The gut microbiota-inflammation-brain axis in end-stage renal disease: perspectives from default mode network

Abstract

The gut-brain axis in end-stage renal disease (ESRD) is attracting more and more attention. However, the mechanism of gut-brain axis based cognitive disorders in ESRD patients remains unclear. The purpose of this study was to investigate the linkages between the gut microbiota, inflammatory cytokines, brain default mode network (DMN) and cognitive function in ESRD patients. Methods: This prospective study enrolled 28 ESRD patients (13 males and 15 females, mean age of 44 ± 14 years) and 19 healthy controls (HCs) (12 males and 7 females, mean age of 44 ± 10 years). All subjects underwent stool microbiota analysis, blood inflammatory cytokines examination, brain MRI scans and cognitive assessments. Resting state functional MRI (rs-fMRI) data were used to construct DMN and graph theory was applied to characterize network topological properties. Two samples t-test was applied for the comparisons between ESRD and HCs. Correlation analysis and mediation analysis were conducted among factors with significant group differences. Results: ESRD patients displayed gut microbiota alterations, increased systemic inflammation and worse cognitive performance compared to HCs (all p < 0.05). Graph analysis revealed disrupted DMN topological organization, aberrant nodal centralities and functional connectivities (FCs) in ESRD patients relative to HCs (all p < 0.05, FDR corrected). Significant correlations were found between gut microbiota, inflammatory cytokines, DMN network measures and cognitive assessments. Mediation analysis found that gut microbiota alteration impaired DMN connectivity by increasing systemic inflammation. Conclusion: The present study first revealed gut microbiota alterations, systemic inflammation, DMN dissociation and cognitive dysfunction in ESRD patients simultaneously and further illuminated their inner relationship.

Keywords: default mode network; end-stage renal disease; gut microbiota; inflammatory cytokine; resting state fMRI.

Figure 1

DMN regions and DMN Nodes. The graphs depict the 50 DMN nodes derived from the functional atlas (BN246) that were used for the primary analysis. The picture in the left side shows the DMN map and the picture in the right side shows the ROI selected according to the DMN map. The blue ROIs represent the regions belong to the anterior DMN and the red ROIs represent the regions belong to the posterior DMN. The picture is made using the BrainNet Viewer software (http://www.nitrc.org/projects/bnv). DMN: default mode network; ICA: independent component analysis; ROI: region of interest.

Figure 2

Differences in Global Network Measures of the DMN. The graphs show global network measures of the DMN. The red histogram represents healthy controls and the blue histogram represents ESRD patients. Black asterisks (*) indicate the significant difference between groups (p < 0.05). AUC: area under the curve; DMN: default mode network; ESRD: end-stage renal disease.

Figure 3

Differences in Nodal Network Measures and Functional Connectivity Measures of the DMN. The top half of the picture represents the differences in nodal network measures and the bottom half of the picture represents the differences in functional connectivity measures. The blue nodes and blue lines indicate decreased nodal centralities and functional connectivities. The red nodes and red lines indicate increased nodal centralities and functional connectivities. The abbreviations of the nodal label were explained in the Table S1.

Figure 4

Correlation Networks of Gut Microbiota, Inflammatory Cytokines, Cognitive Assessments and Brain Network Parameters. Graph shows correlations between gut microbiota, inflammatory cytokines, cognitive assessments and DMN parameters with group differences. Green block represents gut microbiota; yellow block represents cognitive function; blue block represents default mode network; red block represents inflammatory cytokine. Link transparency encodes the r value: the lower color opacity corresponds to the smaller absolute r value of the correlation; and the higher opacity corresponds to the larger absolute r value of the correlation.

Figure 5

The Mediation of Systemic Inflammation in the Effect of Gut Microbiota on DMN Topological Architecture in Patients with ESRD. Mediation analysis demonstrates that IL-6 mediates the relationship of Roseburia and aDMN-pDMN connectivity corrected with age and sex (p < 0.001, β = -4.156, 95%CI: [-22.249, 19.258]). DMN: default mode network; IL-6: interleukin-6.