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<p>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&lt;0.05). We further associated 146 million microbial single nucleotide variations (SNVs) with 953 plasma metabolites and identified 34 study-wide significant associations (<i>P</i>&lt;2.9×10<sup>−8</sup>), 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月18日

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  • Shuai Yang,
  • Beining Ma,
  • Mengke Gao,
  • Jiahua Wu,
  • Dale Pilling,
  • Lin Zhu,
  • Xiuchao Wang,
  • Quanbin Dong,
  • Yifeng Wang,
  • Kelsey Pool,
  • Shane Maloney,
  • Peng Li,
  • Dominique Blache,
  • Luoyang Ding,
  • Lianmin Chen

摘要

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.