Stoyan R. Vezenkov
Center for applied neuroscience Vezenkov, BG-1582 Sofia, e-mail: info@vezenkov.com
For citation: Vezenkov, S.R. (2025) Sleep, the Nervous System, and the Gut: An Ancient Alliance With Modern Consequences. Nootism 1(5), 44-48, https://doi.org/10.64441/nootism.1.5.4
Summary
Across phylogeny, sleep interfaces with the intestine through conserved molecules and distributed circuits. In animals as simple as Hydra, sleep‑like quiescence is modulated by classic neuromodulators; in flies and mice, sleep loss provokes a gut‑centric oxidative crisis, rewires enteroendocrine output, accelerates whole‑body catabolism, and deranges epithelial renewal. A coherent picture is emerging: sleep’s essential biology is shared between brain and gut, with the enteric nervous system (ENS) and enteroendocrine cells (EEs) acting as both sensors and actuators. These insights outline a mechanistically precise, evolutionarily ancient brain–gut axis for sleep.
1) Evolutionary perspective: sleep predates the brain and foreshadows the enteric “Hydra’s NS”
Sleep‑like states do not require a centralized brain. In Hydra vulgaris, which possesses a diffuse nerve net rather than a central nervous system (CNS), quiescent bouts show homeostatic regulation and respond to canonical sleep modulators. Melatonin and GABA promote sleep in Hydra, whereas dopamine—classically arousing in bilaterians—paradoxically promotes quiescence in Hydra, implying that transmitter “valence” was reprogrammed as nervous systems centralized. These results place the origin of sleep control at the level of distributed neural networks and shared small‑molecule modulators, challenging a strictly brain‑centric view. (Kanaya et al., 2020)
This evolutionary vantage makes the vertebrate ENS feel less like an “auxiliary” and more like an echo of Hydra’s nerve net: a semi‑autonomous lattice of sensory, interneuronal, and motor elements capable of local reflexes, independent rhythms, and rich peptidergic co‑transmission. ENS circuits use acetylcholine for excitation, multiple inhibitory cotransmitters, and neuromodulators that are also abundant in the CNS, positioning the gut to both receive and originate sleep‑relevant signals. (Furness, 2012)
Seen through this evolutionary lens, it is unsurprising that gut circuits and EEs are deeply entwined with sleep biology: ancient molecules (GABA, acetylcholine, glutamate, and peptide families) are repurposed across phyla to arbitrate energy, protection, and repair during sleep and wake.
2) Sleep loss injures the gut through ROS – across species
A decisive set of experiments places the intestine, not the brain, at the epicenter of sleep‑loss lethality. In Drosophila, thermogenetic or mechanical deprivation for ~10 days drives a progressive accumulation of reactive oxygen species (ROS) specifically in the gut; recovery sleep clears these ROS. Gut‑targeted expression of antioxidant enzymes (SOD1/2, catalase) or dietary antioxidants (e.g., lipoic acid, melatonin, N‑acetylcysteine) prevents death—even if sleep remains curtailed. Parallel manipulations in mice confirm gut‑localized oxidative stress during deprivation. Together, these data demonstrate that intestinal ROS is both necessary and sufficient to account for the lethality of severe sleep loss. The gut is not a bystander; it is a principal casualty and a tractable therapeutic target. (Bedont et al., 2023; Li et al., 2023; McDonald & Keene, 2010; Zhou et al., 2023)
Mechanistically, the notion that “sleep protects against oxidative stress” is not new, but the organ selectivity is. While brain oxidative stress fluctuates with sleep/wake, the most damaging burden in severe deprivation falls on visceral tissues, with the intestine at the top of the hierarchy – a distribution that neatly fits the gut’s unique redox environment and microbial exposures. (Zhou et al., 2023)
3) A gut endocrine circuit explains energy wasting during sleep loss
Severe sleep deprivation produces rapid systemic energy wasting – depletion of triacylglycerol and glycogen – without necessarily changing sleep amounts when the endocrine pathway is perturbed. In flies, intestinal ROS is sensed by TRPA1 in a subset of AstA‑positive EEs, boosting release of the peptide allatostatin A (AstA). AstA acts remotely to promote adipokinetic hormone (Akh; glucagon‑like) secretion, mobilizing energy stores. Removing AstA specifically from EEs prevents catabolism during ongoing sleep loss – functionally decoupling the metabolic phenotype from sleep itself. The mammalian counterpart appears functionally conserved: in mice, galanin (released from gut/pancreatic sources) increases glucagon from pancreatic α‑cells; blocking galanin receptors or glucagon signaling blunts deprivation‑induced weight loss, hepatic glycogen depletion, and adipose loss. A unifying model emerges: gut oxidative stress → EE peptide (AstA/galanin) → glucagon‑axis activation → whole‑body catabolism. The mechanistic schematic on page 11 (Fig. 8) of Li et al. summarizes this relay; page 7 (Fig. 5) details the mouse galanin–glucagon data.
