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Sleep and the gut microbiome: antibiotic-induced depletion of the gut microbiota reduces nocturnal sleep in mice

Jonathan Lendrum, Bradley Seebach, Barrett Klein, Sumei Liu
doi: https://doi.org/10.1101/199075
Jonathan Lendrum
1Department of Biology, University of Wisconsin – La Crosse, 1725 State St, La Crosse, WI 54601, USA
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  • For correspondence: Jonathan7lendrum@gmail.com
Bradley Seebach
1Department of Biology, University of Wisconsin – La Crosse, 1725 State St, La Crosse, WI 54601, USA
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Barrett Klein
1Department of Biology, University of Wisconsin – La Crosse, 1725 State St, La Crosse, WI 54601, USA
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Sumei Liu
1Department of Biology, University of Wisconsin – La Crosse, 1725 State St, La Crosse, WI 54601, USA
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Abstract

Several bacterial cell wall components such as peptidoglycan and muramyl peptide are potent inducers of mammalian slow-wave sleep when exogenously administered to freely behaving animals. It has been proposed that the native gut microflora may serve as a quasi-endogenous pool of somnogenic bacterial cell wall products given their quantity and close proximity to the intestinal portal. This proposal suggests that deliberate manipulation of the host's intestinal flora may elicit changes in host sleep behavior. To test this possibility, we evaluated 24 h of sleep-wake behavior after depleting the gut microbiota with a 14 d broad-spectrum antibiotic regimen containing high doses of ampicillin, metronidazole, neomycin, and vancomycin. High-throughput sequencing of the bacterial 16S rDNA gene was used to confirm depletion of fecal bacteria and sleep-wake vigilance states were determined using videosomnography techniques based on previously established behavioral criteria shown to highly correlate with standard polysomnography-based methods. Additionally, considering that germ-free and antibiotic-treated mice have been earlier shown to display increased locomotor activity, and since locomotor activity has been used as a reliable proxy of sleep, we suspected that the elevated locomotor activity previously reported in these animals may reflect an unreported reduction in sleep behavior. To examine this potential relationship, we also quantified locomotor activity on a representative subsample of the same 24 h of video recordings using the automated video-tracking software ANY-maze. We found that antibiotic-induced depletion of the gut microbiota reduced nocturnal sleep, but not diurnal sleep. Likewise, antibiotic-treated mice showed increased nocturnal locomotor activity, but not diurnal locomotor activity. Taken together, these results support a link between the gut microbiome and nocturnal sleep and locomotor physiology in adult mice. Additionally, our findings indicate that antibiotics may be insomnogenic via their ability to diminish gut-derived bacterial somnogens. Given that antibiotics are among the most commonly prescribed drugs in human medicine, these findings have important implications for clinical practice with respect to prolonged antibiotic therapy, insomnia, and other idiopathic sleep-wake and circadian-rhythm disorders affecting an estimated 50-70 million people in the United States alone.

Highlights

  • - 14 d broad-spectrum antibiotic treatment effectively depletes the gut microbiota.

  • - Gut microbiota depletion reduces nocturnal sleep, but not diurnal sleep.

  • - Gut microbiota depletion increases nocturnal locomotion, but not diurnal locomotion.

  • - Antibiotics may be insomnogenic: implications for idiopathic sleep disorders.

Footnotes

  • ↵* Permanent Address (J. Lendrum): 5600 11th Ave S, Minneapolis, MN 55417, USA

  • Abbreviations
    AIMD
    antibiotic-induced microbiota depleted
    BCWCs
    bacterial cell wall components
    GF
    germ-free
    IL
    interleukin
    MP
    muramyl peptide
    PGN
    peptidoglycan
    5-HT
    serotonin
    SWS
    slow-wave sleep
    TH
    T helper
    ZT
    Zeitgeber time

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 05, 2017.
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Sleep and the gut microbiome: antibiotic-induced depletion of the gut microbiota reduces nocturnal sleep in mice
Jonathan Lendrum, Bradley Seebach, Barrett Klein, Sumei Liu
bioRxiv 199075; doi: https://doi.org/10.1101/199075
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Sleep and the gut microbiome: antibiotic-induced depletion of the gut microbiota reduces nocturnal sleep in mice
Jonathan Lendrum, Bradley Seebach, Barrett Klein, Sumei Liu
bioRxiv 199075; doi: https://doi.org/10.1101/199075

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