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Birdshot retinochoroidopathy occurs exclusively in individuals who are  HLA-A29  positive. The mechanism to account for this association is unknown. The gut microbiome has been causally implicated in many immune-mediated diseases. We hypothesized that  HLA-A29  would affect the composition of the gut microbiome, leading to a dysbiosis and immune-mediated eye disease. Fecal and intestinal biopsy samples were obtained from 107 healthy individuals from Portland, Oregon environs, 10 of whom were  HLA-A29  positive, undergoing routine colonoscopy. Bacterial profiling was achieved via 16S rRNA metabarcoding. Publicly available whole meta-genome sequencing data from the Human Microbiome Project (HMP), consisting of 298 healthy controls mostly of US origin, were also interrogated. PERMANOVA and sparse partial least squares discriminant analysis (sPLSDA) demonstrated that subjects who were  HLA-A29  positive differed in bacterial species composition (beta diversity) compared to  HLA-A29  negative subjects in both the Portland (p = 0.019) and HMP cohorts (p = 0.0002). The Portland and HMP cohorts evidenced different subsets of bacterial species associated with  HLA-A29  status, likely due to differences in the metagenomic techniques employed. The functional composition of the HMP cohort did not differ overall (p = 0.14) between  HLA-A29  positive and negative subjects, although some distinct pathways such as heparan sulfate biosynthesis showed differences. As we and others have shown for various HLA alleles, the HLA allotype impacts the composition of the microbiome. We hypothesize that  HLA-A29  may predispose chorioretinitis via an altered gut microbiome.

HLA-A alleles including HLA-A29 affect the composition of the gut microbiome: a potential clue to the pathogenesis of birdshot retinochoroidopathy