This endocrine arc also clarifies an important conceptual point: by rescuing metabolic wasting without restoring sleep (or vice versa), these manipulations reveal separable “downstream” and “core” components of the sleep‑loss phenotype. The catabolic syndrome lies downstream of sleep curtailment and gut ROS; it is not merely a correlate of reduced sleep time.
4) Brain–gut communication shapes intestinal stem cell function and barrier physiology
Intestinal stem cells (ISCs) underpin epithelial turnover, barrier integrity, and digestive capacity—all processes that must adjust across vigilance states. Chronic sleep loss disrupts these functions through both neural and microbial routes. In Drosophila models (mechanical deprivation; sleepless/sss mutants), ISCs become hyperactive, epithelial repair falters, barrier function deteriorates (elevated “Smurf” rates), and gut acidification is impaired; excretion phenotypes also emerge. Elevating GABAergic tone – genetically (reducing GABA transaminase) or pharmacologically (GABA_A agonism) – restores ISC proliferation, barrier integrity, and digestion metrics. Antibiotics partially normalize ISC phenotypes and increase sleep time, and 16S profiling reveals dysbiosis in sss mutants. A brain→GABA→gut pathway and the microbiota thus both contribute to sleep–gut crosstalk that governs epithelial homeostasis. The summary model is captured in Figure 6 of Zhou et al. (GABA rescue; barrier and acid–base metrics).
These observations are conceptually consonant with the broader literature: GABA receptors are expressed throughout the gastrointestinal tract, where GABA modulates motility, secretion, and inflammation; enteric and epithelial circuits are wired for rapid bidirectional signaling with the brain via autonomic and vagal channels. (Auteri et al., 2015; Spencer & Hu, 2020)
A complementary “bottom‑up” path is now equally clear: intestinal ROS activates EE sensors (TRPA1), shifting hormone output and, through glucagon‑axis activation, altering systemic energy state – a signal that feeds back to brain sleep circuits. The gut, in other words, is both target and source in sleep-homeostasis loops.
5) Digestion‑linked outputs of chronic sleep loss: nitrogen handling and polyamines
Beyond redox and endocrine coupling, sleep restriction dysregulates nitrogen metabolism. Adult short‑sleeping mutants excrete less urate and ammonium despite equivalent or increased fecal volume; they are disproportionately harmed by high‑protein diets and by certain polyamines, while blockade of terminal polyamine synthesis increases sleep. The nitrogen pathway schematic on pages 4–5 (Figure 2) of Bedont et al. situates these excretion and metabolite findings within Drosophila’s ureotelic/uricotelic networks; the same study shows that sugar‑rich, nitrogen‑poor diets improve survival under chronic restriction. These signatures point to practical biomarkers (nitrogen metabolites; polyamine sensitivity) for sleep‑loss physiology.
Intriguingly, the Hydra study that anchored sleep in diffuse circuits also flagged ornithine metabolism as a sleep regulator with phylum‑specific valence, hinting that nitrogen handling and polyamine biology may be ancient components of sleep’s metabolic coupling. (Kanaya et al., 2020)
6) Cross‑phyletic “cross‑over” of neuromodulators: old molecules, new circuits
A recurring theme is not wholesale invention but functional reassignment of conserved transmitters.
- Dopamine is arousing in flies and mammals, yet sleep‑promoting in Hydra, underscoring evolutionary retuning of transmitter valence as nervous systems centralized. (Kanaya et al., 2020)
- GABA is the canonical CNS inhibitor and a pervasive enteric modulator; in flies, increasing GABA tone rescues ISC and barrier phenotypes during sleep loss, while in mammals GABA receptors distribute across the gut to regulate motility and inflammation. (Auteri et al., 2015)
- Acetylcholine (ACh) and glutamate are ubiquitous. ACh drives excitatory motor patterns in the ENS; glutamatergic signaling has emerged as a key epithelial–vagal language (e.g., specialized “neuropod” cells transduce nutrient signals to vagal afferents via glutamate), offering a plausible route by which gut endocrine and epithelial stress signals could influence sleep circuits. (Auteri et al., 2015; Spencer & Hu, 2020)
- Peptidergic co‑transmission is the rule, not the exception, in gut and brain. (Dzimbova et al., 2020; Vezenkov & Danalev, 2009) The fly AstA and mammalian galanin families, though not strict orthologs, play analogous roles in tuning metabolic responses; Li et al. connect this family to glucagon‑axis activation under sleep loss, and the pharmacology (e.g., GALR antagonist M35; glucagon receptor antagonists) carries translational leverage.
