Background: Increasing evidences have outlined an important role of the microbiota through the gut–brain axis, bidirectional biochemical signaling that takes place between the gastrointestinal tract and the central nervous system via hypothalamic–pituitary–adrenal system (HPA axis) regulation, in modulating vagal nerve activity, neurotransmitters, and immune-related pathways. Interest in elucidating interactions between certain bacterial strains and brain function has surged, but studies investigating the relationships between gut microbial composition and intrinsic brain connectivity in humans are scarce. We hypothesized that between-group differences in gut microbial composition might be associated with between-group differences in functional brain connectivity and clinical symptoms in older patients with depression.
Aim: To assess the differences in gut microbiota and brain functional connectivity (FC) in late-life depression (LLD) patients using seed-based analysis via resting-state functional magnetic resonance imaging.
Methods: We performed fecal 16S rRNA sequencing in a cohort of 32 older adults with LLD, defined as major depressive disorder, and 16 healthy controls (HCs) to characterize the association of gut microbiota and brain functional connectivity (FC). The 16S ribosomal RNA (rRNA) gene sequence libraries were produced using the V3-V4 primer region and sequenced on an Illumina MiSeq sequencer (Illumina Inc., San Diego, CA, USA). Six seed regions were created in the bilateral prefrontal regions for FC analysis and included the dorsal anterior cingulate cortex (dACC), dorsal–lateral prefrontal cortex (dlPFC), and medial prefrontal cortex (mPFC). The Hamilton Depression Rating Scale (HAMD) was used to assess depressive symptoms.
Results: At the genus level, the relative abundances of Enterobacter, Akkermansiaceae, Haemophilus, Burkholderia, and Rothia were significantly higher in depressive patients than in HCs. Reduced FC within mood regulation circuits were mainly found in the frontal cortex (such as the right superior and inferior frontal gyrus, right lateral occipital cortex, left middle frontal gyrus, and left caudate) in the depression patients compared with the HCs. The group-characterized gut microbes in HCs and LLD patients showed opposite correlations with seed-based FC, (Fig. 1) which may account for the aberrant emotion regulation in depressive patients. The abundance of Enterobacter (dominant genus in LLD) was positively correlated with both HAMD scores and group-characterized FC, while Odoribacter (dominant genus in HC) was negatively correlated with both HAMD scores and group-characterized FC. (Fig. 2)
Conclusion: Significant correlations were identified between depression-characterized gut microbes and brain FC and depression severity, which may contribute to the pathophysiology of depression development in LLD patients.

Fig. 1 Group-characterized gut microbiota correlated with group-characterized brain functional connectivity (FC). The FCs were based on the seeds in the dorsolateral prefrontal cortex (dlPFC), dorsal anterior cingulate cortex (dACC), and medial prefrontal cortex (PFC). Gut microbiota and FC matrices are shown as circles and squares, respectively. The correlation networks between gut microbiota and brain networks are shown. The sizes of circles and squares are proportional to the numbers of associated microbiota taxa/brain networks (red = depression-characterized; blue = healthy-characterized). The connection lines represent significant correlations (p < 0.05) between the gut microbes and functional connectivity networks, and the darkness of the line colors represents the magnitude of the correlation (blue = negative correlation; red = positive correlation).

Figure 2. Heatmap of Spearman’s rank correlation coefficients of the relative abundances of different gut microbes at the genus level with brain functional connectivity networks and clinical symptoms in older patients with major depressive disorder (MDD) and healthy controls (HCs). The darkness of the color represents the magnitude of the correlation (blue circles = negative correlations; red circles = positive correlations) (dlPFC = dorsolateral prefrontal cortex; dACC = dorsal anterior cingulate cortex; mPFC= medial prefrontal cortex; MTG=middle temporal gyrus; SFG=superior frontal gyrus; FOC=frontal orbital cortex; LOC=lateral occipital cortex; MFG=middle frontal gyrus; IFG=inferior frontal gyrus; HAMD= Hamilton Depression Rating Scale).

Chung-Yen Lin

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