Systemic inflammation in pre-clinical ulcerative colitis.

BACKGROUND AND AIM: Pre-clinical ulcerative colitis is poorly defined. We aimed to characterize the pre-clinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.

METHODS: We obtained plasma samples, biobanked from individuals who later in life developed ulcerative colitis (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 biological relevance of these findings were validated in an inception cohort of ulcerative colitis patients (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 ulcerative colitis patients (n=41) and matched healthy controls (n=37) were explored.

RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP1) were upregulated (p<0.05) in pre-clinical ulcerative colitis compared to controls based on both univariate and mulativariable models. Ingenuity Pathway Analyses identified several potential key regulators, including IL-1b, TNF, IFN-gamma, OSM, NFĸB, IL-6 and IL-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve ulcerative colitis patients from controls with leave-one-out cross-validation (AUC=0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly upregulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.

CONCLUSIONS: A set of inflammatory proteins are upregulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be upregulated already at exposure to genetic and environmental risk factors.