Microbial genetic variation shapes neurocognitive behavior in sheep

The researchers used Merino sheep as an animal model, systematically collecting samples of their hindgut and ruminal microbiota, plasma metabolites, and neurocognitive behavioral phenotype data. Based on metagenomic sequencing data from fecal and ruminal samples, the authors reconstructed 5,253 species-level metagenomic-assembled genomes (MAGs), including 3,548 previously unreported novel genomes, significantly expanding the microbial genome resources of ruminant digestive tracts.

Based on this database, the study characterized approximately 140 million single nucleotide variation (SNV) sites from 790 species. By associating the phylogenetic evolutionary distances of the 790 species with 21 neurobehavioral trait phenotypes, the study found that hosts harboring different potential strains within the same species exhibited neurobehavioral differences.

Subsequently, by conducting an association analysis between microbial SNVs and host plasma metabolites, the study identified 34 significant associations between SNVs and metabolites, primarily enriched in the Firmicutes and Bacteroidetes phyla, many of which are potential novel species. Metabolites associated with microbial SNVs are primarily related to key physiological processes such as neuroactive regulation and oxidative stress. The authors further integrated the associations between microbial SNVs, metabolites, and phenotypes, identifying 5 metabolites significantly associated with specific SNVs and exploratory behavior. For example, at the 828 position in the bamb gene of Phocaeicola new416, the cytosine base was significantly different from the thymine base in plasma 4-anisic acid levels, and 4-anisic acid showed the strongest correlation with sheep exploratory duration. This mutation may alter protein structure, affecting the biosynthesis of brain-derived neurotrophic factor (BDNF), thereby regulating host exploratory behavior.

This study suggests that microbial genomic SNVs may be important drivers of host phenotypic differences, revealing that microbial genetic variation may influence host neurocognitive behavior by regulating host metabolism. This finding expands our understanding of the "microbiome-metabolism-brain" axis and provides a theoretical foundation for the development of targeted interventions targeting the gut microbiome.