Abstract
The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn’s disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD.
Highlights
In clinical practice, the therapeutic response of patients with ileal Crohn’s disease frequently differs from that of patients with extensive CD-associated inflammation of the colon
Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD
Local Intestinal Tissue Inflammation in Patients with CD Is Characterized by Immune Cell Infiltrates and Varies According to Anatomic Localization. Following their classification according to the Riley score, the intestinal biopsies were subjected to immunohistochemical screening for detection of immune cell infiltrates in order to characterize the type of inflammation. The aim of this analysis was to determine the extent to which TRP-relevant enzymes are carried to the site of inflammation by immune system cells and to compare in detail the mucosal immunological profiles of patients with CD inflammation affecting different bowel regions
Summary
The therapeutic response of patients with ileal Crohn’s disease (iCD) frequently differs from that of patients with extensive CD-associated inflammation of the colon. Disease localization has been unequivocally linked to differing clinical outcomes in patients with CD, the mechanisms behind this differential pathology are still unclear. In this context, the identification of a biomarker capable of clearly differentiating the phenotypes of CD would represent a crucial step on the way to an individualized, patient-specific therapy optimized to achieve complete mucosal healing, a central therapeutic goal of CD therapy
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