A specific set of inflammatory proteins are upregulated several years prior to a diagnosis of ulcerative colitis (UC). These proteins were determined to be highly predictive of a UC diagnosis and activation of certain proteins appeared to be triggered by exposure to both genetic and environmental risk factors. These findings are based on a case-control study published in Gastroenterology.
The current understanding of preclinical UC is poor. Preclinical assessment of inflammatory proteins may provide important insights into the earlier stages of UC, aid in identifying individuals at increased risk for developing the disease, and be used as a diagnostic tool. This study aimed to characterize the systemic, preclinical inflammatory immune response of UC using a comprehensive set of proteins.
Within a population-based screening cohort, plasma samples were obtained and biobanked from individuals who later in life developed UC (n=72), and matched healthy controls (n=140). In total, 92 different proteins related to inflammation were measured utilizing a proximity extension assay. These findings, in terms of biological relevance, were validated in an inception cohort of patients with UC (n=101) and healthy controls (n=50). To evaluate the influence of genetic and environmental risk factors on these markers, a cohort of healthy twin siblings of patients with UC (n=41) and matched healthy controls (n=37) were investigated.
Single-protein logistic regression models identified 6 specific proteins: stromelysin-2 (MMP10), C-X-C motif chemokine 9 (CXCL9), eotaxin (CCL11), signaling lymphocytic activation molecule 1 (SLAMF1), C-X-C motif chemokine 11 (CXCL11) and monocyte chemotactic protein 1 (MCP1). These 6 proteins were upregulated (P <.05) in preclinical UC and when compared with healthy controls based on both univariate and multivariable models.
The ingenuity pathway analysis identified a number of potential key regulators, including: interleukin-1B (IL-1B), tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), oncostatin M (OSM), NF-KappaB (NFkB), interleukin-6 (IL-6), and interleukin-4 (IL-4).
For validation, a multivariable model was constructed to predict disease in the inception cohort. The model had a high predictive capacity of separating treatment-naïve patients with UC from healthy controls (area under the curve, 0.92).
Consistently, MMP10, CXCL9, CXCL11, and MCP1, but not CCL11 and SLAMF1, were significantly upregulated in healthy twin siblings. However, their relative abundances appeared higher in incident UC.
This study had multiple limitations. The study population consisted of individuals with relatively advanced age at diagnosis, which may potentially limit the generalizability of these findings to all patients with UC. Additionally, there was a lack of multiple prediagnostic samples. Further, in the preclinical cohort, the only samples analyzed were those obtained before the diagnosis of UC, while follow-up samples after the diagnosis of UC in the inception cohort were also not analyzed. Finally, there was a lack of data on potential concomitant immune-mediated diseases and family history of IBD. Additional studies are needed to replicate these findings in independent cohorts.
The study authors concluded, “we identified an upregulation of six plasma proteins indicating activation of both pro-inflammatory and tissue repairing pathways several years before clinically overt ulcerative colitis.”
They added, “Our findings provide novel data on the early sequence of inflammatory events that eventually cause ulcerative colitis since activation of several of the proteins were triggered by exposure to genetic and environmental risk factors. Further knowledge about early disease mechanisms might disclose novel therapeutic targets and may open avenues for disease prediction and interventions to delay or even stop progression to clinically manifest disease.”
Disclosure: Some study authors declared affiliations with the industry. Please see the original reference for a full list of authors’ disclosures.
Disclosure: This research was supported by multiple sources. Please see the original reference for a full list of disclosures.
Bergemalm D, Andersson E, Hultdin J, et al. Systemic inflammation in pre-clinical ulcerative colitis. Gastroenterol. Published online July 20, 2021. doi:10.1053/j.gastro.2021.07.026