Exploring interactions between host and gut microbiota in ulcerative colitis and primary sclerosing cholangitis associated inflammatory bowel disease: An appraisal through faecal microbiota transplantation and systems biology

Quraishi, Mohammed Nabil ORCID: 0000-0003-2338-8397 (2020). Exploring interactions between host and gut microbiota in ulcerative colitis and primary sclerosing cholangitis associated inflammatory bowel disease: An appraisal through faecal microbiota transplantation and systems biology. University of Birmingham. Ph.D.

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Abstract

Inflammatory bowel disease (IBD) has progressively become a global epidemic and now affects nearly 0.5% of the Western population. The aetiological factors that initiate and drive mechanisms associated with IBD remain unclear. A cure has been even more elusive. Changes in the gut microbial diversity and profiles in individuals with this disease is a characteristic feature, however a causal relationship has yet to be proven. In my PhD I have attempted to explore host-microbiota interactions and its influence on mechanisms of ulcerative colitis (UC) and primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD).

Patients with UC have a greater abundance of Clostridiaceae at inflamed compared to non-inflamed sites. Immunophenotyping demonstrated significantly higher proportions of colonic mucosal Th17 and IL-17 producing CD4 cells in patients with UC and PSC-IBD compared to healthy controls. Through an open label study (STOP-Colitis pilot phase), I demonstrated that faecal microbiota transplantation (FMT) resulted in a clinical response in 47% of patients (8/17; intention to treat). This response was associated with a significant increase in colonic mucosal regulatory T cells (Treg), effector memory Tregs, gut homing Tregs and IL-10 producing CD4 T cells population along with a concurrent decrease in Th17, IL-17 producing CD4 T cells and CD8 populations. Colonic mucosal transcriptomics revealed that responders to FMT had significant downregulation of antimicrobial defence and proinflammatory immunological pathways and an increase in butanoate metabolic pathways compared to both baseline and non-responders. Finally, through a multi-omic exploration of colonic mucosal biology, I demonstrated that the gene expression profiles in patients with PSC-IBD was significantly different to UC and was associated with dysregulation of bile acid homeostasis and signalling in association with colonic dysbiosis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):