insights

Read Time: 8 Minutes

Sleep is a dynamic process that affects every system of the body, and the interplay of different environmental and lifestyle factors influences sleep quality and architecture.¹ Recent research suggests that some of these factors may influence sleep via the microbiota-gut-brain axis, both directly and indirectly.^1-3 What is the connection between lower sleep quality and quantity and a dysbiotic gut microbiome? What emerging interventions targeting the microbiota-gut-brain axis may be beneficial for the treatment of impaired sleep patterns?

From a young age, microbial communities within the body interact with the sleep-wake cycle in a complex manner.¹ The gut microbiome, which produces a variety of metabolites and compounds with neuroactive and immunomodulatory properties, including short-chain fatty acids, secondary bile acids, and neurotransmitters, may affect brain function and behavior through the microbiota-gut-brain axis.⁴ These microbial products are also involved in sleep physiology.³ While the mechanisms underlying the microbiota-gut-brain axis are not fully understood, some evidence has suggested that neuroendocrine, immune, and metabolic pathways may regulate interactions.³

Growing evidence reports a positive correlation between sleep efficiency and the diversity of the gut microbiota from childhood through adulthood.³ For example, a recent study of 143 largely Caucasian children ages 3-4 found that children with a high total nighttime sleep duration (average 9.48 hours), greater sleep efficiency, and less time awake at night showed a higher relative abundance of Bifidobacterium and Bacteroides.⁵ Both bacteria have been linked to sleep-related neurochemicals in previous studies, such as serotonin and its precursors tryptophan and gamma-aminobutyric acid. In the 2022 study by Wang et al, five taxa showed greater abundance in children who had shorter night-time sleep duration, less sleep efficiency, and longer waking time, including Blautia, Coprococcus, and other Lachnospiraceae.⁵

Evaluating individuals with healthy sleep quality, a 2020 pilot study of 28 young adults by Grosicki et al found higher proportions of the abundance of Blautia and Ruminococcus (belonging to Firmicutes), lower proportion of Prevotella (belonging to Bacteroidetes), and higher ?-diversity of the gut microbiota among individuals reporting superior sleep quality.⁶ Researchers hypothesize that sleep quality may be positively correlated with the ratio of Firmicutes/Bacteroidetes and microbial diversity.^3,6

A 2021 cross-sectional pilot study found that adult short sleepers have different microbial composition, such as an increased abundance of the bacteria Pseudomonas (0.14% vs. 0.08%) in feces and a lower abundance of Sutterella (0.38% vs. 1.25%) compared to normal length sleepers.^1,7 Interestingly, Sutterella has been associated with lower relative abundance in patients with depression and may play a role in the microbiota-gut-brain axis.⁷ Several other studies indicate that a lower sleep quantity and quality are associated with a dysbiotic gut microbiome characterized by a lower microbial diversity, an increase of pathogenic microbiota, or the loss of beneficial microbes.^4,8-9

Sleep-Related Disorders & the Microbiome

 Obstructive sleep apnea (OSA)

OSA leads to fragmented night sleeping and daytime sleepiness due to episodes of obstruction of the upper airway; it is accompanied by repeated sleep fragmentation and forced awakening from sleep due to airway collapse.^1,3 Studies suggest that those suffering from OSA may have a prolonged N1 stage and a shortened REM sleep stage.³

Evidence suggests that intermittent hypoxia may result in changes to the gut microbiota, including increased Firmicutes richness and decreased Bacteroidetes richness, as well as decline in ?-diversity.^3,10 A 2020 pilot study in children with OSA showed a significant decrease in gut microbial diversity compared to healthy children and an increase of inflammation and gut barrier disruptor–related strains.^1,3,11 In 2019, Ko et al found gut microbial dysbiosis, in varying degrees, in adults with OSA-hypopnea syndrome.^1,12 Specifically, short-chain fatty acid–producing bacteria was decreased and the level of interleukin-6 was increased compared to controls.^1,12

More recently, a 2023 prospective case control study of 48 Chinese adults age 18-65 found that the severity of OSA was related to differences in the structure and composition of the fecal microbiome.¹³ Enriched Fusobacterium, Megamonas, and Lachnospiraceae_UCG_006 and reduced Anaerostipes was found in patients with severe OSA. Enriched Ruminococcus_2, Lachnoclostridium, Lachnospiraceae_UCG_006, and Alloprevotella was found in patients with high intestinal barrier biomarkers. Lachnoclostridium and Lachnospiraceae_UCG_006 were the common dominant bacteria of OSA and intestinal barrier damage. Fusobacterium and Peptoclostridium were independently associated with apnea-hypopnea index. The dominant genera of severe OSA were also associated with glucose, lipids, neutrophils, monocytes, and BMI.¹³

