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Microbes in the Moonlight: How the Gut Microbiota Influences Sleep (2511.02766v2)
Published 4 Nov 2025 in q-bio.NC
Abstract: The gut microbiota has emerged as a fundamental regulator of sleep physiology, influencing neural, endocrine, and immune pathways through the gut-microbiota-brain axis (GMBA). This bidirectional communication system modulates neurotransmitter production, circadian rhythms, and metabolic homeostasis, while disruptions in microbial composition have been linked to sleep disorders, neuroinflammation, and systemic immune dysfunction. Recent findings suggest that gut dysbiosis contributes to sleep disturbances by altering serotonin, GABA, and short-chain fatty acid (SCFA) metabolism, with implications for neurodegenerative diseases, metabolic syndromes, and mood disorders. Additionally, the gut microbiota interacts with the endocrine and immune systems, shaping inflammatory responses and stress adaptation mechanisms. This review explores the intricate connections between sleep and the gut microbiota, integrating emerging research on microbiota-targeted therapies, such as probiotics, fecal microbiota transplantation (FMT), and chrononutrition, as potential interventions to restore sleep homeostasis and improve health outcomes
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Overview
This paper is about how the tiny living things in your belly—called the gut microbiota—affect how well you sleep. It explains how the gut and brain “talk” to each other, how this affects your sleep and mood, and how changes in gut bacteria can lead to sleep problems. It also explores possible ways to fix sleep issues by improving gut health, like using probiotics, changing meal timing, and other therapies.
What questions did the paper ask?
To make the topic easier, think of your gut as a busy city of microbes that sends messages to your brain. The paper asks:
- How do gut microbes communicate with the brain and help control sleep?
- What chemicals and “messengers” (like serotonin and GABA) do these microbes make that change sleep?
- How do the immune system and hormones (like melatonin and cortisol) connect gut health to sleep?
- Which gut bacteria seem to help sleep—and which ones seem to make it worse?
- Can we improve sleep by changing the gut microbiota with things like probiotics, special diets, or other treatments?
How did the researchers paper it?
This is a review paper. That means the author did not run a single big experiment. Instead, they carefully read and combined results from many different studies on animals and humans. They looked for patterns, common findings, and strong evidence across:
- Lab studies (for example, giving mice antibiotics and watching how their sleep changes)
- Human studies (like measuring gut bacteria in people with insomnia or sleep apnea)
- Tests of treatments (such as probiotics, fecal microbiota transplantation, and acupuncture)
Think of it like putting together pieces from lots of puzzles to see the bigger picture.
What did they find?
The gut and brain are connected like a two-way phone line
Your gut and brain constantly send messages back and forth. This “phone line” is called the gut–microbiota–brain axis. Signals travel through:
- Nerves (like the vagus nerve)
- Hormones (chemical messages)
- Immune molecules (inflammation signals)
When gut microbes change, they can alter sleep. When sleep changes (like staying up late or being stressed), gut microbes also change.
Microbial chemicals shape sleep
Gut microbes help make or control brain messengers that affect sleep:
- Serotonin: helps mood and is turned into melatonin, which guides your sleep-wake cycle. Microbes influence how much serotonin your body makes from food (like tryptophan).
- GABA: calms the brain and helps you relax. Some bacteria can produce GABA.
- Dopamine, acetylcholine, histamine, orexin, norepinephrine: these also affect wakefulness, REM/NREM sleep, attention, and your body clock. Gut microbes can shift their levels.
- Short-chain fatty acids (SCFAs): these are small molecules made when microbes digest fiber. They help gut cells and can send signals that influence sleep and stress. Abnormal SCFA levels have been linked to poor sleep.
A simple way to think about these: they are like different “apps” controlling your brain’s sleep settings. Gut microbes can update or glitch these apps.
Sleep types and rhythms matter
- Your body clock (circadian rhythm) tells you when to feel awake or sleepy. Irregular schedules, late-night screens, and shift work can mess this up—and also change your gut microbes.
- Some studies show that feeding time and diet can fix or harm the gut’s daily rhythm, which then affects sleep quality.
The immune system, “leaky gut,” and inflammation
- A healthy gut has a strong “fence” that keeps bad stuff out. Dysbiosis (an unhealthy mix of microbes) can break the fence—this is called “leaky gut.”
- When that happens, bits from bacteria (like LPS) can leak into the bloodstream, causing inflammation. Inflammation can reach the brain and disrupt sleep.
- Sleep loss itself can activate the immune system, increase inflammatory signals, and raise the risk of infections and some diseases.
Hormones connect sleep and the gut
- Melatonin (helps you sleep) and cortisol (stress hormone) change with your sleep schedule. Late-night light and stress can throw them off.
- Gut microbes influence hormones and blood sugar control. Poor sleep can worsen blood sugar and microbiota balance—and vice versa.
Which bacteria help or harm sleep?
