Journal of Crohn's and Colitis最新文献

{"title":"Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme","authors":"Laurent Peyrin-Biroulet, Marla C Dubinsky, Bruce E Sands, Julian Panés, Stefan Schreiber, Walter Reinisch, Brian G Feagan, Silvio Danese, Andres J Yarur, Geert R D’Haens, Martina Goetsch, Karolina Wosik, Michael Keating, Krisztina Lazin, Joseph Wu, Irene Modesto, Aoibhinn McDonnell, Lauren Bartolome, Séverine Vermeire","doi":"10.1093/ecco-jcc/jjae038","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae038","url":null,"abstract":"Background and Aims Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Methods Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. Results We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. Conclusions Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Farming activities and risk of inflammatory bowel disease: a French nationwide population-based cohort study","authors":"Pascal Petit, Ariane Leroyer, Sylvain Chamot, Mathurin Fumery, Vincent Bonneterre","doi":"10.1093/ecco-jcc/jjae050","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae050","url":null,"abstract":"Background and Aims Epidemiological data regarding inflammatory bowel disease (IBD) are lacking, in particular for occupationally exposed populations. We investigated whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with IBD than others. Methods Nationwide population-based insurance claims and electronic health records from all FMs that worked at least once over the period 2002-2016 were used (n=1088561, 69% males). The outcome measure was the association between 26 farming activities and the risk of IBD, Crohn’s disease (CD), and ulcerative colitis (UC), measured as hazard ratios (HRs), after adjusting for age, sex, pre-existing medical comorbidities, and farm location. The time to first chronic disease declaration was used as the underlying timescale. A model was generated for every activity and disease, utilizing a reference group comprising all FMs who abstained from the specified activity from 2002 to 2016. Results There were 1752 IBD cases, with 704 CD (40.2%) and 1048 UC (59.8%) cases, respectively. Elevated HRs were observed for fruit arboriculture (HR from 1.17 to 1.52) and dairy farming (HR from 1.22 to 1.46) for all IBD, in crop farming for CD only (HR=1.26 [95CI%: 1.06-1.49]), and in shellfish farming (HR from 2.12 to 2.51) for both CD and IBD. Conclusions Further research regarding specific farming activities and exposures likely to modify the microbiota (e.g., pesticides, pathogens) is required to identify potential occupational risk factors (agricultural exposome) for IBD. Exposure to Mycobacterium avium subspecies paratuberculosis, cryptosporidium, environmental toxins, micro/nanoplastics, and pesticides represents promising research avenues.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical Activity Is Associated With A Decreased Risk Of Developing Inflammatory Bowel Disease: A Systematic Review And Meta-Analysis","authors":"Ho Tuan Tiong, Dali Fan, Chris Frampton, Ashwin N Ananthakrishnan, Richard B Gearry","doi":"10.1093/ecco-jcc/jjae053","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae053","url":null,"abstract":"Background and aims Modifiable risk factors in Inflammatory Bowel Disease (IBD), such as physical activity, may be utilised as prevention strategies. However, the findings of previous studies on the association between physical activity and IBD risk have been inconsistent. We aimed to perform a systematic review and meta-analysis to estimate the effect of physical activity on IBD risk. Methods A search was conducted for relevant studies published before April 2023 that assessed the effect of pre-IBD diagnosis levels of physical activity on IBD incidence. Individual summary statistics (relative risks; RR), and confidence intervals (CI) were extracted with forest plots generated. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. Results 10 observational studies were included. For cohort studies, there were 1,182 Crohn’s disease (CD) and 2,361 ulcerative colitis (UC) patients, with 860,992 participants without IBD. For case-control studies, there were 781 CD to 2,636 controls, and 1,127 UC to 3,752 controls. Compared to individuals with low physical activity levels, the RRs of CD in individuals with high physical activity levels for cohort and case-control studies were 0.78 (95% CI 0.68-0.88, P = 0.0001) and 0.87 (95% CI 0.79-0.95, P = 0.003), respectively. For UC, the RRs were 0.62 (95% CI 0.43-0.88, P = 0.008) and 0.74 (95% CI 0.51-1.07, P = 0.11). Conclusion This meta-analysis suggests that physical activity is inversely associated with the risk of developing IBD, more so in CD than in UC.