Elevated peripheral and nervous system inflammation is associated with decreased short-chain fatty acid levels in Zika virus-infected macaques

Zika virus (ZIKV) infection typically results in mild symptoms; however, it can cause elevated inflammation in the CNS and the development of more serious conditions, including severe neurological syndromes. Previous studies have demonstrated that ZIKV infection may cause mucosal dysfunction as well as elevated inflammation in rectal and vaginal mucosal tissue. Here, we used non-human primate (NHP) models and clinical specimens from ZIKV-infected humans to examine microbiome, inflammation, and microbial translocation in the gut, blood, and CNS. We observed elevated markers indicative of microbial translocation and inflammation in the CNS of ZIKV-infected macaques and humans. While overall taxonomic shifts in microbial communities did not differ, bacterial-derived short-chain fatty acid (SCFA) levels were reduced. Decreased SCFA levels significantly negatively correlated with elevated peripheral and CNS inflammatory markers, suggesting a link between ZIKV-driven disease pathology and microbial function. Taken together, our study provides new insight into a previously unconsidered mechanism underlying ZIKV pathogenesis.IMPORTANCEZika virus poses a significant burden on public health, demonstrated by the 2015-2016 epidemic that remains with devastating health consequences especially in countries such as Brazil. However, the mechanisms that underlie what leads to inflammation of the central and peripheral nervous system and disease in Zika virus have been poorly characterized. Here, we demonstrated that Zika virus resulted in gut microbiome dysbiosis, which led to decreased short-chain fatty acids, increased inflammation, and microbial translocation, likely brought on by reduced gut barrier integrity. This study represents the first evidence that microbial dysbiosis and gut damage may underlie Zika virus pathogenesis and ensuing neurological effects, providing a potential target for intervention for future virus pandemics.