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.

Automated summary

Growing evidence suggests a connection between the gut microbiome and cognition, with viruses as a commonly overlooked component of the gut virome. This study found that higher levels of Caudovirales and Siphoviridae in the gut microbiome were associated with better executive processes and verbal memory, while increased Microviridae levels were linked to greater impairment in executive abilities. Transplanting microbiota with specific high levels of Caudovirales resulted in improved memory performance in mice and up-regulated memory-promoting genes in the prefrontal cortex. Adding lactococcal Siphoviridae phages to the diet of fruit flies also enhanced memory scores and upregulated memory-related brain genes. These findings suggest that bacteriophages play a role in the microbiome-brain axis.