Gut microbiota drive autoimmunity to neuroretina in a humanized gnotobiotic mouse model of spontaneous autoimmune uveitis 9300

Abstract Description Autoimmune uveitis is a sight-threatening inflammation driven by retina-specific T cells. Using a transgenic mouse model of spontaneous autoimmune uveitis(R161H), we demonstrated that commensal gut flora can provide innate and adaptive immune stimuli that trigger ocular autoimmunity. We now examined whether uveitis-promoting microbes are present in human gut, by colonizing germ-free R161H mice with fecal microbiota from healthy human donors. Human gut commensals supported uveitis development in these mice, albeit with slightly lower disease scores and a reduced gut Teff/Treg ratio than did conventional mouse flora. “Humanized” gnotobiotic mice retained a distinct but simplified gut microbiota compared to their original donor. Higher uveitis scores correlated with a greater microbial diversity and expansion of specific bacterial taxa (Akkermansia), together with lower levels of short-chain fatty acids (SCFAs) and a lower abundance of SCFA-producing bacteria. Furthermore, association with human flora “spiked” with Akkermansia resulted in higher uveitis scores and a more prominent Th1 effector response in the gut. We suggest that Akkermansia may promote uveitis in vivo by outcompeting SCFA-producing microbes and by promoting a Type 1 inflammatory response. In conclusion, both stimulatory and inhibitory microbes are present in normal human gut flora and can modulate ocular autoimmunity. Regulatory components from the gut are being examined to inform microbiome-directed therapies. Funding Sources NIH/NEI Intramural funding, project # Z01 EY000184 NEI Bench-to-Bedside award – NEI Germ Free facility Topic Categories Mucosal and Regional Immunology (MUC)