Microbial Manipulation as a Therapy in Crohn's Disease

Crohn’s disease is a chronic relapsing inflammatory disease of the gastrointestinal tract. Its global incidence and prevalence rates have risen over the last two generations; its burden reflects this rising. Physical, social and psychological morbidity result in reduced quality of life and substantial healthcare utilisation. Crohn’s disease pathogenesis involves genetic susceptibility, immune activation, and a perturbed gut microbial community. The current standard of care, immune suppression, targets only the host immune system. Despite a range of recent novel therapeutic drug classes, a therapeutic plateau persists. Microbial therapeutics offer an alternative approach that targets the antigenic drive of intestinal inflammation. This thesis involves a collection of studies that evaluate the impact of microbial therapies on Crohn’s disease. Systematic reviews of the literature were conducted examining efficacy data for selective and broad microbial therapies in Crohn's disease. The review of probiotics aimed to establish a clinically useful evidence-based guide for practitioners, and the community, given their large commercial presence and widespread use. I conducted the first systematic review of the FMT efficacy data in Crohn’s disease, which has highlighted the absence of high-quality research evaluating this question. The MIRO (Microbial Restoration in Crohn’s disease) study is the first study, using a randomised placebo-controlled trial design, to evaluate whether optimised FMT is effective in inducing or maintaining remission in Crohn’s disease. This innovative and novel therapeutic intervention incorporated FMT as the primary therapy, following antimicrobial and dietary modification “pre-conditioning”. An extensive dataset of symptom scores, dietary and psychological scores, sonographic, biochemical, endoscopic and histological endpoints enabled a comprehensive examination of the impact of FMT on active Crohn’s disease. A trend towards superior FMT clinical efficacy compared to placebo was demonstrated. Endoscopic inflammation, a more objective measure of disease activity, significantly improved in the FMT arm compared to placebo; endoscopy is regarded as the “gold standard” of intestinal inflammation assessment. Supporting these findings, statistically significant improvements in clinical and endoscopic scores from week zero to week eight were demonstrated only in the FMT group. A significant difference in donor effect was demonstrated. This suggests that future studies should consider the potentially greater therapeutic benefit from multi-donor FMT and donor selection based on donor microbial profiles. This world-first study demonstrates that optimised FMT therapy in Crohn’s disease has a promising therapeutic effect and is safe. The microbial analysis plan will enable comprehensive microbiome characterisation analysing microbial diversity, taxonomic composition, and functional profiles in Crohn's disease patients. Comparisons of distinct patterns between FMT responders and nonresponders will be performed, in addition to assessing the relationship between donor engraftment and outcomes. The microbiome response to diet and antibiotics will be determined. Finally, integration of metabolomic and transcriptomics will provide an understanding of the molecular mechanisms driving outcomes. The data in this thesis provide a clear rationale for pursuing further multimodal microbial therapeutics studies. The ongoing data generation from the scientific studies will enable a shift towards personalised medicine, with associated improved Crohn’s disease therapeutic outcomes.

Author dc:creator

• Fehily, Sasha

• Crohn’s disease
• Microbiota
• Faecal Microbiota Transplantation
• Inflammatory bowel disease
• Microbial modulating therapies
• Diet therapy
• Probiotics

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Handle dc:identifier.uri

https://hdl.handle.net/11343/368594

OAI identifier oai:identifier

oai:jupiter.its.unimelb.edu.au:11343/368594