The gastrointestinal tract contains trillions of microorganisms that exist symbiotically with the host due to a tolerant, regulatory cell-rich intestinal immune system. However, this intimate relationship with the microbiome inevitably comes with risks, with intestinal organisms being the most common cause of bacteremia. The vasculature of the brain-lining meninges contains fenestrated endothelium, conferring vulnerability to invasion by circulating microbes. We propose that this has evolutionarily led to close links between gut and meningeal immunity, to prime the central nervous system defense against the most likely invaders. This paradigm is exemplified by the dural venous sinus IgA defense system, where the antibody repertoire mirrors that of the gut.