Association of Gut Microbiota with Spontaneous Autoimmune Uveitis Studied by Human Flora Reconstitution of Germ-free Mice

Abstract

Purpose : Autoimmune uveitis is a T cell driven intraocular inflammation that affects the neuroretina and can lead to blindness. In a mouse model of spontaneous autoimmune uveitis (R161H), retina-specific T cells are primed in the gut through their TCR and trigger disease (PMID: 26287682). To support the relevance to human disease, we examined development of uveitis and its association with bacterial taxa in gnotobiotic mice harboring human flora.

Methods : Germ-free (GF) R161H and their wild type (WT) littermates were inoculated with fecal samples from 3 healthy human individuals in separate isolators. Fecal pellets from reconstituted mice and their offspring were collected periodically and subjected to 16S amplicon sequencing. Uveitis scores were determined by histology at termination of the experiment. Diversity analyses and multivariate association of microbiome profiles with disease severity readouts were performed with QIIME2 and R.

Results : Human flora-reconstituted R161H mice developed uveitis with higher scores than GF R161H mice, but lower than unmanipulated specific pathogen-free (SPF) R161H mice or re-conventionalized (ex-GF) R161H mice associated with SPF flora at weaning. Human flora-reconstituted mice retained a simplified gut microbial community compared to the original sample, while maintaining characteristic microbial profiles that differentiated the individual human donors. Gut microbiome of reconstituted R161H mice tended to be more diverse than that of WT littermates. Among R161H offspring, mice with high disease scores appeared to harbor more diverse gut flora than those with low scores. Differentially abundant bacterial taxa were identified between mice with high and low disease scores, providing microbial candidates that might contribute to activation or suppression of autoreactive T cells.

Conclusions : Our results show that healthy human gut commensals can support uveitis in R161H mice. Variations in human microbiome profiles influence the diversity of reconstituted mouse gut flora, and may associate with degrees of autoreactive T cell activation and development of autoimmunity. R161H associated with human gut flora could provide a more translatable platform than mouse flora to explore microbial candidates and products that may modulate autoreactive T cells in uveitis.

This is a 2020 ARVO Annual Meeting abstract.