Obstructive Sleep Apnea and the Gut Microbiome

Abstract

We investigated how the combined influence of intermittent hypoxia (IH) and high-fat diet (HFD)—modelling obstructive sleep apnea (OSA)—can induce gut microbiota dysbiosis and alter host gene expression. The study involved 16 mice randomly assigned to four experimental groups receiving distinct treatments as follows: normoxia-normal diet (NM-ND), normoxia-high-fat diet (NM-HFD), intermittent hypoxia-normal diet (IH-ND) and intermittent hypoxia-high-fat diet (IH-HFD). IH-treated mice were subjected to ten IH cycles per hour (six-minute cycles, first three at 9% O2 and the next three at 21% O2). Mucosa and fecal microbiota were characterized by pyrosequencing of the hypervariable V4 region of the 16S ribosomal RNA and analyzed via Quantitative Insights into Microbial Ecology (QIIME) software package. Host response was analyzed through microarray analysis of colonic genes. Nevertheless, the focus of the experiment’s microbiome and microarray analysis shifted to the proximal colon. Alpha-diversity and beta-diversity analysis of the mucosal and fecal microbiota suggested a more potent impact of HFD on distinct differences in bacterial profile, accompanied by an increase in Firmicute:Bacteroidetes ratio. Bacterial community profiles in the proximal colon were demonstrated to have more significant (p<0.05) dissimilarities in contrast to the distal colon. We found that members of the same taxa behaved differently; more specifically the Peptostreptococcaceae family and the Lachnospiraceae family (both from the Firmicute phylum) grew in abundance on HFD but decreased and increased in numbers, respectively, with the added treatment of IH. Two-way ANOVA on samples calculated that dietary content had the most significant (p < 0.05) impact on gene expression; followed by the combined impact of diet and oxygen status, and then oxygen status alone. Furthermore, gene ontology (GO) analysis revealed significant (p < 0.05) biological functions (ex. cell-to-cell adhesion) while gene set analysis (GSA) further identified the genes (ex. Cldn2, -4 and -15) that may be responsible for regulating these altered processes. Taken together, the combined impact of IH and HFD on the gut microbiota significantly caused dysbiosis on a specific site more than another (proximal colon versus distal colon, respectively), had varied effects on different taxonomic levels and elicited changes on host gene expression involved in intestinal impermeability—playing a key role in immune and metabolic responses that may underlie disease.