Investigation of Novel Therapies to Modulate Inflammatory and Metabolism Profiles in the Ulcerative Colitis and Irritable Bowel Syndrome

Abstract

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders with overlapping pathophysiologies. Both conditions may be driven by a complex interplay of dysregulated immune responses, dysbiosis, environmental factors and impaired intestinal barrier function in genetically predisposed individuals.

This research aims to: (i) define the need for novel therapies in IBD; (ii) understand the pathogenesis of ulcerative colitis (UC) and IBS; (iii) investigate the mechanisms of action of infliximab in UC; and (iv) evaluate the therapeutic potential of novel natural plant extracts in UC and IBS. We hypothesise that metabolism significantly contributes to mucosal inflammation in these conditions and that natural plant extracts will exhibit anti-inflammatory effects via alteration of metabolic pathways in human colonic explants.

Despite advancements in IBD therapy with biologic and small-molecule agents, there appears to be a therapeutic ceiling of efficacy with single-agent therapy. A combination of two biologic therapies, or a biologic therapy and small molecule agent, with differing mechanisms of action, has the potential to improve IBD therapy outcomes. Information on the effectiveness and safety of this treatment strategy in IBD remains limited.

Following the introductory Chapter 1, Chapter 2 reports a retrospective multicentre study of 109 IBD patients treated with combination biologic or small-molecule therapies. Corticosteroid-free clinical response rates at 12 and 52 weeks were 39% and 38% respectively. Adverse events occurred in 26% of therapeutic trials and were predominantly disease-related. Combination therapy was moderately effective with an acceptable safety profile, highlighting the need for more effective strategies.

Chapter 3 reports assessments of inflammatory and metabolism profiles of healthy controls (HC), UC patients and IBS patients. Twenty-six patients who were undergoing colonoscopy were prospectively recruited in three cohorts (6 HC, 6 IBS, and 14 UC). Recto-sigmoid biopsies were collected, and ex vivo colonic tissue explants were generated and cultured for 24 hours. Baseline real-time energy metabolism profiles and secretion of ten inflammatory mediators were assessed.

We observed that UC and IBS patients exhibited distinct inflammatory and metabolic profiles compared to HC. Active UC was associated with elevated pro-inflammatory cytokines (IL-2, IL-6, IFN-γ, and IL-1β) and dysregulated energy metabolism, with shifts in energy production linked to disease duration. These findings identify novel therapeutic targets for UC.

Chapter 4 investigates whether these profiles were modifiable by an existing therapy (infliximab) and three natural plant extracts with therapeutic potential. Informed by traditional medicinal knowledge and in vitro screening for anti-inflammatory potential, these three plant extracts (Cardamine pratensis (cuckoo flower), Potentilla erecta (tormentil), and Erica tetralix (cross-leaved heath)) were selected for further exploration within the "Unlocking Nature's Pharmacy from Bogland Species" project, overseen by the NatPro Centre, Trinity College Dublin. Colonic explants from each patient recruited in Chapter 3's study were co-cultured with and without treatments (infliximab, cuckoo flower, tormentil and cross-leaved heath).

Our study demonstrated that infliximab reduced TNF-α, IL-12p70, and IL-4 secretion in UC explants. Reduction in IL-4 following infliximab treatment was a novel observation and likely reflects the broader cytokine network modulation that occurs during treatment. The plant extracts exhibited pleiotropic effects, with cross-leaved heath reducing IL-4 and IL-6 in IBS explants, warranting further investigation for its potential application in gastrointestinal and allergy-related disorders.

In conclusion, this thesis underscores the need for innovative therapies in IBD and IBS, expands understanding of metabolism-inflammation interactions in UC, and identifies novel drug targets. The therapeutic potential of cross-leaved heath highlights the promise of natural extracts in addressing unmet clinical needs.