Caudovirales bacteriophages are associated with improved executive function and memory in flies, mice, and humans

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis. [Display omitted] •Specific Caudovirales are linked to better executive function and memory•Caudovirales are associated with specific bacterial composition and functionality•High Caudovirales FMT increases memory and IEG expression in recipient mice•Lactococcal 936 bacteriophage supplementation increases memory in flies Here, Mayneris-Perxachs et al. reveal an association of the dominant bacteriophages with human host cognition in parallel to a specific bacterial composition and functionality. Microbiota transplantation and bacteriophage supplementation increased the memory of recipient mice and flies through the upregulation of memory-promoting genes. This highlights the potential of targeting bacteriophages cognitive improvement.