Rationale: Obstructive sleep apnea (OSA), characterized by intermittent hypoxia and hypercapnia (IHC), affects the composition of the gut microbiome and metabolome. The gut microbiome has circadian oscillations that play a crucial role in regulating circadian homeostasis and overall metabolic homeostasis. Since circadian disruption can explain how IHC can perturb many physiological regulatory systems, we hypothesized that IHC alters gut luminal dynamics by affecting the cyclical oscillations of key microbial families and metabolites known to affect the circadian clock, inflammation, and atherosclerosis.
Objective: To determine the circadian dynamics of the fecal microbiome and metabolome of Apoe-/- mice after a week of IHC exposure.
Methods and Results: Individually-housed, 10-week-old Apoe-/- mice on an atherogenic diet were split into two groups. One group was exposed to daily IHC conditions for 10 hours (ZT2 to ZT12) while the other was maintained in room air. Six days after initiation of the IHC condition, fecal samples were collected every 4 hours for 24 hours (6 timepoints). We performed 16S rRNA gene amplicon sequencing and untargeted LC/MS to assess changes in the microbiome and metabolome. IHC induced global changes in the cyclical dynamics of the gut microbiome and metabolome. Ruminococcaceae, Lachnospiraceae, S24-7, and Verrucomicrobiaceae had the greatest shifts in their circadian oscillations. In the metabolome, bile acids, glycerolipids (phosphocholines, phosphoethanolamines), and acylcarnitines were greatly affected. Multi-omic analysis of these results demonstrated that Ruminococcaceae and T𝝱MCA co-occur and are associated with IHC conditions and Coriobacteriaceae and CDCA co-occur and are associated with control conditions.
Conclusions: IHC significantly changes the circadian dynamics of the fecal microbiome and metabolome, increasing members and metabolites that are pro-inflammatory and pro-atherogenic, while decreasing protective ones.
DOI link: https://doi.org/10.1128/mSystems.00116-21
EBI accession for microbiome: ERP110592
MassIVE ID for metabolome: MSV000084847