Chronic intermittent hypoxia induces gut microbial dysbiosis and infers metabolic dysfunction in mice.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder, and has been associated with adverse metabolic outcomes. There is increasing evidence indicating the important role of gut microbiota in OSA and its comorbidities, while the perturbation of intestinal microbial community elicited by OSA has yet to be well-characterized. Here, we investigated the effect of chronic intermittent hypoxia (IH), a hallmark feature of OSA, on gut microbiota in mice. METHODS: Male C57BL/6 mice were exposed to a pattern of chronic IH or normoxic conditions for 6 weeks. Fecal samples were collected. The composition of microbiota was determined by 16S rRNA gene amplicon sequencing, and PICRUSt2 was performed to predict functional potential of gut microbiome. RESULTS: In IH mice, accompanied with elevated systemic inflammation, gut microbiota were significantly altered, characterized by enriched Bacteroides, Desulfovibrionaceae and decreased Bifidobacterium. Bacterial operational taxonomic units (OTUs) were clustered into co-abundance groups (CAGs) as potential functional unit in response to IH exposure. One CAG including bacteria of Bacteroides acidifaciens and Desulfovibrionaceae was positively correlated with systemic inflammation in mice, while another CAG composed of bacteria in Muribaculaceae was negatively correlated. Prediction of metabolic pathways showed that, changes in microbiota from IH treatment mainly impacted on bile acid and fatty acid metabolism. CONCLUSION: Our data demonstrated that dysbiosis of gut microbiome was associated with systemic inflammation and metabolism disorder, and emerges as a mediator for IH and its consequences. Targeting microbiota will be a promising approach to curtail metabolic risks of OSA clinically.

The roles of Cdk5-mediated subcellular localization of FOXO1 in neuronal death.

Deficiency of cyclin-dependent kinase 5 (Cdk5) has been linked to the death of postmitotic cortical neurons during brain development. We now report that, in mouse cortical neurons, Cdk5 is capable of phosphorylating the transcription factor FOXO1 at Ser249 in vitro and in vivo. Cellular stresses resulting from extracellular stimulation by H2O2 or ß-amyloid promote hyperactivation of Cdk5, FOXO1 nuclear export and inhibition of its downstream transcriptional activity. In contrast, a loss of Cdk5 leads to FOXO1 translocation into the nucleus: a shift due to decreased AKT activity but independent of S249 phosphorylation. Nuclear FOXO1 upregulates transcription of the proapoptotic gene, BIM, leading to neuronal death, which can be rescued when endogenous FOXO1 was replaced by the cytoplasmically localized form of FOXO1, FOXO1-S249D. Cytoplasmic, but not nuclear, Cdk5 attenuates neuronal death by inhibiting FOXO1 transcriptional activity and BIM expression. Together, our findings suggest that Cdk5 plays a novel and unexpected role in the degeneration of postmitotic neurons through modulation of the cellular location of FOXO1, which constitutes an alternative pathway through which Cdk5 deficiency leads to neuronal death.