Systemic Inflammation in Preclinical Ulcerative Colitis

Daniel Bergemalm, Erik Andersson, Johan Hultdin, Carl Eriksson, Stephen T. Rush, Rahul Kalla, Alex T. Adams, Åsa V. Keita, Mauro D'Amato, Fernando Gomollon, Jørgen Jahnsen, Jack Satsangi, Dirk Repsilber, Pontus Karling, Jonas Halfvarson, IBD CHARACTER consortium

Research output: Contribution to journalArticleResearchpeer-review

55 Citations (Scopus)

Abstract

Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.

Original languageEnglish
Pages (from-to)1526-1539.e9
Number of pages23
JournalGastroenterology
Volume161
Issue number5
DOIs
Publication statusPublished - Nov 2021

Keywords

  • CXCL9
  • Inflammatory Bowel Disease
  • MMP10
  • Preclinical Disease
  • Proximity Extension Assay

Cite this