1: 2.7±0.5* vs vehicle-HT29) respect IFNγ-HT29 cells (Vimentin: 0.6±0.01 vs vehicle-HT29; αSMA: 1.1±0.4 vs vehicle-HT29; SNAIL1: 0.7±0.06 vs vehicle-HT29).

Conclusion
IFNγ could be responsible for the increase in the number of CD86/CD16 macrophages in CD patients. A macrophage phenotype expressing CD86/CD16 may act as a source of EMT mediators in intestinal tissue from CD patients.
P097 Abnormal frailty screening is independently associated with both all-cause and disease-related hospital admissions in older patients with inflammatory bowel diseases
Authors: Asscher V , Waars S , Fens J , Wieland M , van der Meulen-de Jong A , Stuyt R , Baven-Pronk M , van der Marel S , Jacobs R , Haans J , Van Deudekom F , Mooijaart S , Maljaars J 
Published: May 2021

Abstract

Background
Frailty could be useful for risk stratification in older patients with Inflammatory Bowel Diseases (IBD). However, no prospective evidence is yet available. We aimed to assess how frailty screening associates with hospital admissions and functional and (health related) quality of life (HR)QoL decline.

Methods
This is a prospective multicenter cohort study. Consecutive IBD patients aged ≥65 years were included at outpatient departments and infusion centers in six hospitals. Clinical disease activity was assessed through Harvey Bradshaw Index (HBI) or partial Mayo Score (pMS) (remission: HBI&lt;5 or pMS&lt;2), biochemical disease activity by C-reactive protein ≥10 mg/L and/or calprotectin ≥250 µg/g. Frailty screening was performed by Geriatric 8 (G8) questionnaire (abnormal: ≤14). At 18 months, data regarding hospital admissions and mortality were retrieved from medical records and, when possible, verified during follow-up visits. Functional status (Katz Index of Independence in Activities of Daily Living (ADL) and Lawton Instrumental Activities of Daily Living (IADL)) and (HR)QoL (short Inflammatory Bowel Disease Questionnaire and EuroQol-5D) were assessed at baseline and follow-up. Hospital admissions were analyzed with Kaplan Meier and Cox regression, functional and (HR)QoL decline with logistic regression. Analyses were corrected for age and biochemical disease activity.

Results
405 patients were included, median age 70 (IQR 67–74), 85 (21%) clinical disease activity, 93 (23%) biochemical disease activity and 196 (48%) abnormal G8. Until February 2021, 293 (72%) patients were eligible for follow-up: 255 participated in follow-up visits, 38 patients did not (15 not reachable, 16 not willing, 7 died). 74 all-cause and 33 IBD-related hospital admissions occurred. Abnormal G8 was associated with occurrence of both all-cause (adjusted HR 3.9, 95%CI 1.9–7.8, p&lt;.001, Fig. 1) and IBD-related hospital admissions (adjusted HR 4.1, 95% CI 1.4–12.3, p=0.012, Fig. 2). Seven patients died during follow-up; six had abnormal G8. 19 (37%) out of 51 patients with both active biochemical disease and abnormal G8 were hospitalized compared to 4 (14%) out of 29 patients with active disease and normal G8 (p=.026). Abnormal G8 associated with functional (IADL: aOR 3.0, 95% CI 1.3–6.9, P.009, ADL: aOR 1.6, 95% CI 0.7–3.3, p.241) and QoL decline (EQ5D: aOR 2.4, 95% CI 1.4–4.3, p.002), not with HRQoL (sIBDQ: aOR 1.3, 95% CI 0.8–2.2, p=.336).

Conclusion
Abnormal frailty screening independently associates with both all-cause and IBD-related hospital admissions and with functional and QoL decline. Therefore, we provide the first prospective evidence for frailty screening as a useful risk stratification tool in IBD.
P126 Older adults with acute severe ulcerative colitis have similar steroid failure and colectomy rates as younger adults
Authors: Kakkadasam Ramaswamy P , Subhaharan D , Edwards J , Willmann L , Shukla D , Moattar H , Bhullar M , Dorrington A , Ishaq N , McIvor C , Mohsen W 
Published: May 2021

Abstract

Background
There is paucity of data on the outcomes of Acute Severe Ulcerative Colitis (ASUC) in older adults (≥60 years of age). The primary objective of our study was to assess steroid failure rate. The secondary outcomes assessed were need for colectomy during same admission, at 3 and 12months; mortality during admission for ASUC, at 3 months and 12months. Outcomes were compared with younger adults (&lt; 60 years).

