The brain-gut-microbiome (BGM) system plays an influential role on mental health. We characterized BGM patterns related to resilience using fecal samples and multimodal MRI. Data integration analysis using latent components showed the high resilience phenotype was associated with lower depression and anxiety symptoms, higher frequency of bacterial transcriptomes (related to environmental adaptation, genetic propagation, energy metabolism, anti-inflammation), increased metabolites (N-acetylglutamate; dimethylglycine), and cortical signatures (increased resting state functional connectivity between reward circuits and sensorimotor networks; decreased grey matter volume and white matter tracts within the emotion regulation network). Our findings support a multi-omic signature involving the BGM system suggesting that resilience impacts psychological symptoms, emotion regulation and cognitive function as reflected by unique neural correlates and microbiome function supporting eubiosis and gut barrier integrity. Bacterial transcriptomes provided the highest classification accuracy suggesting that the microbiome is critical in shaping resilience and highlights that microbiome modifications can optimize mental health.