CHIKV_Microbiome. Gut microbe-derived short-chain fatty acids regulate inflammation in musculoskeletal tissues after alphavirus infection

Although the intestinal microbiota can regulate autoimmunity and antiviral immunity, the basis for this remains poorly understood. Here, we show in mice that depletion of the intestinal microbiome with oral antibiotics results in exacerbated musculoskeletal inflammation after infection with chikungunya virus (CHIKV), an arthritogenic alphavirus. Antibiotic-induced gut dysbiosis leads to intestinal permeability and joint inflammation, and occurs independently of viral burden. Joint swelling depends partially on MyD88 expression in intestinal epithelium, with contributions from Toll-like receptor 4, monocytes, and bystander CD4+ T cells. Germ-free mice do not exhibit the enhanced alphavirus-induced inflammatory arthritis seen after microbiota depletion. Finally, antibiotic-treated mice colonized with single bacteria that generate short-chain fatty acids or treated with exogenous short-chain fatty acids show diminished musculoskeletal inflammation during CHIKV infection. Thus, intestinal microbes and their metabolites regulate the pathogenesis of viral arthritis through an interplay between intestinal epithelial cells, pattern recognition receptors, and immune cells.