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic kidney disease in inflammatory bowel disease, a systematic review and meta-analysis","authors":"Ward Zadora, Tommaso Innocenti, Bram Verstockt, Bjorn Meijers","doi":"10.1093/ecco-jcc/jjae049","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae049","url":null,"abstract":"Inflammatory bowel disease (IBD) is associated with various immune mediated disorders including spondylarthritis, pyoderma gangrenosum, primary sclerosing cholangitis and uveitis. Chronic kidney disease (CKD) is defined by a reduction in kidney function (eGFR less than 60ml/min/1.73m2) and/ or damage markers that are present for at least three months, regardless of the aetiology. Case reports and cohort studies suggest that IBD is associated with CKD. The extent and magnitude of a potential association is unknown. A comprehensive search was conducted in EMBASE, MEDLINE, Web of Science, the Cochrane database, and SCOPUS. Two separate reviewers were involved in the process of article selection and evaluation. Odds ratios were calculated in those papers with a comparison between an IBD population and a non-IBD control population, the Mantel Haenszel test was employed, utilizing a random effect model. The systematic review was registered in PROSPERO (RD42023381927). Fifty-four articles were included in the systematic review. Of these, eight articles included data on prevalence of CKD in IBD patients (n = 102,230) vs. healthy populations (n = 762,430). Of these, diagnosis of CKD was based on ICD codes in five studies vs. on eGFR in three studies. The overall odds ratio of developing CKD in the IBD population is 1.59 (95%CI 1.31-1.93), without any difference between studies using diagnostic coding (OR 1.70 95%CI 1.33-2.19) vs. diagnosis based on eGFR (OR 1.36 95%CI 1.33-1.64). IBD is associated with a clinically meaningful increased CKD prevalence. We provide recommendations on diagnostic evaluation, as well as suggestions for future research.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New surgery and hospital-diagnosed infections in elderly patients with inflammatory bowel disease undergoing surgery - a nationwide cohort study","authors":"Bente Mertz Nørgård, Olav Sivertsen Garvik, Floor Dijkstra Zegers, Jan Nielsen, Ken Lund, Torben Knudsen, Jens Kjeldsen","doi":"10.1093/ecco-jcc/jjae047","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae047","url":null,"abstract":"Background Elderly patients with inflammatory bowel disease (IBD) are fragile in many aspects. Therefore, in these patients, we studied post-operative complications (new abdominal surgery and serious infections after the first IBD surgery). Methods This is a nationwide cohort study based on Danish health registries and included patients with IBD undergoing surgery. The study population was split into ulcerative colitis (UC) and Crohn’s disease (CD). The exposed cohort (elderly) constituted those at an age of ≥ 60 years at first IBD surgery, and the unexposed (adults) those with surgery at the age of 18-59 years. We estimated adjusted Hazard Ratios (aHR) of a) new abdominal surgery within 2 years, and b) serious (hospital-diagnosed) infections within 6 and 12 months. We adjusted for several confounders including type of index surgery (laparoscopic or open). Results The aHR for a new surgery among elderly with UC and CD were 0.69 (95% CI 0.58-0.83) and 0.98 (95% CI 0.83-1.15), respectively. In elderly with UC, the aHRs of infections within 6 and 12 months after surgery were 1.07 (95% CI 0.81- 1.40) and 0.85 (95% CI 0.67-1.08), respectively. In the elderly with CD, the aHRs of infections within 6 and 12 months were 1.45 (95% CI 1.12-1.88) and 1.26 (95% CI 1.00-1.59), respectively. Conclusion The elderly with IBD did not have an increased risk of new abdominal surgery within two years of the first surgery. Elderly with CD, but not UC, had an increased risk of serious infections within 6 months of surgery.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fecal Microbiota Transplantation engraftment after budesonide or placebo in patients with active ulcerative colitis using pre-selected donors: a randomized pilot study","authors":"Emilie van Lingen, Sam Nooij, Elisabeth Terveer, Emily Crossette, Amanda Prince, Shakti Bhattarai, Andrea Watson, Gianluca Galazzo, Rajita Menon, Rose Szabady, Vanni Bucci, Jason Norman, Janneke van der Woude, Sander van der Marel, Hein Verspaget, Andrea van der Meulen – de Jong, Josbert Keller","doi":"10.1093/ecco-jcc/jjae043","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae043","url":null,"abstract":"Background Fecal microbiota transplantation (FMT) shows some efficacy in treating patients with ulcerative colitis (UC), although variability has been observed among donors and treatment regimens. We investigated the effect of FMT using rationally selected donors after pretreatment with budesonide or placebo in active UC. Methods Patients ≥ 18 years old with mild to moderate active UC were randomly assigned to three weeks budesonide (9 mg) or placebo followed by four weekly infusions of a donor feces suspension. Two donors were selected based on microbiota composition, Treg induction and SCFA production in mice. The primary endpoint was engraftment of donor microbiota after FMT. In addition, clinical efficacy was assessed. Results In total, 24 patients were enrolled. Pretreatment with budesonide did not increase donor microbiota engraftment (p=0.56) nor clinical response, and engraftment was not associated with clinical response. At week 14, 10/24 (42%) of patients achieved (partial) remission. Remarkably, patients treated with FMT suspensions from one donor were associated with clinical response (80% of responders, p<0.05) but had lower overall engraftment of donor microbiota. Furthermore, differences in the taxonomic composition of the donors and the engraftment of certain taxa were associated with clinical response. Conclusion In this small study, pretreatment with budesonide did not significantly influence engraftment or clinical response after FMT. However, clinical response appeared donor-dependent. Response to FMT may be related to transfer of specific strains instead of overall engraftment, demonstrating the need to characterize mechanisms of actions of strains that maximize therapeutic benefit in ulcerative colitis.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P611 Relation between AntiTNF levels during the induction and clinical and radiological outcomes in perianal Crohn´s disease","authors":"C Amiama Roig, C Suarez Ferrer, E Martin Arranz, J L Rueda Garcia, M Sánchez Azofra, J Poza Cordón, I Gonzalez Diaz, C Amor Costa, M D Martín-Arranz","doi":"10.1093/ecco-jcc/jjad212.0741","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjad212.0741","url":null,"abstract":"Background Perianal Crohn's disease(PCD) significantly impacts quality of life with poor long-term prognosis. Anti-tumor necrosis factor(anti-TNF) therapy improves fistula closure rates. However, achieving permanent closure remains challenging. Our aim is to evaluate the relation between antiTNF(infliximab (IFX) and adalimumab(ADA) serum concentrations at induction(w2 and 6), and clinical and radiological outcomes at w24 and w52 Methods We conducted a single tertiary center, retrospective, cohort study including patients with an established diagnosis of PCD treated with antiTNF because of perianal activity. Variables related to their PCD(phenotype, location, fistulas type) were collected. Regarding treatment, we collected serum levels at week 2,6,24 and 52, concomitant treatment and setons presence. We defined clinical response as the absence of drainage on physical examination and clinical remission as the absence of external fistula openings. Radiological response was defined as the absence of T2 hypersignal, gadolinium enhancement, abscess and proctitis in pelvic MRI Results 65 patients were included, baseline characteristics are in Table1. None of the demographic characteristics collected were statistically significant related to clinical or radiological response although non smokers(p=0.01), ileal(p=0.02) and non-stricturing disease(p=0.01) had statistically significant higher drug levels. Taking into account the clinical response at w52, IFX mean levels at w2 were 25.8µg/mL(SD 4.1) in non responders and 30.9µg/mL(SD 14) in responders(p=0.39). At w6 they were 17.2µg/mL(SD 12.2) and 19.4µg/mL(SD 13.8) respectively(p=0.7). ADA mean levels at w2 were 13.3µg/mL(SD 7.7) in non responders and 14µg/mL(SD 6.3) in responders(p=0.87). At w6 they were 10.1µg/mL(SD 3.3) and 12µg/mL(SD 6.1) respectively(p= 0.59). For radiological response at w52 IFX mean levels at w2 were 27µg/mL(SD 15.3) in non responders and 32.7µg/mL(SD 14.5) in responders(p=0.45). At w6 the mean levels were 15.9µg/mL(SD 6.7) and 23.7µg/mL(SD 14.8) respectively(p=0.27). In ADA group the mean levels at w2 were 14.8µg/mL(SD 7.6) in responders and only one patient did not respond. At w6 ADA mean levels were 12.3µg/mL(SD 5.9) in non responders and 12.7µg/mL(SD 6.2) in responders(p=0.94). Early response at w24 was related with a long-term response at w52, 89.9% of the patients who responded at w52, had already responded at w24. Conclusion In our study we observed that almost 90% of the patients who had an early response also responded at w52, so trying to achieve an early response should be an aim in clinical practice. Despite