Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

Elife. 2016 Apr 20;5. pII: 313442

Gacias M, Gaspari S, Santos PM, Tamburini S, Andrade M, Zhang F, Shen N, Tolstikov V, Kiebish MA, Dupree JL, Zachariou V, Clemente JC, Cassaccia P.

Gene-environment interactions impact the development of neuropsychiatric disorders, such as autism, anxiety, and depression, but the contributions of each to disease progression are unclear. Bacteria and other micro-organisms exist in our environment and also live within our bodies where they work to help digest food and perform other bodily functions. There is growing evidence that gut bacteria can influence mental health, however, the mechanism is unknown. In this study, we identified gut bacteria that promotes an increase in the metabolite cresol, which induces depressive-like behavior in mice by impairing myelin function. Stress-induced depressive-like behavior in mice was reversed by treatment with antibiotics given orally. In the brain region implicated in playing a role in the pathology of depression, stress induced a reduction in several myelin-related genes in the mice that was reversed by antibiotic treatment. Berg’s metabolomics platform profiled gut tissue from mice transplanted with bacteria from non-treated mice showed high amounts of cresol, compared with control experiments. Cresol caused a reduction in expression of myelin-related genes when exposed to cells in the brain that are responsible for forming myelin. This collaboration demonstrates the cross-talk between the gut and the brain through metabolism that can affect mood and behavior, and showcases the powerful applications of metabolomics analysis in deconvoluting neurological function.

homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ₁₀) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.

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