Protein Signatures for Predicting Future Crohn Disease and Ulcerative Colitis Diagnoses

Specific protein signatures could predict a future diagnosis of Crohn disease and ulcerative colitis, potentially enabling earlier intervention and improving patient outcomes. | Image Credit: Kiattisak - stock.adobe.com

Researchers identified and validated specific protein signatures that could enable the early prediction of Crohn disease and ulcerative colitis, offering a novel avenue for proactive intervention in inflammatory bowel disease (IBD), according to a study published in Gastroenterology.1

Inflammatory bowel disease (IBD) occurs when a range of genetic and environmental risk factors result in a dysregulated immune response. Clinicians can confirm an IBD diagnosis through blood tests, stool samples, endoscopic procedures, a colonoscopy, different methods of imaging tests, and various other studies, including surgery.2 A preclinical period, characterized by systemic subclinical inflammation, disrupted barrier function, the development of antibodies to microbial antigens, and potentially autoantibodies, usually follows an IBD diagnosis.1

Patients with IBD often respond incompletely to medication, and the existing therapies are unable to reverse the progressive nature of the disease. Doctors commonly prescribe 5-aminosalicylic acids, corticosteroids, immunomodulators, antibiotics, and biologics to patients with Crohn disease and ulcerative colitis.3 Some biologics, which researchers grow in a lab to halt inflammation, include adalimumab, infliximab, and ustekinumab.4

Researchers analyzed preclinical biobanked blood samples from large, population-based cohorts to identify predictive protein signatures in a discovery cohort and they validated their performance in an external, independent cohort.1

Overall, the median time from sampling to a diagnosis of IBD was 8.7 years for Crohn disease and 7.2 years for ulcerative colitis. In the discovery cohort, researchers associated 34 proteins with preclinical Crohn disease. A signature of 29 proteins in the discovery cohort differentiated preclinical Crohn disease cases from controls, with an area under the curve (AUC) of 0.85 (95% CI, 0.78-0.93).

The corresponding analysis of preclinical ulcerative colitis identified 45 proteins that were differentially regulated in the preclinical discovery Malmö diet and cancer cohort. Additionally, the predictive capacity remained high (AUC, 0.87; 95% CI, 0.77-0.97) when researchers applied the model to the preclinical validation cohort.

The performance of the logistic regression model increased toward diagnosis in the preclinical cohorts. Researchers observed a high predictive capacity when they restricted the analysis of the discovery cohort to samples that were more than 16 years prior to diagnosis (AUC, 0.82). The model for preclinical Crohn disease performed better for men (AUC, 0.99; 95% CI, 0.98-1.00) compared with women participants (AUC, 0.76; 95% CI, 0.57-0.94). Researchers observed no significant differences when they stratified the analyses for age at inclusion.

The logistic regression signature predicted ulcerative colitis with a numerically higher capacity within the preclinical discovery cohort (AUC, 0.77; 95% CI, 0.71-0.83) compared with the preclinical validation cohort (AUC, 0.67; 95% CI, 0.59-0.76).

The stratified analyses indicated that the preclinical ulcerative colitis signature performed better for older (AUC, 0.79; 95% CI, 0.69-0.90) than younger participants (AUC, 0.55; 95% CI, 0.42-0.68) in the preclinical validation cohort. The logistic regression model demonstrated a high discriminatory capacity for newly diagnosed ulcerative colitis cases in the inception cohort (AUC, 0.95; 95% CI, 0.92-0.99). The logistic regression model had a lower capacity to differentiate between Crohn disease and ulcerative colitis in newly diagnosed patients (AUC, 0.67; 95% CI, 0.59-0.74).

Researchers analyzed preclinical Crohn disease and external twin controls, with the logistic regression model yielding an AUC of 0.89. When researchers accounted for genetic and shared environmental factors, including matching twins with preclinical Crohn disease to their healthy twin siblings (P = .04), the predictive ability reduced to an AUC of 0.58. Researchers must interpret these findings with caution, but they do indicate that genetic and shared environmental factors may have a predominant influence on the predictive logistic regression protein signature.

Researchers observed only a minor difference in predictive performance when they contrasted preclinical ulcerative colitis against unrelated twin controls (AUC, 0.74) and against their healthy twin siblings (AUC, 0.58). This finding indicates genetic and shared environmental factors have a limited impact on the logistic regression protein signature of ulcerative colitis.

Study limitations include reliance on a case control design, which requires researchers to consider alternative study designs. Although inflammation is a hallmark of both Crohn disease and ulcerative colitis, differences in immune pathway involvement and cellular responses between the two subtypes of IBD could cause varying expression levels of specific markers. The preselection of proteins could also lead to a more robust signature for Crohn disease, as the chosen protein markers may align more closely with its pathophysiological processes. Ultimately, the relatively high median age at diagnosis in the preclinical cohorts limits the study. Researchers should interpret these findings cautiously when they consider their applicability to younger populations.

“Collectively, these findings support the possibility of prognosticating IBD. The long preclinical period in Crohn disease endorses the adoption of early preventive strategies (eg, dietary modifications and medication) to potentially attenuate disease progression and improve the natural history of Crohn disease,” study authors concluded.

References

1. Olle Grännö, Bergemalm D, Salomon B, et al. Preclinical protein signatures of Crohn’s disease and ulcerative colitis: a nested case-control study within large population-based cohorts. Gastroenterology. 2024;168(4):741-753. doi:10.1053/j.gastro.2024.11.006

2. Inflammatory bowel disease (IBD) - diagnosis and treatment. Mayo Clinic. December 18, 2024. Accessed June 10, 2025. https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/diagnosis-treatment/drc-20353320

3. Medication options for Crohn’s disease. Crohn’s & Colitis Foundation. 2025. Accessed June 10, 2025. https://www.crohnscolitisfoundation.org/patientsandcaregivers/what-is-crohns-disease/treatment/medication

4. Ulcerative colitis - diagnosis and treatment. Mayo Clinic. November 22, 2024. Accessed June 10, 2025. https://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/diagnosis-treatment/drc-20353331