From many studies, certain bacteria are often linked to better sleep:
- Helpful: Lactobacillus and Bifidobacterium strains, Faecalibacterium prausnitzii, Akkermansia muciniphila (in some cases)
- Harmful or linked to problems: Aeromonas, Collinsella, some Ruminococcaceae groups, and others in certain sleep disorders
These links are not perfect and can vary from person to person, but they suggest that changing gut bacteria may improve sleep.
Specific sleep disorders and microbiota changes
- Insomnia: often shows shifts in gut bacteria, inflammation signals, and neurotransmitter pathways.
- Obstructive sleep apnea (OSA): associated with certain bacterial patterns and immune changes.
- REM sleep behavior disorder (RBD) and narcolepsy: show unique gut microbiota signatures that may relate to inflammation and brain signaling.
Possible treatments targeting the gut–sleep link
The paper highlights several promising approaches:
- Probiotics and prebiotics: adding helpful bacteria or food for them may improve sleep and mood.
- Fecal Microbiota Transplantation (FMT) and Washed Microbiota Transplantation (WMT): transferring healthy microbes from a donor to a patient; early studies suggest better sleep and reduced inflammation in some cases.
- Chrononutrition: timing meals to match your body clock (like avoiding late-night eating) to support microbial rhythms and sleep.
- Managing SCFAs: they may serve as markers of sleep issues and targets to adjust through diet.
- Neuropeptide-based therapies: drugs that target orexin (wakefulness) or other peptides to rebalance sleep; some already approved for insomnia.
- Acupuncture and immune-based approaches: may help by reducing stress hormones, balancing neurotransmitters, and stabilizing gut microbes.
Why is this important?
Sleep is crucial for memory, mood, growth, and health. This review shows that your gut bacteria are not just passengers—they’re active teammates helping control sleep, stress, and inflammation. If we understand this gut–brain teamwork, we can design better treatments for sleep problems without relying only on sleeping pills.
What could this mean for the future?
- Doctors might use microbiota-based tests to spot early signs of sleep disorders.
- Personalized treatments could adjust your gut microbes through diet, probiotics, or timing of meals to improve sleep.
- Combining gut-targeted strategies with standard sleep care (like good sleep habits and therapy) may work better than either alone.
- More research is needed to learn which microbes and molecules matter most, and how to tailor treatments for different people.
In short, taking care of your gut—by eating fiber-rich foods, keeping regular routines, and managing stress—could be a smart path to better sleep and better overall health.
Knowledge Gaps
Knowledge gaps, limitations, and open questions
The paper synthesizes a broad literature on the gut-microbiota-brain axis and sleep but leaves several concrete uncertainties and untested assumptions that future work should address. The following list pinpoints actionable gaps:
- Causal inference in humans: Most findings are correlational or based on animal models; randomized, controlled, mechanistic human studies linking specific taxa/metabolites to polysomnography-defined sleep architecture are lacking.
- Stage-specific mechanisms: How defined microbial metabolites (e.g., acetate, butyrate, propionate, kynurenines) modulate specific sleep features (NREMS/REMS proportions, spindle density, theta power, micro-arousals) via identified neural circuits (vagus, SCN, locus coeruleus) remains unresolved.
- SCFA paradox: Evidence that elevated fecal SCFAs correlate with poorer sleep in older adults conflicts with reports of beneficial SCFA effects in stress models; dose–response, compartmental (fecal vs plasma vs CSF), and phenotype-specific effects need clarification.
- Gut-derived GABA efficacy: Whether GABA produced by Bacteroides/Parabacteroides/Escherichia affects CNS function given BBB constraints, and through which pathways (vagal vs immune vs endothelial), has not been demonstrated in humans.
- Orexin modulation by microbiota: Human evidence that acetate/SCFAs directly modulate orexin neuron activity and sleep–wake regulation is absent; the causal pathway and clinical significance are unknown.
- Dopamine and microbial contribution: Functional validation of microbiota-dependent dopamine modulation in vivo (beyond associations) and its net effect on wakefulness and circadian entrainment in humans is missing.
- Norepinephrine–microbiota risks: The stress-induced NE-driven expansion of facultative pathogens (e.g., Clostridium, Streptococcus) needs translation to human stress/sleep contexts and mitigation strategies.
- BBB permeability in sleep dysbiosis: Quantitative human data proving that gut dysbiosis and LPS/TLR4 signaling increase BBB permeability with downstream sleep disruption are lacking.
- Immune pathways to sleep disruption: The specific roles and timing of cytokines/cell types (e.g., IL-16, TNF-α, GM-CSF/IL-23/Th17) in mediating sleep loss effects in humans, and their modulation by microbiota, remain to be mapped.
- Maternal sleep deprivation (MSD): Human longitudinal studies confirming MSD-induced offspring microbiota changes, neuroinflammation, and sleep phenotypes—and testing preventive microbiota interventions—are absent.
