TY - JOUR
T1 - Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis
AU - Sofia, M. Anthony
AU - Ciorba, Matthew A.
AU - Meckel, Katherine
AU - Lim, Chai K.
AU - Guillemin, Gilles J.
AU - Weber, Christopher R.
AU - Bissonnette, Marc
AU - Pekow, Joel R.
N1 - Funding Information:
Conflicts of Interest: M. Anthony Sofia has served as a consultant for Janssen. Matthew A. Ciorba has served as a consultant for UCB AbbVie, Theravance, Gilead, Pfizer, Incyte, and Takeda. Joel R. Pekow has served as a consultant for Verastem and CVS Caremark, an advisory board member for Janssen, and has received research funding from Takeda and AbbVie. Marc Bissonnette, Gilles J. Guillermin, Chai K. Lim, Katherine Meckel, and Christopher R. Weber have no disclosures to report., Supported by: The study was funded in part by the National Institutes of Health grant numbers P30 DK42086, UL1 TR000430, and K08 DK090152 to Joel R. Pekow and RO1DK109384 to Matthew A. Ciorba. The study was funded in part by the Crohn’s and Colitis Foundation of America, grant number #370763 and the Givin’ it all for Guts Foundation (http://givinitallforguts.org/) to Matthew A. Ciorba. The study sponsors were not involved in the study design, collection, analysis, or interpretation of data.
Publisher Copyright:
© 2018 Crohn's & Colitis Foundation. Published by Oxford University Press.
PY - 2018/6/8
Y1 - 2018/6/8
N2 - 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.
AB - 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.
KW - Mucosal healing
KW - Tryptophan
KW - Ulcerative colitis
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U2 - 10.1093/ibd/izy103
DO - 10.1093/ibd/izy103
M3 - Article
C2 - 29796641
AN - SCOPUS:85054204708
SN - 1078-0998
VL - 24
SP - 1471
EP - 1480
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
IS - 7
ER -