7) Sleep–feeding coupling provides context for gut findings
Sleep and feeding are genetically and circuit‑level intertwined. In Drosophila, starvation acutely suppresses sleep, primarily by impairing sleep initiation rather than maintenance; the circadian transcription factors Clock and cycle modulate this trade‑off. Mammalian satiety peptide CCK is somnogenic, and the fly CCK ortholog (drosulfakinin) is positioned to relay nutrient state to sleep circuits. These “choice” circuits – whether to exploit or conserve – likely evolved to balance arousal, feeding, and digestion; sleep loss pushes the balance toward catabolism and defense, placing unique stress on the intestine.
A working model
Top‑down (brain → gut). Weak sleep drive or chronic arousal perturbs central neurotransmission (notably GABAergic), altering gut physiology: ISCs become dysregulated, barrier function and acidification wobble, and microbial communities shift. Enhancing GABA tone and modulating microbiota (antibiotics, in flies) partially rescue these phenotypes and increase sleep – implicating a brain→GABA→gut route with microbial crosstalk.
Bottom‑up (gut → brain/system). Sleep loss triggers gut ROS, sensed by TRPA1 in AstA+ EEs, driving peptide release (AstA in flies, galanin in mammals), which remotely stimulates Akh/glucagon output to mobilize energy stores. Manipulating this endocrine relay alters catabolism without changing sleep amounts, placing the metabolic syndrome downstream of sleep curtailment. The Li et al. schematic (Fig. 8, p. 11/14) depicts the full cascade; mouse experiments (Fig. 5, p. 7/14) show that blocking GALR or glucagon attenuates weight and glycogen loss during deprivation.
Metabolic milieu. Chronic sleep loss also impairs nitrogen excretion and alters polyamine biology – features that can serve as readouts and intervention targets (e.g., lowering dietary nitrogen during unavoidable sleep loss). The nitrogen pathway schematic (Fig. 2, pp. 4–5/17) in Bedont et al. situates these outputs within core metabolic pathways.
Open questions
- Why the gut? What initiates gut‑selective ROS during sleep loss—mitochondrial overload, ER stress, altered ENS tone, or microbial redox chemistry? Dissecting epithelial versus neuronal sources will sharpen targets for antioxidant delivery and timing.
- How do central circuits couple to EEs? In mammals, vagal and sympathetic outputs, together with circulating factors, likely intersect EE tone; defining the exact synaptic and paracrine steps that reproduce the brain→GABA→gut ISC control seen in flies remains a priority. (Bonaz et al., 2018)
- Are circadian/sleep nodes gatekeepers of EE output? Given that Clock/cycle shape sleep during starvation, does the sleep/circadian apparatus directly regulate galanin or other EE peptides during deprivation? The ENS expresses many of the requisite receptors and downstream effectors, but the mapping is incomplete.
- Human generalizability. Partial, chronic sleep curtailment – the “modern” phenotype – may produce subtler redox and endocrine signatures than total deprivation; controlled studies that pair sleep manipulation with stool/plasma redox profiling and α‑cell hormone assays are needed. Early human data already show microbiome changes after short sleep restriction, supporting feasibility. (Benedict et al., 2016)
- How do slow-wave brain patterns observed in ASD, addiction, and PTSD influence the brain-gut axis? Given that these conditions are characterized by fragmented or abnormal slow-wave sleep patterns during wakefulness, how might these atypical brain activity states modulate the gut microbiome, intestinal permeability, and neuroendocrine signaling? Specifically, how do these brain patterns influence the production and release of gut hormones like AstA or galanin, and how does this contribute to the systemic energy dysregulation and GI dysfunction observed in these conditions? Further exploration of this could provide insight into novel therapeutic targets for managing both the central and peripheral symptoms of these disorders. (Manolova & Vezenkov, 2025; Vezenkov & Manolova, 2025a, 2025b)
Concluding remarks
What began as a paradox – why should a brain state endanger the intestine? – now reads as evolutionary continuity. Sleep evolved in distributed neural nets using conserved molecules; the modern ENS retains this logic and connects intimately to enteroendocrine and epithelial programs that allocate energy, maintain barriers, and manage microbial relationships. Severe sleep loss exposes the cost of breaking this alliance: the gut oxidizes, EE hormones shift the body to emergency catabolism, and epithelial repair goes awry. The compelling upshot is pragmatic: the gut offers accessible biomarkers and intervention points, from antioxidants and hormone‑axis modulators to microbiota and vagal strategies. If we learn to stabilize this ancient alliance during the modern insult of insufficient sleep, we may blunt sleep loss’s systemic toll without pretending that the need for sleep is negotiable.
References
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