Sleep fragmentation increases blood pressure and is associated with alterations in the gut microbiome and fecal metabolome in rats.

Katherine A Maki,Miki Watanabe-Chailland,Michael W Calik,Anne M Fink,Stefan J Green,Lindsey E Romick-Rosendale,Larisa A Burke,Dagmar Sweeney

doi:10.1152/physiolgenomics.00039.2020

Abstract

The gut microbiota, via the production of metabolites entering the circulation, plays a role in blood pressure regulation. Blood pressure is also affected by the characteristics of sleep. To date, no studies have examined relationships among the gut microbiota/metabolites, blood pressure, and sleep. We hypothesized that fragmented sleep is associated with elevated mean arterial pressure, an altered and dysbiotic gut microbial community, and changes in fecal metabolites. In our model system, rats were randomized to 8 h of sleep fragmentation during the rest phase (light phase) or were undisturbed (controls) for 28 consecutive days. Rats underwent sleep and blood pressure recordings, and fecal samples were analyzed during: baseline (days −4 to −1), early sleep fragmentation (days 0–3), midsleep fragmentation (days 6–13), late sleep fragmentation (days 20–27), and recovery/rest (days 28–34). Less sleep per hour during the sleep fragmentation period was associated with increased mean arterial pressure. Analyses of gut microbial communities and metabolites revealed that putative short chain fatty acid-producing bacteria were differentially abundant between control and intervention animals during mid-/late sleep fragmentation and recovery. Midsleep fragmentation was also characterized by lower alpha diversity, lower Firmicutes:Bacteroidetes ratio, and higher Proteobacteria in intervention rats. Elevated putative succinate-producing bacteria and acetate-producing bacteria were associated with lower and higher mean arterial pressure, respectively, and untargeted metabolomics analysis demonstrates that certain fecal metabolites are significantly correlated with blood pressure. These data reveal associations between sleep fragmentation, mean arterial pressure, and the gut microbiome/fecal metabolome and provide insight to links between disrupted sleep and cardiovascular pathology.

Highlights

The metabolites of bacterial carbohydrate fermentation in the colon affect blood pressure [31, 68, 78], suggesting an important role for the gut microbiota in cardiovascular health and disease [22, 39]
We analyzed 24 h mean arterial pressure (MAP) and fecal samples from control and sleep fragmentation (SF) rats on 13 separate days to characterize the temporal effects of SF on microbial community structure, composition, and diversity
When the SF bar was turned off (ZT 9 –Zeitgeber time (ZT) 23 and ZT 0), sleep was not statistically different between SF and control rats, indicating that SF rats did not recover from SF by increasing sleep during the remaining 16 h of each day

Summary

Introduction

The metabolites of bacterial carbohydrate fermentation in the colon affect blood pressure [31, 68, 78], suggesting an important role for the gut microbiota in cardiovascular health and disease [22, 39]. Prior studies have shown that metabolites produced by the gut microbiota, such as SCFAs and succinate, can increase blood pressure by stimulation of renin release and activation of the renin-angiotensin system [40, 63, 67]. Elevated fecal levels of SCFAs were correlated with increases in blood pressure in humans and rodents [22, 43]. Advancing understanding of fecal metabolome and blood pressure relationships may provide insight to the metabolic consequences and systemic effects that result in changes in the bacterial communities of the gut microbiota

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