IBS stress reactivity phenotype is associated with blood transcriptome profiles and microstructural and functional...

Evidence suggests significant interindividual differences in stress reactivity (SR), but mechanisms and therapeutic implications of these differences are poorly understood. The aim of this study was to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of unprovoked tonic increased sympathetic nervous system (SNS) activation and neuroimaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs). A cross-sectional study design, transcriptomics profiling, multimodal neuroimaging, and psychosocial assessments were obtained in 291 IBS participants and HCs. Unsupervised clustering was applied to derive High and Low SR subgroups across all participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression. The High, compared to Low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Neuroplastic brain changes were observed in the High SR group consistent with an upregulation of ascending arousal systems, sensory processing and integration regions, and functional connectivity changes in the central autonomic network. In IBS, SR moderated sex differences in extraintestinal symptoms. The findings support a model of tonically increased, unprovoked SNS activity as a plausible risk factor for increased reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater likelihood in IBS. These findings may have important implications for personalized treatment interventions in IBS.