- Endocrine mediation: Precise causal links between microbiota perturbations and HPA axis dysregulation, GH/IGF-1 suppression, and melatonin synthesis in humans are undefined; interventional endocrine readouts are rare.
- Chrononutrition parameters: Optimal timing windows, meal composition, and adherence thresholds that restore microbial rhythmicity and improve objective sleep metrics in diverse populations are unknown.
- Microbial circadian clocks: The molecular basis of microbial “clock-like” behavior and its entrainment by host feeding/sleep cycles is poorly characterized; gene-level microbial rhythms and their host impacts remain to be defined.
- Insomnia subtypes and taxa: Robust, reproducible microbiota signatures distinguishing objective insomnia (O-IN) and paradoxical insomnia (P-IN), and their functional relevance, have not been validated across cohorts.
- Biomarker development: Standardized, high-specificity microbiota/metabolite biomarkers for sleep disorder diagnosis, stratification, and monitoring (beyond PSQI correlations) have not been established.
- Standardization of measures: Heterogeneity in sleep assessment (subjective vs PSG), microbiome profiling (16S vs shotgun metagenomics), and metabolomics pipelines hampers comparability; consensus protocols are needed.
- Strain-specific efficacy: The colonization stability, in vivo neurotransmitter production, and long-term safety of candidate strains (e.g., Lactobacillus plantarum PS128, L. reuteri NK33, Bifidobacterium longum) across age, sex, and comorbidities need rigorous, multicenter trials.
- FMT/WMT for sleep: Placebo-controlled trials defining indications (insomnia, OSA, RBD), durability of benefit, donor selection criteria, dose/frequency, and safety (including WMT) are lacking.
- Nutraceuticals: Ingredient-specific mechanisms (e.g., β-glucan, prebiotics, silymarin), dose–response, and standardized formulations with objective sleep endpoints are under-tested.
- Acupuncture mechanisms: Comparative effectiveness versus CBT-I/pharmacotherapy and proof that microbiota modulation mediates its sleep benefits require blinded, mechanistic trials.
- Host factors and personalization: How host genetics (clock genes, HCRTR2), sex hormones, age, and comorbidities (metabolic syndrome, depression) shape microbiota–sleep responses is poorly defined; predictive models for personalized interventions are missing.
- Long-term outcomes: Whether microbiota-targeted therapies sustainably improve cardiometabolic and neuropsychiatric risks associated with chronic insomnia/OSA and remain effective after discontinuation is unknown.
- Drug–microbiota interactions: Systematic evaluation of how common medications (antibiotics, PPIs, antidepressants, hypnotics) alter microbiota and sleep outcomes—and how to adjust interventions accordingly—is limited.
- CPAP and microbiota: The impact of OSA treatments (e.g., CPAP) on gut microbiota composition/function and whether combined microbiota interventions enhance outcomes is unstudied.
- Multi-omics and time-resolved sampling: Integrated metagenomics–metabolomics–transcriptomics with diurnal sampling aligned to sleep cycles are rare but necessary to resolve temporal dynamics and mechanisms.
- Central neurotransmitter measurements: In vivo human measurements (e.g., PET, CSF, isotope tracers) linking peripheral microbial metabolites to central neurotransmitter changes and sleep-stage alterations are lacking.
- Safety surveillance: Comprehensive adverse event monitoring for microbiota-modulating therapies (e.g., dysbiosis, pathogen overgrowth, mood effects) over extended periods is insufficient.
- Minimal clinically important difference: Thresholds for clinically meaningful improvements in sleep (latency, efficiency, fragmentation) attributable to microbiota interventions are not defined for trial design.
- Non-gut microbiomes: The roles of oral, nasal, and skin microbiota in sleep regulation (e.g., via upper airway inflammation in OSA) are underexplored relative to the gut.
- Environmental confounders: Integrated studies that jointly manipulate light exposure, shift work schedules, diet, and microbiota to disentangle and treat circadian misalignment effects are absent.
Practical Applications
Immediate Applications
Below are practical uses that can be deployed now, leveraging the paper’s findings on gut microbiota, sleep, and the immune/endocrine axes.
- Targeted probiotic and functional food formulations for sleep support
- What: Formulate and market evidence-aligned probiotic blends (e.g., Lactobacillus plantarum PS128/P72, L. reuteri NK33, L. brevis DL1-11/GABA-fermented milk; Bifidobacterium longum/adolescentis) and prebiotic-fiber beverages positioned to “support sleep quality and stress resilience.”
- Sectors: Healthcare, Nutrition/Food, Consumer Health
- Tools/Products/Workflows: Shelf-stable capsules, fermented dairy/non-dairy SKUs, GABA-enriched beverages; labeling focused on sleep-support claims compliant with local regulation.
- Assumptions/Dependencies: Strain-specific effects; quality control for viable counts; health-claims regulation; efficacy strongest as adjunct, not standalone insomnia treatment.