the limited number of patients, our study shows a trend in the relationship between higher antiTNF levels and clinical and radiological response rates","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139559212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P425 Clinical Characteristics of Steroid-Dependent Ulcerative Colitis Patients after Acute Severe Ulcerative Colitis Treatment in East Asia and Australia/New Zealand: AOCC and ANZIBDC collaboration study","authors":"D H Kim, S H Park, H S Kim, S J Kim, K O Kim, Y J Lee, E M Song, E S Kim, H S Lee, Y K An, J Begun, L Ruddick-Collins, R Fernandes, J Liu, Q Cao, T Kobayashi, S C Wei","doi":"10.1093/ecco-jcc/jjad212.0555","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjad212.0555","url":null,"abstract":"Background Intravenous steroid therapy (IVS) is the main initial treatment for acute severe ulcerative colitis (ASUC). The study aimed to assess corticosteroid dependency after treating ASUC and to explore potential differences between East Asian and Caucasian populations within the steroid-dependent group. Methods Patients from East Asia (China, Japan, South Korea, and Taiwan) and Australia/New Zealand diagnosed with ASUC based on the Trulove and Witts criteria from January 2015 to September 2022 were retrospectively included in the study. We specifically chose individuals responsive to intravenous corticosteroid treatment and divided them into two groups based on steroid dependency. \"Steroid dependency\" was defined as the inability to reduce steroid medication to a dosage below 10 mg/d (equivalent to prednisolone) within three months of initiating steroid treatment or experiencing a relapse within three months of discontinuing steroid therapy. Patients with a history of biologics or small molecules and those currently receiving them were excluded. Results Among 861 patients with ASUC (430 from East Asia and 431 from Australia/New Zealand), 626 received initial IVS, and 381 showed steroid response. Among these steroid responders, 102 patients (26.7%) were classified as steroid-dependent with no significant difference between East Asians and Caucasians (28.3% vs. 24.1%, p=0.44). For 1 year after ASUC, the colectomy rate (7.8% vs. 2.9%, p=0.04) and ASUC relapse rate (18.6% vs. 10.2%, p=0.03) were higher in the steroid-dependent than non-dependent group. For the management of steroid dependency, East Asians mainly repeated steroid treatment (60.9%), while Caucasians mostly switched to infliximab (57.1%). In the Cox regression analysis of 3-year follow-up data for the steroid-dependent group, Caucasians showed a significant increase in colectomy rates (adjusted hazard ratio [aHR] 1.59, 95% confidential interval [CI] 1.12-2.25, p<0.01) compared to East Asians. Additionally, relapse rates increased in Caucasians (aHR 1.37, 95% CI 1.13-1.65, p<0.01), while relapse rates decreased in thiopurine users (aHR 0.32, 95% CI 0.12-0.87, p=0.03). Conclusion Around one-fourth of patients with ASUC who initially responded to IVS became steroid-dependent. East Asians showed a more favorable prognosis compared with Caucasian in this steroid-dependent group.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139559389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P144 Modulation of Immunometabolism via NLRX1 or PLXDC2: Novel Bimodal Mechanisms for the Treatment of Inflammatory Bowel Diseases","authors":"S Danese, J F Colombel, F Rieder, L Peyrin-Biroulet, B Siegmund, S Vermeire, M Dubinsky, S Schreiber, A Yarur, R Panaccione, B Feagan, R Mosig, F Cataldi, B Verstockt","doi":"10.1093/ecco-jcc/jjad212.0274","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjad212.0274","url":null,"abstract":"Background Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism. It controls both intracellular processes and extracellular inflammatory responses by regulating both cellular energy supply & demands, factors that determine how a cell responds to the extracellular signals. Hence, immunometabolic pathways represent an attractive target as a gate of entry & checkpoint for the inflammatory cascade. Nucleotide-binding oligomerization domain, Leucine Rich repeat containing X1 (NLRX1) & PLeXin Domain-Containing protein 2 (PLXDC2) have been identified in immunometabolic pathways for multiple cell types in immune mediated inflammatory diseases (IMIDs) and inflammatory bowel diseases (IBD)2,3. The goal of this analysis was to compare these two key immunometabolic pathways. Methods For both programs, in vitro murine T cell & macrophage differentiation & in vivo mouse dextran sodium sulfate (DSS) colitis models, gene expression, metabolic profiles & cytokine expression were assessed. Results NX-13, a novel NLRX1 