Uncovering the Role of the Gut Microbiome in Alopecia Areata: A Novel Link Between Environmental Triggers and Autoimmunity. Mus musculus strain:C3H/HeJ

Alopecia Areata (AA) is an autoimmune skin disease affecting the hair follicle. Alterations in the gut microbiome composition and AA were previously reported in people, however, the role of the gut microbiome in AA remains elusive. To study the functional relevance of the gut microbiome in AA, we treated C3H/HeJ mice with a cocktail of broad-spectrum antibiotics (Abx) and found that C3H/HeJ Abx-treated mice were protected from AA. Additionally, using 16S rRNA-seq and untargeted metabolomics we identified an overrepresentation of Ligilactobacillus murinus and its metabolites in the gut, which precede the development of AA. In line with these findings, depletion of L. murinus using a high-salt diet suppressed L. murinus and significantly attenuated AA. Mechanistically, we found that both Abx, as well as a high-salt diet, suppressed the generation of pathogenic NKG2D+CD8+ T cells in C3H/HeJ mice, which were previously shown to be both necessary and sufficient in AA. To study the effects of the gut microbiome on the priming of NKG2D+CD8+ T cells, we analyzed the composition of immune cells in Abx-treated mice using combined scRNA-seq and scTCR-seq. We identified that the gut microbiome suppresses clonal expansion of pathogenic NKG2D+CD8+ T cells by inhibiting the activation of myeloid-derived antigen-presenting cells in the skin. Additionally, we identified a new population of arginase 1 expressing monocyte-derived dendritic cells, which constitute the perifollicular infiltrate in AA and are suppressed following antibiotic-induced depletion of the gut microbiota. These data define a potential new mechanism by which microbiome dysbiosis contributes to the pathogenesis of AA, and invite new therapeutic approaches for the treatment of this disease.