Chronic inflammation and its effects in Inflammatory Bowel Disease – study of deep histology, tissue remodelling and biomarkers, with clinical outcomes

Shivaji, Uday Nagesh ORCID: 0000-0002-6800-584X (2025). Chronic inflammation and its effects in Inflammatory Bowel Disease – study of deep histology, tissue remodelling and biomarkers, with clinical outcomes. University of Birmingham. Ph.D.

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Abstract

Inflammatory Bowel Diseases (IBD), mainly comprising of Ulcerative Colitis (UC) and Crohn’s Disease (CD) are chronic inflammatory conditions characterised by phases of remission and relapse, sometimes despite treatment. They can cause significant physical and psychological morbidity, and unfortunately increasing in both incidence and prevalence globally. With better understanding of pathogenesis, better description of immunological pathways, treatment options have increased, in particular immunological therapies that have revolutionised management of IBD. However, patients lose response to most therapies over time and finding newer targets remains a subject of ongoing research.
There are several complications that occur in IBD, and most are considered outcomes of chronic inflammation (CI) in the gut. Uncontrolled CI could be due to late diagnosis, suboptimal therapy, loss of response to therapies, or because inflammation at the tissue level remains obscure and unrecognised. By undertaking research with strong, pragmatic methodology, using advanced technology with a multi-omics approach, and conducting deep immunological analysis of intestinal tissue, I have been able to demonstrate that sustained CI can remain active at the tissue level and indeed has detrimental effects at all stages of disease.
I have conducted a series of retrospective studies in different cohorts of IBD to investigate clinical outcomes of sustained CI. In these studies, I have reported that deep histological analysis shows CI and muscular hypertrophy to be dominant features within CD-related fibrotic strictures; delayed IBD diagnosis in inception patients leads to worse clinical outcomes up to 4 consecutive years; elective and non-elective discontinuation of biological therapy in IBD results in poor clinical outcomes. Using these results, I also designed a prospective study (TRAFIC Study) to investigate molecular signals and biomarkers of CI in IBD.
Applying multiomics to analyse intestinal tissue (post-surgical resection of CD-related strictures), and using immunohistochemistry (IHC) techniques, I have demonstrated that gene expression within the stricture is different compared to non-strictures (margins).
The specific interrogation of the JAK-STAT pathway showed increased gene expression of JAK1, STAT1, STAT2 & STAT3 within the stricture, compared to margins. This suggests that JAK1 inhibitors could have a role as anti-inflammatory therapies for stricturing disease.
IHC of selected novel cytokines Interleukin-33 and Interleukin-36gamma, demonstrated high expression levels within the strictures and margins. By correlating these findings with clinical outcomes, our results suggest that IL-36g could be a potential target of therapy for CD and may also have antifibrotic potential. The therapeutic potential of IL-33 is less clear mainly because of significant pleiotropic effects and cannot be recommended at this time.
Combined detection of IL-33 and IL-36g in resection margins could assist in stratifying patients at risk of early post-operative recurrence, making them potential biomarkers in IBD.
These pathways and cytokines of interest are promising targets of therapy, but further confirmation is essential before harnessing their potential, which is currently underway.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):