- Chrononutrition programs in clinical care and workplaces
- What: Implement meal-timing guidance (time-restricted eating, avoiding late meals) aligned with circadian rhythm to enhance microbial rhythmicity and sleep quality.
- Sectors: Healthcare, Employer Wellness, Education, Shift-Work Industries (healthcare, logistics, manufacturing)
- Tools/Products/Workflows: Dietitian-led protocols integrated into CBT-I; cafeteria scheduling; app-based reminders for shift workers.
- Assumptions/Dependencies: Adherence; scheduling constraints; individual variability.
- Sleep clinic add-on: microbiome-informed nutrition counseling
- What: Incorporate a brief dietary assessment emphasizing fiber intake, tryptophan-rich foods (legumes, fruits/vegetables), and fermented foods to support serotonin/melatonin pathways.
- Sectors: Healthcare
- Tools/Products/Workflows: 15–20 minute nutrition add-on during CBT-I; standardized handouts; EHR templates.
- Assumptions/Dependencies: Nutritionist availability; patient adherence; not a replacement for first-line therapies.
- Microbiome-aware antibiotic stewardship for insomnia and mood comorbidities
- What: Clinician education to avoid nonessential antibiotics during insomnia treatment windows to reduce risk of dysbiosis-linked sleep disturbances.
- Sectors: Healthcare, Policy
- Tools/Products/Workflows: Alerts in e-prescribing; brief CME modules.
- Assumptions/Dependencies: Antibiotics still used when clinically indicated; institutional buy-in.
- OSA risk augmentation with microbiome patterns (pilot)
- What: Use reported associations (e.g., Ruminococcaceae UCG-009 risk; Bifidobacterium protective) to develop preliminary risk algorithms that complement STOP-BANG/ESS in research clinics.
- Sectors: Healthcare, Academic
- Tools/Products/Workflows: Pilot stool testing with risk score overlay; referral triage to polysomnography.
- Assumptions/Dependencies: Observational evidence; not diagnostic; IRB oversight for pilot use.
- Integrative inflammation management for poor sleepers
- What: Offer anti-inflammatory diet patterns (high fiber, polyphenols), stress-reduction, and sleep hygiene together to mitigate LPS/TLR4-pathway activation linked to dysbiosis.
- Sectors: Healthcare, Employer Wellness
- Tools/Products/Workflows: Group programs; remote coaching; outcome tracking with PROMs.
- Assumptions/Dependencies: Multi-component adherence; heterogeneous baseline microbiota.
- Consumer sleep apps with microbiome education and meal-timing nudges
- What: Add modules on fiber/prebiotics, fermented foods, and meal timing to existing sleep-tracking apps; link nudges to circadian and microbiome goals.
- Sectors: Software/Digital Health
- Tools/Products/Workflows: In-app curricula, push notifications, habit trackers.
- Assumptions/Dependencies: Behavior change is incremental; content must avoid medical claims.
- Acupuncture as an adjunct for insomnia with microbiome-sensitive protocols
- What: Offer acupuncture alongside standard care where available, noting evidence of neurotransmitter modulation and microbiota shifts with potentially fewer side effects versus hypnotics.
- Sectors: Healthcare (Integrative Medicine)
- Tools/Products/Workflows: Protocolized sessions; outcome measures (PSQI, sleep diaries).
- Assumptions/Dependencies: Practitioner expertise; variable insurance coverage; heterogeneity in response.
- Shift-worker operational policies blending light, meal timing, and caffeine limits
- What: Update rostering and break schedules to align bright-light exposure with shifts, restrict late caffeine, and encourage early-shift meal windows to support SCN–microbiota coupling.
- Sectors: Policy (Occupational Health), Energy/Manufacturing/Logistics, Healthcare Systems
- Tools/Products/Workflows: HR policy templates; cafeteria hours aligned with shifts; fatigue risk management systems.
- Assumptions/Dependencies: Operational flexibility; union agreements; measurable KPIs (errors, absenteeism).
- Basic SCFA and inflammatory panel in sleep research cohorts
- What: Add fecal SCFAs and simple blood inflammatory indices (e.g., SII) to ongoing sleep cohorts to stratify phenotypes (e.g., short-sleep-duration insomnia).
- Sectors: Academia, CROs
- Tools/Products/Workflows: SOPs for sample collection; biobank linkage; pre-registered analysis plans.
- Assumptions/Dependencies: Assay standardization; diurnal variation control.
- Patient education to protect the gut barrier (“leaky gut”) during poor sleep
- What: Brief counseling on high-fiber diets, avoidance of ultra-processed foods, moderate alcohol, and stress management to reduce intestinal permeability and systemic inflammation.
- Sectors: Healthcare, Public Health
- Tools/Products/Workflows: Handouts; SMS tips; community workshops.
