Human gut commensals support development of ocular autoimmunity in retina-specific T cell receptor transgenic mice

Abstract

Abstract Autoimmune uveitis is a major cause of blindness, in which intraocular inflammation is driven by T cells that target the neuroretina. In a mouse model of spontaneous autoimmune uveitis (R161H), retina-specific T cells are primed in the gut through their transgenic TCR, and trigger disease. To support the relevance to human disease, we examined the development of uveitis and its association with gut microbiota in gnotobiotic R161H mice colonized with gut flora from healthy human donors. We then performed fecal metagenomic sequencing, gut immunophenotyping by flow cytometry and disease monitoring. Our results indicate that human gut commensals support development of autoimmunity in the spontaneous uveitis model. Human flora mice compared to SPF mice harboring normal mouse flora displayed altered intestinal effector and regulatory CD4 T cell profiles, and had decreased fecal metabolites including microbe-derived short chain fatty acids. Microbiome analyses showed that human flora mice retained a distinct but simplified gut microbial community compared to their original donor sample. Mice with high disease scores appeared to harbor more diverse gut flora than those with low scores. Verrucomicrobia, Actinobacteria, and Fusobacteria were enriched in mice with high disease scores, whereas Firmicutes appeared enriched in mice with low disease scores. In-vivo association studies are underway to examine the ability of candidate microbes to modulate autoimmune uveitis. These findings suggest that some taxa of human commensals may have enhancing or suppressive effects on the development of ocular autoimmunity. These candidate microbes can be explored as targets or as probiotics for therapeutic use.