Delineating the causal role of the gut microbiota in experimental colitis

The gut microbiota is altered (dysbiosis) in patients with inflammatory bowel disease (IBD), although it is not currently understood whether this is causal of, or consequential to, disease development. Delineating the nature of these associations is imperative to inform microbiota-based IBD therapeutics. One such avenue is targeting of Enterobacteriaceae expansion, a dysbiotic signature common to murine and human colitis, through tungstate-mediated inhibition of Enterobacteriaceae growth. Although Enterobacteriaceae expansion is common to multiple animal models, tungstate inhibition of Enterobacteriaceae and amelioration of pathology has been predominantly shown in dextran sodium sulfate (DSS) colitis. Thus, in this thesis we aimed to replicate and expand on the therapeutic potential of tungstate in animal models, namely DSS, Helicobacter hepaticus + anti-interleukin-10 receptor (aIL-10R) and Citrobacter rodentium colitis. We found limited effects of tungstate on DSS-induced Enterobacteriaceae expansion and no effects on pathology development across all models. Thus, the ability of tungstate to ameliorate disease appears context-dependent. Although tungstate targets a feature of dysbiosis, it does not inform on the bacteria-bacteria and host-bacteria interactions which underpin disease pathogenesis. The H. hepaticus + aIL-10R model is poised to explore such interactions, as disease is dependent on the presence of other commensals, including the gnotobiotic 12-member Oligo-Mouse-Microbiota (OMM12). In this thesis, we characterise dysbiosis and intestinal metabolite alterations in the H. hepaticus + aIL-10R OMM12 model and show that E. clostridioformis YL32 is a key colitogenic member in this context. This is likely due to interactions between E. clostridioformis YL32 and H. hepaticus, as H. hepaticus upregulates putative virulence gene expression in E. clostridioformis YL32 mice, in-turn associated with changes in host inflammatory gene expression. Importantly, these interactions are therapeutically targetable as selective depletion of E. clostridioformis YL32 reverts established colitis. This work serves as proof of concept that microbiota inter-bacterial and host-bacterial interactions serve as novel therapeutic strategies for IBD.