Integrated phosphoproteomic and metabolomic profiling reveals perturbed pathways in the hippocampus of gut microbiota dysbiosis mice

Abstract

The dysbiosis of gut microbiota is an important environmental factor that can induce mental disorders, such as depression, through the microbiota–gut–brain axis. However, the underlying pathogenic mechanisms are complex and not completely understood. Here we utilized mass spectrometry to identify the global phosphorylation dynamics in hippocampus tissue in germ-free mice and specific pathogen-free mice (GF vs SPF), fecal microbiota transplantation (FMT) model (“depression microbiota” and the “healthy microbiota” recipient mice). As a result, 327 phosphosites of 237 proteins in GF vs SPF, and 478 phosphosites of 334 proteins in “depression microbiota” vs “healthy microbiota” recipient mice were identified as significant. These phosphorylation dysregulations were consistently associated with glutamatergic neurotransmitter system disturbances. The FMT mice exhibited disturbances in lipid metabolism and amino acid metabolism in both the periphery and brain through integrating phosphoproteomic and metabolomic analysis. Moreover, CAMKII-CREB signaling pathway, in response to these disturbances, was the primary common perturbed cellular process. In addition, we demonstrated that the spliceosome, never directly implicated in mental disorders previously, was a substantially neuronal function disrupted by gut microbiota dysbiosis, and the NCBP1 phosphorylation was identified as a novel pathogenic target. These results present a new perspective to study the pathologic mechanisms of gut microbiota dysbiosis related depression and highlight potential gut-mediated therapies for depression.

Regulation of Gut Microbiota Disrupts the Glucocorticoid Receptor Pathway and Inflammation-related Pathways in the Mouse Hippocampus

“…Interestingly, AQR, LSM3, BUD31, SART1 and SF1 are important components of spliceosome that catalyzes the pre-mRNA splicing. The downregulations of these spliceosome related proteins in GF mice comparted with the SPF mice, suggesting the inhibition of pre-mRNA alternative splicing, this findings was consistent with that of our previous study focused on the phosphorylation modification changes in the hippocampus of GF mice [30].…”

Integrative Analysis of Long Non-coding RNAs, Messenger RNAs, and MicroRNAs Indicates the Neurodevelopmental Dysfunction in the Hippocampus of Gut Microbiota-Dysbiosis Mice

“…However, the exact effects of new genetic biomarkers, i.e., mmu-miR-465c-5p, mmu-miR-883b-3p, and mmu-miR-377-3p, on neurodevelopment needed to be further warranted. Consistently, our previous phosphoproteomics study indicated that axon guidance was the primary functional change shared among gut microbiota-dysbiosis-induced depression mice, stress-induced depression rats and MDD postmortem brains (Wang et al, 2020). Taken together, it is suggested that alterations in neurodevelopment, such as axonal guidance, neurogenesis and myelination, underlie the pathological mechanisms by which gut microbiota-dysbiosis induces depression in mice.…”

“…Gut microbiota can regulate depression via the microbiota-gut-brain axis ( Foster and McVey Neufeld, 2013 ). Previously, disruption to mitochondria-mediated biological processes, the MAPK pathway and the CAMKII-CREB pathway, and the hypothalamic-pituitary-adrenal (HPA) axis were identified in gut microbiota-dysbiosis depressed mice ( Li et al, 2018 ; Liu et al, 2020a ; Wang et al, 2020 ). Many pathways in the gut-brain axis, from intricate neuronal pathways to subtle small molecule messaging systems, are involved in the mechanisms by which gut microbiota dysbiosis causes depression-related brain dysfunction and behavioral changes ( Cryan et al, 2019 ).…”

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

“…Glutamatergic activity in the brain may be directly affected by the gut–brain axis. A recent study in mice used mass spectrometry of phosphorylation sites in hippocampus tissue to examine the gut–brain axis effects on the brain of depressive and control-type microbiota profiles [ 196 ]. The phosphorylation dysregulations were consistently associated with glutamatergic neurotransmitter disturbances.…”