- Assumptions/Dependencies: Feasible lifestyle changes; culturally adapted materials.
- IBD clinics screening sleep quality and offering microbiota-aligned sleep interventions
- What: Routine sleep screening in IBD visits with referral to dietitian for microbiota-supportive sleep strategies; consider research referral for WMT trials.
- Sectors: Healthcare
- Tools/Products/Workflows: PROMIS sleep scales; diet consult pathway; research registry.
- Assumptions/Dependencies: Clinic workflow capacity; WMT remains investigational outside specific regions.
Long-Term Applications
Below are higher-impact opportunities requiring additional research, validation, regulatory clearance, or scaling.
- Microbiome-based therapeutics for insomnia and sleep fragmentation
- What: Develop live biotherapeutic products (defined consortia, engineered GABA/5-HT-modulating strains) targeting sleep architecture.
- Sectors: Biotech, Pharma
- Tools/Products/Workflows: IND-enabling packages; phase I–III RCTs; GMP manufacturing.
- Assumptions/Dependencies: Causality and mechanism validation; safety over chronic use; regulatory pathways for LBP.
- Washed microbiota transplantation (WMT) as a regulated therapy for sleep disorders
- What: Advance WMT from promising pilots to multicenter RCTs for refractory insomnia, comorbid IBD/IBS with sleep impairment, and post-antibiotic dysbiosis.
- Sectors: Healthcare, Biotech
- Tools/Products/Workflows: Donor screening, automated washing platforms, pharmacovigilance.
- Assumptions/Dependencies: Long-term safety; donor variability; clear indications; regulatory acceptance.
- SCFA-targeted interventions and diagnostics
- What: Create therapeutics that titrate SCFA signaling (formulations, receptor agonists/antagonists) and clinical tests that use SCFA profiles as biomarkers for insomnia phenotypes.
- Sectors: Pharma, Diagnostics
- Tools/Products/Workflows: GPCR-target assays (FFAR2/3, GPR109A), CLIA-certified SCFA panels, companion apps.
- Assumptions/Dependencies: Clarifying bidirectional associations (e.g., high fecal SCFAs may reflect poor epithelial uptake); inter-individual variability.
- Personalized “microbiome-sleep” medicine in clinics
- What: Integrate microbiome sequencing, metabolomics, and immune signatures with actigraphy/polysomnography to tailor diet, probiotics, and timing interventions.
- Sectors: Healthcare, Digital Health
- Tools/Products/Workflows: Multi-omics pipelines, clinical decision support, payer coverage models.
- Assumptions/Dependencies: Cost-effectiveness; data interpretation standards; clinician training; privacy protections for microbiome data.
- Orexin–microbiota cross-talk therapeutics
- What: Modulate orexinergic tone via microbiota pathways (e.g., SCFA-mediated effects on orexin-A neurons) to treat insomnia/hypersomnia without cognitive side effects.
- Sectors: Pharma, Biotech
- Tools/Products/Workflows: Preclinical assays linking SCFAs to OX1R/OX2R activity; combination therapies with orexin antagonists/mimetics.
- Assumptions/Dependencies: Translational fidelity from rodent to human; receptor selectivity.
- Immune-axis drug development to blunt sleep-loss inflammation
- What: Target PGD2/DP1 signaling or GM-CSF/IL-23/Th17 loops to prevent cytokine-storm–like responses and autoimmune exacerbations after severe sleep deprivation.
- Sectors: Pharma
- Tools/Products/Workflows: Biomarker-stratified trials; safety monitoring for infection risk.
- Assumptions/Dependencies: Benefit-risk balance; precise patient selection; chronic vs acute use scenarios.
- Maternal sleep and microbiome programs to reduce offspring neuroinflammation risk
- What: Preconception and prenatal protocols (sleep counseling, diet, probiotics) aimed at preventing MSD-linked microbiota and cytokine changes in offspring.
- Sectors: Public Health, Obstetrics
- Tools/Products/Workflows: Prenatal care bundles; digital coaching; registry-based outcomes.
- Assumptions/Dependencies: Longitudinal evidence; intergenerational follow-up; equity in access.
- OSA diagnostics enhanced by microbiome and immune signatures
- What: Develop validated adjunct diagnostics combining stool microbiome, bile acid metabolites, and PBMC transcriptomic panels (e.g., 32-gene signature) for OSA severity/prognosis.
- Sectors: Diagnostics, Sleep Medicine
- Tools/Products/Workflows: Multi-marker kits; machine-learning classifiers; reimbursement coding.
- Assumptions/Dependencies: Standardization; incremental clinical utility beyond PSG; payer acceptance.
- Engineered diets for sleep: precision fiber, polyphenols, and amino acid routing
- What: Design medical foods that steer tryptophan/kynurenine flux toward 5-HT/melatonin and enhance butyrate producers to stabilize sleep architecture.
