Gut microbial genetic variations are associated with exploratory behavior via SNV-driven metabolic regulation in a...

Host neurocognitive functions are influenced by the gut microbiome, but the role of microbial genetic variation in shaping host neural behavior remains unexplored. Here, we profiled multi-omics data and neurobehavioral phenotypes in a model of 200 Merino sheep. Genomic reconstruction of deeply sequenced fecal and ruminal samples generated 5,253 species-level metagenomic-assembled genomes, of which 3,548 were identified as novel species when compared with existing databases of sheep. Association between strain-level genetic dissimilarities and host neurobehavioral traits showed that phylogenetic differences in 85% of species were associated with exploratory behavior (FDR<0.05). We further associated 146 million microbial single nucleotide variations (SNVs) with 953 plasma metabolites and identified 34 study-wide significant associations (P<2.9×10^-8), which involve potential microbial genetic regulation of host neuroactivity and oxidative stress-related metabolites, including 4-Anisic acid and D-galacturonate. Integrated analysis revealed that microbial SNVs may regulate host cognitive exploration through regulating metabolites via structural modulation of encoded proteins. For instance, we found that novel time- zone entry was associated with 4-Anisic acid, which was determined by SNV via structural regulation of membrane transporters. Our findings suggest that microbial genetic variation plays a critical role in modulating host neurocognition, possibly through metabolite regulation, which provides novel insights for targeted interventions in neurometabolic disorders.