Development of novel therapies for gut dysbioses

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This thesis reports results of 30 years of systematic clinical investigations carried out by the author in the general area of “infection-driven inflammation”. The Centre for Digestive Diseases (CDD) endoscopy clinic was founded by the author in 1984 closely coinciding with Drs Barry Marshall and Robin Warren reporting gastric spiral bacteria with pathogenic role in ulcer disease. CDD was able to source gastric biopsies with Helicobacter pylori(HP) from numerous patients with ulcer disease creating the environment necessary for HP research. Hence, Section 1 of the Thesis describes systematic studies which asked questions such as ‘which is the best therapy’, ‘what is the role of acid suppression’ and the ‘role of cigarettes’? This culminated in the development of ‘triple therapy’, the first clinically effective HP cure commercialised later as Helidac. Success in HP research soon led to the treatment of the candidate infective cause of Crohn’s disease called Mycobacterium avium subspecies paratuberculosis (MAP). This comprised of three antibiotics which were active intracellularly - another ‘triple therapy’ akin to HP treatment. However, curing HP could be achieved in 7 days and ulcer healing in 6 weeks whereas MAP – one of the slowest growing bacterial pathogens – required treatment for many months to heal the bowel. So in Section 2 of the Thesis the effect of Anti-MAP therapy on healing Crohn’s disease was studied. Funding from the Broad Foundation supported culture and PCR of MAP while an Israeli company, RedHill Biopharma has funded current pivotal trials with a view to an FDA approval. Section 3 of the Thesis describes research in Faecal Microbiota Transplantation (FMT). FMT was first used at CDD in 1988 in a patient with indeterminate colitis - the first patient world-wide treated for colitis and cured. Generally Clostridium difficile infection (CDI) is treated with FMT at CDD with a cure rate exceeding 95%. Subsequently over 6,000 FMT treatments were carried out and new indications for FMT were discovered, both within and outside of the GI tract. These included ulcerative colitis, irritable bowel syndrome, constipation, MS, arthritis, acne, and others, reported in enclosed publications. CDD work in FMT contributed to the global growth of microbiome research and culminated in the creation of the lyophilised encapsulated FMT. Each of the three Sections has addressed “infection-driven inflammation” in different body regions. It is hoped that reported findings in this Thesis will lead to new therapies that will result in significant clinical improvements.
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