Methods
All admissions for ASUC (fulfilling Truelove and Witts Criteria) between January 1, 2013 and July 31st, 2020 at two Australian tertiary IBD centres were retrospectively analysed. Review of electronic medical records was performed and clinical, endoscopic, laboratory data were collected. Non-parametric data were compared using Kruskal-Wallis test. Parametric data were compared using paired t-test.

Results
226 episodes of ASUC were analysed, 45 episodes were in patients who were ≥ 60 years of age at the time of ASUC event. Median Charlston comorbidity index was 3 (IQR: 2–4). In older adults, 19 (42.2%) failed intravenous steroid therapy and required rescue therapy. 2 (10.5%) episodes underwent direct colectomy, 17 episodes received medical rescue therapy (11 infliximab, 6 ciclosporin); 7 (63.6%) episodes received IFX 5mg/kg, 4 episodes (36.4%) received IFX 10mg/kg. 6 (13.3%) episodes had a colectomy during the admission for ASUC; 9 (20.9%) episodes had colectomy within 3 months and 9(20.9%) episodes underwent colectomy within 12 months. In patients &lt; 60 years of age, steroid failure rate was 46.9% (85/181), 10.5% (19/181) underwent colectomy during the same admission, 17.6% (30/181) underwent colectomy by 3 months and 28.8% (42/181) had undergone colectomy at 12 months. In older adults, mortality during same admission occurred in 1 (2.2%) patient, 3-month mortality was 6.8% (3 patients) and 12-month mortality was 11.4% (5 patients). There was no mortality in patients &lt; 60 years of age.

Conclusion
In older adults, steroid failure, the need for colectomy during the same admission and colectomy at 12 months is similar to a population &lt;60 years of age. Mortality (at 3 and 12 months) is significantly higher.
P160 Can the Lemann index at diagnosis predict the risk of early surgery in Crohn’s disease?
Authors: Hassine A , Akkari I , Mrabet S , Ben Jazia E 
Published: May 2021

Abstract

Background
Identifying patients with Crohn’s disease (CD) with rapid disease progression or at high risk for early surgery is a crucial pillar in the treatment decision to ensure optimal patient management. The objective of this study was to assess the correlation between the Lemann index at the time of diagnosis and abdominal surgery in the first year after diagnosis of Crohn’s disease and to find the risk factors for early surgery.

Methods
This is a retrospective study of all patients with CD followed in our center over a period of 4 years (January 2016- January 2020), and who were evaluated by endoscopy and MRI at baseline. The Lemann Index is a score that measures cumulative damage to digestive tissue from entero-MRI and endoscopy data. It was calculated by noting the previous surgery, the location and extension of the disease and any intestinal complications. The sociodemographic and clinical characteristics of the patients were studied. Hypothesis tests were applied to identify associations.

Results
112 patients with CD were included in this study, of which 53.6% were female. The mean age at diagnosis was 33.29 years [15–63]. Active smoking was found in 34 patients (30.4%). Regarding the localization of CD, it was ileal (L1 according to the Montreal classification), colonic (L2), and ileocolonic (L3) in respectively 16.1%, 42.9% and 41%. The disease phenotype was inflammatory (B1) in 60.7%, stricturing (B2) in 21.42%, and penetrating (B3) in 17.85%. Anoperineal manifestations were noted in 24 patients. An upper digestive tract was present in 19.6% of patients. The initial flare was judged to be severe in 33.9% of cases, moderate in 55.4% of cases and mild in 10.7% of cases, with a mean CDAI of 305.21 [115–493]. During the first year after diagnosis of CD, 19.6% of patients (n = 22) required surgical treatment. The indications for surgery were: the presence of an intra-abdominal collection (27.3%), severe acute corticosteroid-resistant colitis (18.2%); ileocaecal stenosis resistant to medical treatment (27.3%) or acute bowel obstruction (27.3%). The LI at diagnosis was much higher in the early surgery group: 5.22 +/- 2.65 vs. 2.63 +/- 1.88; with a statistically significant difference (p = 0.01). A severe initial flare as well as a penetrating phenotype were predictors of early abdominal surgery (p = 0.022, p = 0.024, respectively).

Conclusion
According to our study, a high Lemann score at diagnosis correlates well with the risk of early surgery in Crohn’s disease. Further, larger-scale studies would be needed to establish the reliability of this test in predicting this risk.