- Sectors: Medical Nutrition, FoodTech
- Tools/Products/Workflows: Smart-fiber blends, microencapsulation, adaptive meal plans via apps.
- Assumptions/Dependencies: Personalized responses; regulatory category (medical food vs supplement).
- Neuroimmune probiotics (e.g., heat-killed immunoregulatory strains)
- What: Translate Mycobacterium vaccae-like immunoregulatory approaches into standardized, safe products to mitigate sleep-disruption–induced inflammation and cognitive deficits.
- Sectors: Biotech, Consumer Health
- Tools/Products/Workflows: Nonviable postbiotic formulations; immunophenotyping endpoints.
- Assumptions/Dependencies: Human efficacy replication; safety in immune-compromised populations.
- Vagus/microbiota neuromodulation
- What: Combine dietary SCFA modulation with noninvasive vagus nerve stimulation to adjust NE oscillatory amplitude and stabilize NREM/REM transitions.
- Sectors: MedTech, Digital Therapeutics
- Tools/Products/Workflows: Wearable VNS devices; sleep-stage–contingent stimulation algorithms.
- Assumptions/Dependencies: Mechanistic validation in humans; safety over chronic use.
- Regulatory-grade microbiome assays in sleep trials
- What: Standardize stool collection, sequencing, and metabolite quantification SOPs for registration trials of sleep therapeutics.
- Sectors: Academia, CROs, Regulators
- Tools/Products/Workflows: Reference materials; inter-lab proficiency programs.
- Assumptions/Dependencies: Consensus on core outcomes and metadata (diet, light, activity).
- Population-level policy pilots
- What: Municipal or industry pilots to align meal timing and canteen menus with circadian health (high-fiber, fermented options earlier in shifts), coupled with sleep education.
- Sectors: Policy, Public Health, Large Employers
- Tools/Products/Workflows: Policy toolkits; implementation science frameworks; KPI dashboards (errors, healthcare utilization).
- Assumptions/Dependencies: Stakeholder alignment; cultural tailoring; measurable ROI.
- Clinical pathways for comorbid GI–sleep disorders
- What: Integrated protocols for IBS/IBD and insomnia/OSA that coordinate gastroenterology, sleep medicine, and nutrition around the microbiota–sleep axis.
- Sectors: Healthcare Systems
- Tools/Products/Workflows: Shared care plans; co-located clinics; bundled payments.
- Assumptions/Dependencies: Health-system incentives; outcome attribution across specialties.
- Ethical and privacy frameworks for microbiome-informed sleep care
- What: Develop governance for storage/use of microbiome data in sleep clinics, including consent, de-identification, and secondary use.
- Sectors: Policy, Healthcare
- Tools/Products/Workflows: Consent templates; data stewardship boards.
- Assumptions/Dependencies: Evolving privacy law; public trust.
Notes common to many applications:
- Evidence base includes animal studies and small human trials; causality is not always established.
- Microbiome responses are highly individualized; personalization and iterative monitoring improve effects.
- Regulatory classification (drug, device, medical food, supplement) determines claims, trials, and market access.
- Lifestyle factors (light exposure, stress, physical activity) remain foundational and interact with microbiota-targeted interventions.
Glossary
- Acetylcholine: A neurotransmitter that contributes to REM sleep regulation and sleep-wake cycling. "Acetylcholine, a neurotransmitter, plays a role in regulating REM sleep through cholinergic neurons in the brainstem and basal forebrain, which project to wide areas of the cerebral cortex and interact with other neuromodulatory systems to produce the sleep-wake cycle and different sleep stages"
- Antibiotic-induced microbiota- depleted (AIMD) mice: An animal model where gut microbes are depleted by antibiotics to study microbiota functions. "studies in antibiotic-induced microbiota- depleted (AIMD) mice revealed disrupted sleep architecture"
- Blood-brain barrier (BBB): A selective barrier that protects the brain from circulating toxins and pathogens. "This inflammation compromises blood-brain barrier (BBB) integrity, facilitating the translocation of inflammatory mediators and metabolites into the brain"
- Chronobiology: The study of biological rhythms and their mechanisms. "advancements in chronobiology have revealed that gut microbiota exhibits a circadian rhythm closely synchronized with host sleep-wake cycles"
- Chrononutrition: Timing food intake to align with circadian rhythms to improve health outcomes. "Chrononutrition, or the timing of food intake in alignment with circadian rhythms, has shown potential to enhance microbial rhythmicity and improve sleep outcomes"
- Circadian misalignment: A mismatch between internal biological clocks and external time cues. "Modern societal habits, such as irregular schedules and nighttime light exposure, often cause circadian misalignment, which has been linked to conditions like metabolic syndrome and certain cancers"
- Circadian rhythm: Endogenous 24-hour cycles coordinating physiological processes. "The circadian rhythm, regulated by a hierarchical system of cellular clocks with the suprachiasmatic nucleus as the central pacemaker, synchronizes physiological processes with the 24-hour cycle"
