Abstract

Recent microbiome-brain axis findings have shown evidence of the modulation of microbiome community as an environmental mediator in brain function and psychiatric illness. This work is focused on the role of the microbiome in understanding a rarely investigated environmental involvement in schizophrenia (SZ), especially in relation to brain circuit dysfunction. We leveraged high throughput microbial 16s rRNA sequencing and functional neuroimaging techniques to enable the delineation of microbiome-brain network links in SZ. N=213 SZ and healthy control (HC) subjects were assessed for the oral microbiome. Among them, 139 subjects were scanned by resting-state functional magnetic resonance imaging (rsfMRI) to derive brain functional connectivity. We found a significant microbiome compositional shift in SZ beta diversity (weighted UniFrac distance, p= 6x10-3; Bray-Curtis distance p = 0.021). Fourteen microbial species involving pro-inflammatory and neurotransmitter signaling and H2S production, showed significant abundance alterations in SZ. Multivariate analysis revealed one pair of microbial and functional connectivity components showing a significant correlation of 0.46. Thirty five percent of microbial species and 87.8% of brain functional network connectivity from each component also showed significant differences between SZ and HC with strong performance in classifying SZ from HC, with an area under curve (AUC) = 0.84 and 0.87, respectively. The results suggest a potential link between oral microbiome dysbiosis and brain functional connectivity alteration in relation to SZ, possibly through immunological and neurotransmitter signaling pathways and the hypothalamic-pituitary-adrenal axis, supporting for future work in characterizing the role of oral microbiome in mediating effects on SZ brain functional activity.