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. 2020 Nov 11;10(1):19554.
doi: 10.1038/s41598-020-76562-9.

Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice

Yukino Ogawa  1   2   3 , Chika Miyoshi  1 , Nozomu Obana  4 , Kaho Yajima  2 , Noriko Hotta-Hirashima  1 , Aya Ikkyu  1 , Satomi Kanno  1 , Tomoyoshi Soga  2 , Shinji Fukuda  5   6   7   8 , Masashi Yanagisawa  9   10   11   12
Affiliations

Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice

Yukino Ogawa et al. Sci Rep. .

Abstract

Dysbiosis of the gut microbiota affects physiological processes, including brain functions, by altering the intestinal metabolism. Here we examined the effects of the gut microbiota on sleep/wake regulation. C57BL/6 male mice were treated with broad-spectrum antibiotics for 4 weeks to deplete their gut microbiota. Metabolome profiling of cecal contents in antibiotic-induced microbiota-depleted (AIMD) and control mice showed significant variations in the metabolism of amino acids and vitamins related to neurotransmission, including depletion of serotonin and vitamin B6, in the AIMD mice. Sleep analysis based on electroencephalogram and electromyogram recordings revealed that AIMD mice spent significantly less time in non-rapid eye movement sleep (NREMS) during the light phase while spending more time in NREMS and rapid eye movement sleep (REMS) during the dark phase. The number of REMS episodes seen in AIMD mice increased during both light and dark phases, and this was accompanied by frequent transitions from NREMS to REMS. In addition, the theta power density during REMS was lower in AIMD mice during the light phase compared with that in the controls. Consequently, the gut microbiota is suggested to affect the sleep/wake architecture by altering the intestinal balance of neurotransmitters.

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Conflict of interest statement

S.F. serves as CEO and holds equity in Metabologenomics Inc., a company involved in microbiome-based healthcare and drug discovery.

Figures

Figure 1
Figure 1
Metabolome profiling of cecal contents in the antibiotic-induced microbiota-depleted (AIMD) and control groups. (a) Number of metabolites in the cecal contents of the AIMD (n = 13) and/or control (n = 12) groups as detected by CE-TOFMS. (b) Volcano plot of metabolites that were increased and decreased in the AIMD group (n = 13) compared with the control group (n = 12). The possible mean differences between the AIMD and control groups were assessed using one-way analysis of variance (ANOVA) followed by post hoc Benjamini–Hochberg false discovery rate correction (q value). The black and gray dots represent the metabolites that, respectively, did or did not change significantly under the AIMD condition. The dashed lines indicate the threshold of fold changes on the x-axis (> 2.0) and q values on the y-axis (> 0.05). (c) Principal component analysis (PCA) of the metabolome profiles of the cecal contents. The circles and triangles represent the control (n = 12) and AIMD (n = 13) groups, respectively. (d–h) Concentrations of metabolites in the cecal contents, including phenylalanine, tyrosine, L-dopa, dopamine, noradrenaline, and adrenaline, in the catecholamine synthesis pathway (d) and tryptophan and serotonin in the serotonin synthesis pathway (e). The concentrations of vitamin B6, e.g., pyridoxin, pyridoxal, pyridoxamine, and pyridoxamine phosphate (f), taurine (g), glycine, GABA, and acetylcholine (h). The average value is indicated by the x-mark in each box plot. Values outside of a ± twofold standard deviation range are plotted as open circles. The possible mean difference was assessed using two-tailed Welch’s t test. N.D. not detected.
Figure 2
Figure 2
Comparison of sleep/awake architectures between antibiotic-induced microbiota-depleted (AIMD) and control mice. (a–c) Total time in the wakefulness, non-rapid eye movement sleep (NREMS), and REMS states in the light phase (a), dark phase (b), and over 24 h (c). (d–f) Duration of the wakefulness, NREMS, and REMS episodes in the light phase (d), dark phase (e), and over 24 h (f). (g–i) The number of episodes of the wakefulness, NREMS, and REMS states in the light phase (g), dark phase (h), and over 24 h (i). The circles and triangles represent individual 2-day mean values for the control (n = 12) and AIMD (n = 13) groups, respectively (a–i). The black bars represent the mean values. (j–l) Hourly plots of the total times in the wakefulness (j), NREMS (k), and REMS (l) states. (m–o) Hourly plots of the durations of the wakefulness (m), NREMS (n), and REMS (o) episodes. The black line and gray line represent the control (n = 12) and AIMD (n = 13) groups, respectively (j–o). The horizontal open and filled bars on the x-axes indicate the 12 h light and 12 h dark phase, respectively. The possible mean difference was assessed using Welch’s t test (a–i) or two-way ANOVA followed by post hoc two-tailed Welch’s t test (j–o). *** p < 0.005; ** p < 0.01; * p < 0.05. No significant difference in variance was observed (p = 0.137 (k), p = 0.762 (n) and p = 0.541 (o), two-way ANOVA).
Figure 3
Figure 3
Comparison of phase-transition-related parameters. (a,b) Rapid eye movement sleep (REMS) latency (a) and inter-REMS intervals (b) in the light phase, dark phase, and over 24 h. The circles and triangles represent individual 2-day mean values of the control and antibiotic-induced microbiota-depleted (AIMD) groups, respectively. The black bars represent mean values. (c) The number of transitions between the wakefulness, non-REMS, and REMS episodes in the light and dark phases. The black letters in the upper row and gray letters in the lower row represent 2-day mean values ± SEM of the control (n = 12) and AIMD (n = 13) groups, respectively. Transitions showing significant differences are represented by thick arrows. The possible mean difference was assessed using two-tailed Welch’s t test. n.s. not significant.
Figure 4
Figure 4
Analysis of the EEG spectra recorded during the wakefulness, non-rapid eye movement sleep (NREMS), and REMS states. (a–c) Mean relative power spectra of EEG during the wakefulness (a), NREMS (b), and REMS (c) states over 2 days. (d,e) Hourly changes in delta power density during NREMS (d) and theta power density during REMS (e). The black line and gray line represent the control (n = 12) and AIMD (n = 13) groups, respectively. The horizontal open and filled bars on the x-axes indicate the 12 h light and 12 h dark phases, respectively. The possible mean difference was assessed using two-way ANOVA followed by post hoc two-tailed Welch’s t test. * p < 0.05 (e; p < 0.001, two-way ANOVA). No significant difference in variance was observed (p = 0.330 (a), p = 0.941 (b), p = 0.147 (c) and p = 0.055 (d), two-way ANOVA).
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