agonist, resulted in regulation of cellular metabolism: activation of mitochondrial genes such as mt-nd3 & odgh, and concomitant down-regulation of glucose uptake by murine T cells (Fig1A). Simultaneously, NLRX1 stabilization by NX-13 increased antioxidant enzyme expression & reduced reactive oxygen species in T cells. NX-13 specifically reduced effector T cell differentiation (Fig1B) & inflammatory cytokine expression, while Treg differentiation was increased. Ultimately, these bimodal effects converge to dampened colitis severity scores in acute DSS colitis (Fig1C). PLXDC2 activation by LABP-69 directly reduced glycolysis, reflected by decreased extracellular acidification & oxygen consumption in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS, Fig1D). LABP-69 also reduced superoxide levels in BMDM. Of note, PLXDC2 activation downregulated cellular expression of the inflammatory cytokines TNFα & IFNγ by T cells (Fig1E). The PLXDC2 agonist PX-04 decreased inflammation in acute DSS colitis in mice as shown by disease activity score (Fig1F). Conclusion Agents targeting immunometabolism demonstrate a novel, innovative concept with potential therapeutic applicability in IBD & other IMID. NLRX1 & PLXDC2 represent distinct pathways that modulate the intracellular metabolic state simultaneously with extracellular inflammation and hence can be targeted to break the inflammatory cascade to stop chronic inflammation. These bimodal MOAs will be studied further to understand how they may synergistically address multiple aspects of chronic immune diseases such as IBD. 1Chi Cell Mol Immunol (19) 2Leber et al. J Immunol 203(12) 3Tubau-Juni et al. J Immunol 206(Supp)","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139559427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DOP26 Metagenomic and metabolomic profiles in IBD: understanding microbial and metabolic shifts from a large deeply phenotyped cohort","authors":"B Marius, N Rolhion, L Creusot, A Lefevre, I Alonso, L Brot, C Danne, A Bourrier, L Parrot, D Mélanie, N Benech, I Nion-Larmurier, P Mclellan, C Landman, L Beaugerie, P Seksik, P Emond, J Kirchgesner, H Sokol","doi":"10.1093/ecco-jcc/jjad212.0066","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjad212.0066","url":null,"abstract":"Background Alterations in gut microbiota composition and functions are involved in the pathogenesis of Inflammatory Bowel Disease (IBD) and the role of specific bacterial taxa has been particularly pointed out. The role of microbiota-derived metabolites, including those produced from tryptophan, are major actors in host-microbiota interactions in health and in IBD. Large studies analyzing both gut microbiota and metabolomics data are scarce. Methods In the current study, we analyzed a total of 764 individuals from Saint Antoine Hospital cohort, including 447 patients with Crohn's disease (CD), 262 patients with Ulcerative Colitis (UC) and 55 healthy subjects. We performed shotgun metagenomic sequencing on fecal samples and integrated the results with deep clinical phenotyping and targeted metabolomics data encompassing 294 different molecules. Results We observed strong changes in the taxonomic composition and functional capabilities of the microbiota in CD and UC patients compared to healthy subjects. Besides disease itself, the most important drivers of microbiota composition were the disease location (Montreal classification), recent antibiotic treatment, disease activity (flare vs remission) and history of ileocecal resection. Interestingly, IBD diagnosis explained much more the variations of microbiota functions than taxonomy. The decrease in microbiota diversity was stronger in CD than in UC. In parallel to a decreased amount of Faecalibacterium in IBD, we also observed a decrease in the diversity of Faecalibacterium strains, with a stronger decrease in CD. Our multifactorial analysis revealed specific microbial taxa and functions affected by disease-related factors. We particularly identified many correlations between tryptophan metabolites and microbial abundance. Targeted gene analysis of tryptophan-related enzymes in metagenomes further supported these findings. A network analysis considering bacterial taxa and metabolites revealed profound alterations in IBD with some specificities between CD and UC. Conclusion We pointed out new microbiome and metabolome alterations associated with IBD, with some phenotype specificities. Overall, our findings provide crucial information and a substantial resource for understanding the interactions between the host and microbiome in the context of IBD.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139559729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}