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Role of the Gut Microbiome in Sleep Health
Jonathan LendrumDepartment of Biology, University of Wisconsin-La Crosse, La Crosse, WI 54601
Correspondence: [email protected]
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Why do we spend 1/3 of our lives asleep? Why is there such a large variation in sleep requirements?
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Santiago Ramon’s 1895 Sleep Hypothesis
The great neuroscientist Santiago Ramón y Cajal (1852–1934) studied neurons extensively and, also, glial cells — astrocytes in particular. Based on his observation that the length of astrocytic processes varies greatly between cells, he imagined that astrocytes dynamically extend and retract their processes. He hypothesized, in 1895, that: (1) during sleep, endfeet of astrocytes invade the synaptic cleft to serve as a ‘circuit breaker’, pausing synaptic transmission and (2) during wakefulness, those endfeet retract, restoring synaptic transmission.
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(2013)There are approximately 90 billion neurons in the brain that consume nearly 25% of the bodies total energy demand.
BRAIN (CNS)• 2% of body weight (3 pounds)• 15% of cardiac output• 20% total O2 consumption• 25% total glucose consumption
All biological activity is associated with production of waste products (escaped NTs).
Does the brain really recycle all cellular waste products?
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An intercellular “glymphatic” (g- glial mediated) pathway uses cerebrospinal fluid to clear cell waste from the brain during sleep phases and may reveal new targets for treating neurodegenerative diseases.
AQP4 deletion suppresses clearance of beta-amyloid by 60%
Norepinephrine (NE) regulates cortical neuronal activity and the volume of the interstitial space.
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Gut Microbiome- The Forgotten Endocrine Organ
Microbiota is the coevolved ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space.
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Gut-Microbiome• Trains Immune System• Suppresses Pathogens• Synthesizes Vitamins (K)• Main Source of SCFAs• Ferments Carbohydrates• Maintains Gut Barrier• Regulates Brain and Gut--Development ( gene pool)
Microbiota-Gut-Brain-(Sleep?) Axis
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Bacteroides (5x)- Animal protein/fat
Despite the clock-like nature of microbiome diversification in African apes, the gut microbiomes of humans have undergone an accelerated rate of change and are more different form those of each wild ape population than expected based on the evolutionary time separating Homo from Pan and Gorilla.
Sleep Intensity Hypothesis
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Thesis• My review argued that the gut microbiome and human
sleep behavior coevolved with one another to maximize net energy conservation while maintaining optimal niche exploitation.• The gut microbiome provides a pathway for optimal
energy acquisition and sleep regulation (somnogenic peptides, etc).• Alternatively, sleep provides the pathway for optimal
energy conservation (convective waste clearance).
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Experimental Design
Harlan T.D. 08806i Low Fat (10% kcal) Diet
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Experimental Design
Day: 6am/6pm
Night: 6pm/6am Record Sleep/Wake BehaviorCages Fit With Infrared Cameras
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Results- Highlights
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Results- Broad-Spectrum Antibiotic Gavage Induces Intestinal Dysbiosis
Antibiotic
Control
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Illumina Next Generation Sequencing 16s rRNA (V2-V3 region), Bioinformatics QIIME
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Results- Perturbation of Gut Microbiota Increases Intestinal Permeability and Colonic Secretion
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Results- Antibiotic Gavage Mimics Germ-Free Phenotype
• Enlarged Caecum• Loss of mucosal architecture • Expansion of lamina propria• Enterocyte hyperplasia
Control Caecum Antibiotic Caecum
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Results- Antibiotic-Induced Dysbiosis Alters Intestinal Motility, Immune Homeostasis and Fecal Gross Energy Content
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Impaired Immune State
Altered Gut Function
Shifted Metabolic State
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Perturbation of Gut Microbiota Alters Sleep Architecture
7-9am 9-11am 11-1pm 1-3pm 3-5pm 5-7pm 7-9pm 9-11pm 11-1am 1-3am 3-5am 5-7am0
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Control Antibiotic
Mea
n %
of S
leep
Light Dark
Figure 5. 24-hour sleep profile of antibiotic treated animals exhibits a statistically significant reduction in the mean % of sleep during the dark phase of day (6pm-6am). Paired sample t-tests were analyzed for light and dark phases separately. The dark phase p-value <0.01** with a 14.2% difference of means.
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Conclusions
The results of this study suggest that broad-spectrum antibiotic-induced reduces gastrointestinal motility, enhances colonic ion secretion, impairs mucosal barrier function, reduces energy harvest capacity, alters sleep architecture and may contribute to congruent neurological and gastrointestinal disorders via microbiota-gut-brain axis pathways.
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Thesis Conclusions
• Through evolutionary adaptation of temporal cycling of sleep/wake behavior, we are able to compartmentalize important physiological processes over time. This allows for certain physiological processes to maximize their efficiency by not interfering with contradicting processes at the same time (futile cycling). Sleep wake/ cycling down regulates specific biological processes in waking and up regulates them in sleep, thereby decreasing energy demands imposed by wakefulness, reducing cellular infrastructure requirements, and resulting in overall energy conservation.
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Acknowledgments
Supported by: NIH R15 DK097460-01A1 (SL) and UW-L undergraduate research grant (JL). The authors thank the University of Wisconsin-Biotechnology Center DNA Sequencing Facility for providing sequencing and bioinformatics services.
• Dr. Bradley Seebach- Neurophysiologist• Dr. Sumei Liu- Gastroenterologist• Dr. Barrett Klein- Sleep Expert• Dr. Andrew Berns- Computer Science Sleep Analysis
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QUESTIONS?
Jonathan LendrumDepartment of Biology, University of Wisconsin-La Crosse, La Crosse, WI 54601
Correspondence: [email protected]
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Role of the Gut Microbiome in Sleep Health
Jonathan LendrumDepartment of Biology, University of Wisconsin-La Crosse, La Crosse, WI 54601
Correspondence: [email protected]
QUESTIONS?
