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

Abstract

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. ; This work was partially funded by the Instituto de Salud Carlos III (Madrid, Spain) through the project PI15/01934, PI18/01022, PI21/01361) to J.M.F.-R. and the project PI20/01090 (co-funded by the European Regional Development Fund. "A way to make Europe") to J.M.-P., the grants SAF2015-65878-R from the Ministry of Economy and Competitiveness, Prometeo/2018/A/133 from Generalitat Valenciana, Spain and also by the Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Catalan Government (AGAUR, #SGR2017-669, #2017 SGR- 734, ICREA Academia Award 2015 to R.M. and ICREA Academia Award 2022 to J.M.F.R.), the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020), the European Regional Development Fund (project No. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT), and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). CIBERobn is also co-funded by the European Regional Development Fund. We also acknowledge the funding from the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia (Agency for Management of University and Research grants (2017SGR696) and Department of Health (SLT002/16/00250)) to R.M M.A.-R. is funded by the Instituto de Salud Carlos III, Río Hortega (CM19/00190). J.M.-P. is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund "Investing in your future." A.C.-N. is funded by the Instituto de Salud Carlos III, Sara Borrell. MMG was funded by the Spanish Ministry of Science, Innovation and Universities RTI2018-094248-B-I00.