- Cytokine-storm-like syndromes: Excessive immune activation characterized by overwhelming cytokine release. "including neutrophil accumulation and cytokine-storm-like syndromes"
- Dopamine: A neurotransmitter that promotes wakefulness and influences circadian timing. "Dopamine plays a crucial role in regulating the sleep-wake cycle by promoting wakefulness, with elevated levels often disrupting sleep"
- Dysbiosis: An imbalance in the composition or function of the gut microbiota. "Intestinal dysbiosis disrupts the bidirectional relationship between GM and the central nervous system (CNS)"
- ELISA: Enzyme-linked immunosorbent assay, a technique to measure proteins like cytokines. "Studies using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) revealed significantly higher expression levels of pro-inflammatory cytokines"
- Enteric nervous system (ENS): The intrinsic neural network of the gut regulating gastrointestinal function. "Key components such as the enteric nervous system (ENS) and vagus nerve mediate this interaction"
- Fecal microbiota transplantation (FMT): Transfer of stool from a healthy donor to restore gut microbial balance. "Restoring gut microbial balance through fecal microbiota transplantation (FMT) has been shown to reduce LPS levels in the colon, serum, and other tissues"
- GABA: Gamma-aminobutyric acid, the main inhibitory neurotransmitter involved in sleep regulation. "GABA activation rescued both sleep behavior and intestinal phenotypes"
- Growth hormone (GH): A hormone secreted mainly during deep sleep that supports growth and metabolism. "Growth hormone (GH) is primarily secreted during slow-wave sleep (SWS)"
- Growth hormone-releasing hormone (GHRH): A hypothalamic hormone that stimulates GH release. "its release is regulated by growth hormone-releasing hormone (GHRH) and somatostatin"
- Gut-Microbiota-Brain Axis (GMBA): The bidirectional communication network linking gut microbes and the brain. "Through the Gut-Microbiota-Brain Axis (GMBA), bidirectional communication occurs via neural, endocrine, and immune pathways"
- Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): A cytokine that drives inflammatory immune responses. "This is mediated by upregulation of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), a cytokine that drives the IL-23/Th17/GM-CSF feedback mechanism"
- Histamine H3 receptor (H3R): A receptor regulating histamine and other neurotransmitter release, implicated in sleep-wake control. "with the histamine H3 receptor (H3R) being of particular interest due to its unique function as a pre- and postsynaptic receptor that controls the synthesis and release of histamine and other neurotransmitters in the brain"
- HCRTR2/OX2R: The orexin/hypocretin receptor 2 subtype involved in sleep-wake regulation. "with HCRTR2/OX2R specifically linked to sleep-wake control"
- Hypothalamic-pituitary-adrenal (HPA) axis: The stress-response system regulating cortisol and impacting sleep. "This activation of the HPA axis can result in elevated cortisol levels"
- Insulin-like growth factor 1 (IGF-1): A GH-dependent hormone important for growth and neuroprotection. "GH stimulates the production of insulin-like growth factor 1 (IGF-1)"
- Intestinal permeability: The ease with which substances pass through the gut lining; increased levels indicate a compromised barrier. "a condition characterized by increased intestinal permeability"
- Kynurenine pathway: A metabolic route of tryptophan producing neuroactive metabolites. "tryptophan metabolites, including those from the kynurenine pathway, influence neural activity and inflammation"
- Leaky gut: Colloquial term for increased intestinal permeability allowing toxins to enter the bloodstream. "Dysbiosis contributes to the disruption of this barrier, commonly referred to as 'leaky gut'"
- Lipopolysaccharide (LPS): A bacterial endotoxin that triggers strong immune responses. "allowing microorganisms or microbial components like LPS to enter systemic circulation"
- Mass cytometry: A high-dimensional single-cell analysis technique for immune profiling. "A study utilizing mass cytometry and single-cell RNA sequencing revealed that sleep deprivation increases T and plasma cell frequencies"
- Melanin-concentrating hormone: A neuropeptide that promotes REM sleep. "while melanin-concentrating hormone and galanin promote REM sleep"
- Melatonin: A circadian hormone produced by the pineal gland that regulates sleep timing. "Melatonin, produced by the pineal gland, is a central regulator of the circadian rhythm"
- Microglia: Resident immune cells of the central nervous system mediating neuroinflammation. "binding to Toll-like receptor 4 (TLR4) on microglia"
- MyD88: An adaptor protein in TLR signaling pathways leading to inflammation. "suppressing the TLR4/MyD88/NF-KB signaling pathway"
- NF-KB: A transcription factor complex controlling inflammatory gene expression. "suppressing the TLR4/MyD88/NF-KB signaling pathway"
