Decoding the Gut‐Brain Axis: Multi‐Omics Reveals a Causal Chain Linking Human Genome, Gut Microbiota, Blood Metabolites, and Alertness in the Brain

ABSTRACT The alerting network modulates internal states to facilitate adaptive responses to external stimuli, typically assessed using the Attention Network Test (ANT). However, the human genomic, gut metagenomic, and blood metabolomic bases of alerting remain poorly characterized in Chinese adults. This study employed a multi‐omics approach—integrating genomic, metagenomic, and metabolomic analyses—to investigate fecal samples, serum, and structural brain MRI data from healthy Chinese adults. We first conducted a genome‐wide association study (GWAS) and identified three suggestive SNP loci, including the OSBPL10 as a candidate gene, along with a gene pathway associated with the alerting network, but none with the other two attention networks (orienting and executive control). We then conducted metagenomic and metabolomic analyses and identified Bacteroides intestinalis as gut microbial taxa potentially linked to alerting, along with the metabolite 5‐oxo‐delta‐bilirubin . Preliminary screening (without false discovery rate, FDR, correction) identified 100 differential metabolites as potentially relevant to alerting, which were used in subsequent exploratory causal modeling. Voxel‐based morphometry (VBM) regression demonstrated that alerting performance was correlated with gray matter volume (GMV) in the orbitofrontal cortex (OFC) and the cerebellum. Finally, we conducted two‐step one‐sample Mendelian Randomization (MR) analyses and found a significant serial mediation pathway: B. intestinalis influences the GMV of OFC and cerebellum through N‐pentadecanoylsphingosine‐1‐phosphocholine and alerting. Collectively, this study uncovers novel genetic determinants of alerting and elucidates causal pathways linking gut microbes, metabolites, attentional function, and brain structure within the gut‐brain axis.