The prevalence of obstructive sleep apnea (OSA) has been estimated to be 34% for men and 17% for women between 30 and 70 years old, but is far more common among patients with cardiovascular disease (CVD). Its presence significantly increases the risk for stroke and myocardial infarction. It is not clear how OSA, or its characteristic components, intermittent hypoxia and hypercapnia (IHC), increases CVD, but disruption of circa- dian rhythms has long been suspected. Mouse models of OSA (Apoprotein E knockout [ApoE-/-] mice in IHC conditions) now allow us to better understand how this disease could affect the circadian clock and whether circadian dyssynchrony, a dampening and/or phase shift of the expression of circadian oscillator genes (e.g. Bmal1, Rev-erb?) and metabolic regulators (e.g. CREB), contributes to IHC-induced atherosclerosis. Circadian dyssynchrony usually occurs in the setting of alterations in feeding pattern, dysbiosis, and altered luminal me- tabolites. Hence, the main hypothesis of this proposal is that IHC-induced atherosclerosis results from altered gut microbiome dynamics and circadian dyssynchrony, which can be manipulated with feeding pattern and engineered bacteria. Over the next five years, we will address this hypothesis by pursuing two specific aims. First, we will investi- gate the relationship between feeding pattern, gut microbiome dynamics, and circadian dyssynchrony in IHC- induced atherosclerosis. Our preliminary data show that feeding pattern is altered in ApoE-/- mice in IHC condi- tion. This change in feeding pattern is accompanied with changes in gut microbiome dynamics, especially in loss of cyclical fluctuations in bacteria known to produce secondary bile acids (BAs) and nocturnal BA pools. In ad- dition, there is increased excretion of BAs that activate the farnesoid X receptor (FXR), a BA signaling mecha- nism that is protective against atherosclerosis in ApoE-/- mice. We anticipate these changes in feeding pattern, gut microbiome dynamics, and BA signaling will lead to circadian dyssynchrony. By using various feeding para- digms, such as time-restricted feeding, we will determine whether correcting circadian dyssynchrony alleviates IHC-induced atherosclerosis. In the second specific aim, to better understand how gut microbiome functions could affect IHC-induced atherosclerosis, we will change BA signaling by modulating the luminal BA pool using the help of engineered bacteria. Using engineered bacteria that can deconjugate BAs, we will decrease luminal FXR antagonists and determine if it alleviates IHC-induced atherosclerosis. In addition, we will assess the effect of these changes in BA signaling and host peripheral circadian rhythms. Finally, we will perform the first step to determine whether engineered bacteria can be a potential therapeutic agent in patients with OSA. Overall, this proposal will bridge three different components of IHC-induced atherosclerosis: circadian rhythms, the gut mi- crobiome, and BA signaling. By the end, it will be clear whether these three components are independent con- tributors to IHC-induced atherosclerosis, or if they are different facets of the same pathophysiological process.

Public Health Relevance

Although both the gut microbiome and circadian rhythms contribute significantly to cardiovascular disease, it is not clear whether the two are related to each other. We will investigate the role of microbe-host circadian dynamics and bile acid signaling on atherosclerosis exacerbated by obstructive sleep apnea (OSA). By restoring circadian dynamics with time-restricted feeding or bile acid signaling with engineered native bacteria, we will determine whether these are therapeutic pathways that can reverse the effects of OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Olive, Michelle
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University of California, San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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