- Neuropeptide S (NPS): A neuropeptide that modulates arousal and counters sleep disturbance effects. "Neuropeptide S (NPS) has been shown to alleviate anxiety-like behavior and sleep disturbances caused by paradoxical sleep deprivation (PSD)"
- Norepinephrine (NE): A neurotransmitter involved in arousal with oscillations shaping sleep microarchitecture. "The amplitude of Norepinephrine (NE) oscillations is crucial for shaping sleep micro-architecture"
- Non-rapid eye movement sleep (NREMS): Sleep stage associated with slow-wave activity and restoration. "non-rapid eye movement sleep (NREMS)"
- Obstructive sleep apnea (OSA): A disorder with repeated upper airway obstruction during sleep. "A molecular signature of 32 genes effectively distinguished OSA patients from controls"
- Orexin: A wake-promoting neuropeptide system central to sleep-wake regulation. "Orexin plays a pivotal role in regulating the sleep-wake cycle"
- Orexin receptor antagonists: Drugs that block orexin receptors to promote sleep. "orexin receptor antagonists promoting sleep at night"
- Peripheral blood mononuclear cells (PBMCs): Blood immune cells (e.g., lymphocytes, monocytes) used in transcriptomic profiling. "Single-cell transcriptomics (scRNA-seq) analysis revealed OSA-induced transcriptional changes in peripheral blood mononuclear cells (PBMCs)"
- PGD2/DP1 axis: A signaling pathway where prostaglandin D2 acts via DP1 receptors, linked to inflammatory effects of sleep loss. "Disrupting the PGD2/DP1 axis significantly reduced these inflammatory effects"
- Probiotics: Live microorganisms conferring health benefits, used to modulate the gut-brain axis. "microbiota-targeting interventions, including probiotics and fecal microbiota transplantation, hold therapeutic potential"
- Prostaglandin D2 (PGD2): A lipid mediator implicated in sleep and inflammation. "increased prostaglandin D2 (PGD2) levels in the brain were shown to drive peripheral immune pathologies"
- qRT-PCR: Quantitative real-time polymerase chain reaction used to measure gene expression. "Studies using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) revealed"
- Rapid eye movement sleep (REMS): A sleep stage characterized by vivid dreaming and muscle atonia. "rapid eye movement sleep (REMS)"
- Secondary bile acids: Microbially modified bile acids that act as signaling metabolites along the gut-brain axis. "metabolites such as short-chain fatty acids (SCFAs), secondary bile acids, and amino acid-derived compounds"
- Serotonin: A neurotransmitter regulating mood, sleep, and gut motility; derived from tryptophan. "Serotonin regulates emotions, sleep, appetite, and gut motility"
- Short-chain fatty acids (SCFAs): Microbial fermentation products (e.g., acetate, propionate, butyrate) influencing brain and immune function. "short-chain fatty acids (SCFAs)"
- Single-cell RNA sequencing (scRNA-seq): A technique to profile gene expression at single-cell resolution. "A study utilizing mass cytometry and single-cell RNA sequencing revealed that sleep deprivation increases T and plasma cell frequencies"
- Somatostatin: A peptide hormone that inhibits GH release. "its release is regulated by growth hormone-releasing hormone (GHRH) and somatostatin"
- Suprachiasmatic nucleus (SCN): The brain’s master circadian pacemaker in the hypothalamus. "with the suprachiasmatic nucleus as the central pacemaker"
- Systemic immune-inflammation index (SII): A composite blood marker reflecting systemic inflammatory status. "positive associations between sleep disorders and the systemic immune-inflammation index (SII)"
- Th1/Th2: T helper cell polarization states that govern different immune responses. "Sleep architecture involves dynamic shifts between T helper 1 (Th1)- mediated inflammation during early sleep and T helper 2 (Th2)-mediated responses in late sleep"
- Th17: A T helper cell subset involved in inflammatory and autoimmune responses. "drives the IL-23/Th17/GM-CSF feedback mechanism"
- Theta power density: An EEG spectral measure often analyzed in REM sleep neuroscience. "and reduced theta power density during REMS"
- Time-restricted feeding: Limiting daily eating windows to align with circadian rhythms. "Restoring circadian rhythmicity through strategies like time-restricted feeding and probiotic supplementation has shown promising effects"
- Toll-like receptor 4 (TLR4): An innate immune receptor recognizing LPS and triggering inflammation. "binding to Toll-like receptor 4 (TLR4) on microglia"
- Vagus nerve: A major parasympathetic nerve mediating gut-brain communication. "Key components such as the enteric nervous system (ENS) and vagus nerve mediate this interaction"
- Vasoactive intestinal peptide (VIP): A neuropeptide implicated in circadian and sleep regulation. "the use of neuropeptides, such as orexins, vasoactive intestinal peptide (VIP) and neuropeptide Y"
- Washed microbiota transplantation (WMT): A refined form of FMT using purified microbial preparations. "washed microbiota transplantation (WMT), as innovative interventions to restore gut integrity and mitigate neuroinflammation"
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