Dataset Information

Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis.

ABSTRACT: Background and Aims:Mucosal appearance on endoscopy is an important indicator of inflammatory burden and determines prognosis in ulcerative colitis (UC). Inflammation induces tryptophan metabolism along the kynurenine pathway (KP) and yields immunologically relevant metabolites. We sought to examine whether changes in serum tryptophan metabolites and tissue expression of KP enzymes are associated with UC endoscopic and histologic disease severity. Methods:Serum and mucosal samples were prospectively obtained at colonoscopy in patients with UC. Mayo disease activity scores, demographics, smoking status, medications, and outcomes were collected. Serum tryptophan metabolites were analyzed using ultra-high performance liquid chromatography (uHPLC), and gas chromatography-mass spectrometry (GC-MS), and enzyme expression was determined by quantitative real-time polymerase chain reaction. Metabolite and enzyme levels were compared by endoscopic subscore, clinical disease activity, time to surgery, and hospitalization. Results:This study included 99 patients with Mayo endoscopic subscores 0-3. Kynurenic acid/tryptophan ratio (KYNA/T) and expression of indolamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase, kynurinase, and kynurenine monooxygenase correlated positively with endoscopic subscore. Adjusting for age of diagnosis, smoking status, disease extent, and medications yielded significant odds of endoscopic inflammation with increasing KYNA/T (OR 1.0015, P = 0.0186) and IDO1 expression (OR 1.0635, P = 0.0215). The highest tertile ratio of KYNA/T had shorter time to surgery (P = 0.009) and hospitalization (P = 0.01) than the lowest. Conclusions:Increasing KYNA/T is closely associated with endoscopic inflammation and predictive of disease outcomes in patients with UC. These findings identify this novel metabolic association and further support the role of the KP in regulating mucosal inflammation in UC. 10.1093/ibd/izy103_video1izy103.video15788135676001.

SUBMITTER: Sofia MA

PROVIDER: S-EPMC6196764 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis.

Sofia M Anthony MA Ciorba Matthew A MA Meckel Katherine K Lim Chai K CK Guillemin Gilles J GJ Weber Christopher R CR Bissonnette Marc M Pekow Joel R JR

Inflammatory bowel diseases 20180601 7

<h4>Background and aims</h4>Mucosal appearance on endoscopy is an important indicator of inflammatory burden and determines prognosis in ulcerative colitis (UC). Inflammation induces tryptophan metabolism along the kynurenine pathway (KP) and yields immunologically relevant metabolites. We sought to examine whether changes in serum tryptophan metabolites and tissue expression of KP enzymes are associated with UC endoscopic and histologic disease severity.<h4>Methods</h4>Serum and mucosal samples ...[more]

PMID: 29796641

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Project description:A major component of aging is chronic, low-grade inflammation, attributable in part by impaired gut barrier function. We previously reported that deletion of ghrelin, a peptidergic hormone released mainly from the gut, exacerbates experimental muscle atrophy in aged mice. In addition, ghrelin has been shown to ameliorate colitis in experimental models of inflammatory bowel disease (IBD), although the role of endogenous ghrelin in host-microbe interactions is less clear. Here, we showed that 22-month-old global ghrelin knockout (Ghrl-/-) mice exhibited significantly increased depressive-like behaviors, while anxiety levels and working memory were similar to littermate wild-type (WT) mice. Furthermore, old Ghrl-/- mice showed significantly increased intestinal permeability to fluorescein isothiocyanate (FITC)-dextran, significantly higher colonic interleukin (IL-1β) levels, and trends for higher colonic IL-6 and tumor necrosis factor-α (TNF-α) compared to WT mice. Interestingly, young Ghrl-/- and WT mice showed comparable depressive-like behavior and gut permeability, suggesting age-dependent exacerbation in gut barrier dysfunction in Ghrl-/- mice. While fecal short-chain fatty acids levels were comparable between old Ghrl-/- and WT mice, serum metabolome revealed alterations in metabolic cascades including tryptophan metabolism. Specifically, tryptophan and its microbial derivatives indole-3-acetic acid and indole-3-lactic acid were significantly reduced in old Ghrl-/-mice. Furthermore, in an experimental model of dextran sulfate sodium (DSS)-induced colitis, Ghrl-/- mice showed exacerbated disease symptoms, and higher levels of chemoattractant and pro-inflammatory cytokines in the colon. Overall, these data demonstrated that ghrelin deficiency is associated with gut barrier dysfunction, alterations in microbially derived tryptophan metabolites, and increased susceptibility to colitis. These data suggested that endogenous ghrelin contributes to maintaining a healthy host-microbe environment, ultimately impacting on brain function.

Project description:BackgroundVariability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC).ObjectiveTo evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated.DesignA two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors.ResultsThere was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity).ConclusionThe Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

Project description:BackgroundThe significance of endoscopic evaluation in the diagnosis and management of ulcerative colitis (UC) has been widely recognized. Over the years, scholars have established several endoscopic scores. Herein, we assessed the clinical application value of the Mayo Endoscopic Subscore (Mayo ES), the Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score, and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score in UC patients, by comparing their correlation with disease activity and their predictive potential for treatment response and clinical outcomes.MethodsUC patients hospitalized from September 2015 to September 2019 were retrospectively analysed. We employed Spearman's rank correlation coefficient to assess the linear association of the assessed endoscopic scores with the clinical parameters. The receiver-operating characteristic curve was applied to evaluate the predictive capabilities of the endoscopic scores for treatment escalation and 1-year readmission.ResultsA total of 178 patients were enrolled; most of them (82%) suffered moderate or severe colitis. Among them, 48 (27%) patients received treatment escalation and 59 (33%) were readmitted within 1 year. The DUBLIN and UCEIS scores demonstrated higher correlations with clinical parameters than the Mayo ES. The DUBLIN scores significantly differed between patients with mild, moderate, and severe colitis (all P < 0.001). The UCEIS scores demonstrated the best predictabilities for treatment escalation and 1-year readmission with an area under the curve of 0.88 and 0.75, respectively. Compared to the UCEIS and DUBLIN scores, the predictive capabilities of the Mayo ES for treatment escalation (both P < 0.001) and 1-year readmission (P < 0.001 and P = 0.002, respectively) were lower. The UCEIS scores exhibited a significant difference between the steroid-responsive group and the steroid-dependent or steroid-refractory group (both P < 0.001), while no significant differences in the Mayo ES and DUBLIN scores were found among the three groups (both P > 0.05).ConclusionThis study demonstrates that both the DUBLIN and UCEIS scores outperform the Mayo ES in assessing disease severity and predicting treatment response and clinical outcomes in UC patients.

Dataset Information

Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis.

Publications

Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis.

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