Evaluating the therapeutic efficacy of synthetic enzyme inhibitors and complementary alternative medicines in restoring redox and immune imbalance during inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic autoimmune disorder of the gastrointestinal tract. Symptoms include abdominal pain, diarrhoea and weight loss, which significantly impair quality of life and create economic and healthcare burdens. While the exact cause is unknown, IBD is thought to arise from genetic susceptibility, altered gut microbiota and environmental triggers. Patients typically exhibit excessive neutrophil infiltration into intestinal mucosa and elevated formation of neutrophil extracellular traps (NETs), driven by enzymes such as myeloperoxidase (MPO), and peptidyl arginine deiminase IV (PAD4). Additionally, altered short chain fatty acids (SCFAs), oxidative stress, and impaired antioxidant defences create a sustained pro-inflammatory state. Current treatments are limited by poor efficacy, side effects, and high non-response rates, leading patients to explore natural products and nutraceuticals.

This thesis investigates synthetic and natural products as complementary therapies targeting redox imbalance and intestinal inflammation in IBD. Chapter 1 reviews IBD pathogenesis, and current/emerging therapies. Chapter 2 outlines ethics and experimental protocols. Chapter 3 examines synthetic MPO and PAD4 inhibitors in DSS-induced colitis. Chapter 4 compares stool SCFA levels in healthy individuals and IBD patients, linking butyrate depletion with disease severity. Chapter 5 evaluates curcumin, Hedyotis Diffusa and Amomum Villosum in DSS-colitis. Chapter 6 summarises findings and discusses the role of complementary medicines in IBD.

Key outcomes include: PAD4 inhibition reduced mucosal NETs but did not halt colitis progression; stool analysis revealed butyrate peaks in remission but sharp declines with active disease; and natural products improved mucosal healing and reduced lesions, though lipidomic profiles did not fully normalise. Collectively, these results highlight the therapeutic potential of alternative approaches in IBD management.