Stress-Resilience Impacts Psychological Wellbeing: Evidence from Brain-Gut Microbiome Interactions

Abstract

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.

Figure 1:. Graphical Summary.

A Demographics shows the CD-RISC (Connor-Davidson Resilience Scale) threshold for group label, and the sample size per group. B Clinical and psychological variables were collected from self-report questionnaires. Metabolites and transcriptomics data were collected from stool samples. Multimodal brain images were collected via magnetic resonance imaging. C Each of the six data blocks were cleaned and prepared as individual datasets. D Data integration for biomarker discovery using latent components as used to create signatures for high and low resilience. E Summary of results. Abbreviations: BMI, body mass index; MRI, magnetic resonance imaging; RNA, Ribonucleic acid; KEGG, Kyoto Encyclopedia of Genes and Genomes; NAG, N-acetylglutamate; DMG, dimethylglycine; Vol, volume; SA, surface area; ERN, emotion regulation network; SMN, sensorimotor network; DMN, default mode network; CAN, central autonomic network; CEN, central executive network; K07335, basic membrane protein A and related proteins; K03315, Na/H antiporter; K01081, 5’-nucleotidase; K07080, uncharacterized protein; K14645, serine protease; K02343, DNA polymerase III subunit gamma/tau; K01596, phosphoenolpyruvate carboxykinase; K01361, lactocepin; K01844, beta-lysine 5,6-aminomutase alpha subunit; K03388, heterodisulfide reductase subunit A2.

Figure 2.. Boxplots of DIABLO-selected Variables of Importance.

Standardized values equate to variables of importance for each dataset between High (blue) and Low (orange) resilience. The line inside each box represents the median standardized value. Each box itself represents the interquartile range which captures 50% of standardized values. The lines extending from each box represent the ranges (extending up to the minimum and maximum) of standardized values outside of the interquartile range. Individual data points beyond the lines are considered outliers. Abbreviations: IPIP, International Personality Item Pool; STAI, Stat-Trait Anxiety Inventory; HAD, Hospital Anxiety and Depression scale; FFM, Five Facet Mindfulness; MASQ, Multiple Ability Self-Report Questionnaire; PSS, Perceived Stress Scale; K07335, basic membrane protein A and related proteins; K03315, Na/H antiporter; K01081, 5’-nucleotidase; K07080, uncharacterized protein; K14645, serine protease; K02343, DNA polymerase III subunit gamma/tau; K01596, phosphoenolpyruvate carboxykinase; K01361, lactocepin; K01844, beta-lysine 5,6-aminomutase alpha subunit; K03388, heterodisulfide reductase subunit A2; K03466, DNA segregation ATPase FtsK/SpoIIIE; K02965, small subunit ribosomal protein S19; K01119, 2’,3’-cyclic-nucleotide 2’-phosphodiesterase / 3’-nucleotidase; K01834, 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase; K05516, curved DNA-binding protein; K07667, two-component system, OmpR family, KDP operon response regulator KdpE; R, right; L, left; SA, surface area; Vol, volume; SbCaG, Subcallosal Gyrus; AngG, Angular Gyrus; InfPrCS, Inferior part of the Precentral Sulcus; VTA, Ventral Tegmental Area; Tha, Thalamus proper; MRF, Mesencephalic Reticular Formation; SuMarG, Supramarginal Gyrus; InfCirIns, Inferior segment of the Circular Sulcus of the Insula; Pal, Pallidum; SbCG S, Subcentral Gyrus and Sulci; SupPL, Superior Parietal Lobule; LORs, Lateral Orbital Sulcus; Pu, Putamen.

Figure 3.. Loading Plots from the DIABLO-selected Variables of Importance.

Loading plots of top contributing variables selected by DIABLO separated by dataset type. Blue represents high resilience; orange represents low resilience. Magnitude of loading coefficient represents the level of contribution for prediction. Greater values represent greater contribution. Abbreviations: MASQ, Multiple Ability Self-Report Questionnaire; FFM, Five Facet Mindfulness; HAD, Hospital Anxiety and Depression scale; IPIP, International Personality Item Pool; PSS, Perceived Stress Scale; STAI, Stat-Trait Anxiety Inventory; K07335, basic membrane protein A and related proteins; K03315, Na/H antiporter; K01081, 5’-nucleotidase; K07080, uncharacterized protein; K14645, serine protease; K02343, DNA polymerase III subunit gamma/tau; K01596, phosphoenolpyruvate carboxykinase; K01361, lactocepin; K01844, beta-lysine 5,6-aminomutase alpha subunit; K03388, heterodisulfide reductase subunit A2; K03466, DNA segregation ATPase FtsK/SpoIIIE; K02965, small subunit ribosomal protein S19; K01119, 2’,3’-cyclic-nucleotide 2’-phosphodiesterase / 3’-nucleotidase; K01834, 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase; K05516, curved DNA-binding protein; K07667, two-component system, OmpR family, KDP operon response regulator KdpE; MRI, magnetic resonance imaging; L, left; R, right; SbCaG, subcallosal gyrus; AngG, angular gyrus; InfPrCS, inferior part of the precentral sulcus; VTA, ventral tegmental area; Tha, thalamus; MRF, mesencephalic reticular formation; SuMarG, supramarginal gyrus; InfCirIns, inferior segment of the circular sulcus of the insula; Pal, pallidum; SupPL, superior parietal lobule; LORs, lateral orbital sulcus; Pu, putamen; SupOcG, superior occipital gyrus; Hip, hippocampus.

Figure 4.. Connectogram Depicting the Correlations within the Variables of Importance from all the Datasets.

Spearman correlations between features across datasets are shown via the lines inside the circle (cutoff r = 0.55). Mean levels of each feature for each group are represented via the lines within each data block forming the circle. A higher line represents a greater mean value for that group. Abbreviations: MRI, magnetic resonance imaging; L, left; R, right; SbCaG, subcallosal gyrus; AngG, angular gyrus; InfPrCS, inferior part of the precentral sulcus; VTA, ventral tegmental area; Tha, thalamus; MRF, mesencephalic reticular formation; SuMarG, supramarginal gyrus; InfCirIns, inferior segment of the circular sulcus of the insula; Pal, pallidum; SupPL, superior parietal lobule; LORs, lateral orbital sulcus; Pu, putamen; SupOcG, superior occipital gyrus; Hip, hippocampus; K07335, basic membrane protein A and related proteins; K03315, Na/H antiporter; K01081, 5’-nucleotidase; K07080, uncharacterized protein; K14645, serine protease; K02343, DNA polymerase III subunit gamma/tau; K01596, phosphoenolpyruvate carboxykinase; K01361, lactocepin; K01844, beta-lysine 5,6-aminomutase alpha subunit; K03388, heterodisulfide reductase subunit A2; K03466, DNA segregation ATPase FtsK/SpoIIIE; K02965, small subunit ribosomal protein S19; K01119, 2’,3’-cyclic-nucleotide 2’-phosphodiesterase / 3’-nucleotidase; K01834, 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase; K05516, curved DNA-binding protein; K07667, two-component system, OmpR family, KDP operon response regulator KdpE.