Reversal of Gut Microbiota Dysbiosis to Improve treatment for autoimmune vasculits

Anti Neutrophil Cytoplasmic Antibody (ANCA) Vasculitis is an autoimmune disease characterised by inflammationof the small blood vessels that induces glomerulonephritis, a severe inflammatory kidney disease. Immunosuppressive treatment results in severe side effects and 30% of patients relapse, become dialysis dependent or die. There is a significant need for new, safer therapies with less side effects. An altered gut microbiota is associated with relapses in other autoimmune conditions, however it is unknown whether gut microbial dynamics influence immune responses in ANCA vasculitis. This study will determine whether the gut microbiota of ANCA vasculitis patients is altered at different stages of disease. To test causality of microbiome perturbations in immune responses in ANCA vasculitis, we will transplant human faecal samples from patients from first diagnosis, remission and relapse into an experimental model of ANCA vasculitis. Short chain fatty acids (SCFAs) derived from the fermentation of dietary fibre by colonic bacteria can modulate immune responses. Our preliminary data demonstrates that a high fibre diet (HFD) as a therapeutic intervention can skew the inflammatory response towards tolerance, with a reduction in kidney injury, glomerular neutrophil accumulation and neutrophil extracellular traps (NETs)-critical components of the immunopathogenesis of ANCA vasculitis. This project will use both a high fibre diet and treatment with SCFAs (butyrate, acetate and propionate) as therapeutic interventions to ameliorate inflammation at different stages of disease in our experimental model of ANCA vasculitis. This project will use proteomic, metabolomic and immunological endpoints to define protective gut microbiota versus dysbiosis of the microbiota in both patients and experimental models of ANCA vasculitis. This work will provide pre-clinical evidence that dysbiosis and manipulation of the gut microbiome can influence immune homeostasis and improve treatment options.