Insomnia

A range of psychiatric and inflammatory disorders as well as metabolic syndromes are comorbid with insomnia.^2,14 Marked changes in gut microbiota diversity and composition was found by Liu et al in 2019 among 10 chronic insomnia patients compared to 10 healthy controls.^1,15 A later study by Li et al observed a decrease in microbiome diversity in acute and chronic insomnia patients, with greater effects on bacterial diversity found in patients with disordered sleep.^1,13 These individuals also show an increase in the inflammatory cytokine interleukin-1?.¹³ Both of these studies noted that an increase of Bacteroidetes phylum could be a biomarker to identify insomnia.¹

A 2022 multiomics analysis reveals that the composition and structure of gut microbiota and metabolism in insomnia patients differs from healthy controls.¹⁴ Compared to healthy controls, the relative abundances of Lactobacillus, Streptococcus, and Lactobacillus crispatus were significantly increased in people with insomnia. (Lactobacilli possess several health-ameliorating attributes, including alleviation of chronic diseases, immune system stimulation, pathogen protection, and nutritional physiology.)¹⁴ Five metabolic pathways in patients with insomnia differed between the two groups as well, including glycerophospholipid metabolism; glutathione metabolism; nitrogen metabolism; alanine, aspartate, and glutamate metabolism; and aminoacyl-tRNA biosynthesis.¹⁵ Researchers also found that IL-1? levels were significantly higher in insomnia patients while TNF-? was significantly reduced; the changes in the level of IL-1? and TNF-? were associated with some specific bacteria and metabolites, such as Prevotella amnii, Prevotella buccalis, Prevotella timonensis, and Prevotella colorans.¹⁵

Clinical Applications: Microecological Therapy

A novel treatment strategy referred to as microecological therapy has emerged, featuring several potential interventions targeting the gut microbiota to improve sleep quality and quantity.³ The targets of this therapy include regulating the abundance of specific bacterial groups, microbial metabolites, intestinal barrier function, and host immune response. Evidence suggests that microbiota manipulations like dietary interventions and the use of probiotics may be beneficial for the treatment of impaired sleep.³

Probiotics

Although probiotics are transient visitors, they play a role in shifting the overall balance of the microbiome, modulating the immune system, and decreasing inflammation.¹⁸ Consuming probiotics in foods or supplements may encourage colonization of commensal organisms over time.¹⁸ Studies suggest that probiotics may improve sleep latency, sleep quality and duration, sleepiness upon wakening, and recovery from fatigue.^19-21

A 2023 systematic review and meta-analysis of six studies showed significant improvement in sleep quality of 343 healthy adults with mild to moderate stress as an effect of daily consumption of L. gasseri compared to controls (-0.77, 95% CI -1.37 to-0.16, P=0.01).²¹ In addition to the cumulative beneficial effect shown using the PSQI global score, four of six studies reported a statistically significant positive effect of L. gasseri on sleep quality as indicated by at least one of the Pittsburgh Sleep Quality Index component scores (sleep latency, duration of sleep, sleep disturbance, and daytime dysfunction due to sleepiness).²¹

In a group of 94 healthy medical students from Japan studying for national exams, researchers found that sleep latency prolongation was less in the intervention group that received Lacticaseibacillus casei strain Shirota.^4,19 EEG measurements also showed that, as the examination approached, the time spent in NREM stage 3 sleep was reduced in the placebo group but maintained in the intervention group. In this double-blind, randomized, placebo-controlled trial, researchers also found a reduction of the mean Pittsburgh Sleep Quality Index (PSQI) score, indicating improved sleep quality among the intervention group compared to the placebo group.^4,19 

In a 2018 randomized crossover study, 40 adults aged 20-64 consumed either Lactobacillus helveticus or placebo for four weeks.^4,20 Sleep efficiency was measured as the total time spent in REM and NREM sleep divided by the total time from sleep onset to awakening. The researchers found that sleep efficiency significantly improved in the intervention group compared with placebo, including improved sleepiness on awakening, onset and maintenance of sleep, dreaming, and recovery from fatigue. It is important to note that the intervention group also received theanine, which has stress-reducing effects, while the placebo group did not.^4,20

Mediterranean Diet

Nutritional imbalances are potential contributors or causes of several chronic conditions, and nutrition-based interventions are fundamental components of many therapeutic strategies used to combat chronic illness and restore optimal health. These personalized treatments may include therapeutic food plans like the Mediterranean diet, a plant-based, antioxidant-rich, unsaturated fat dietary pattern that has been consistently associated with lower rates of disease and total mortality.²² Studies indicate that greater adherence to the Mediterranean diet may be associated with adequate sleep duration and with several indicators of better sleep quality. For example:

• In 2018, Castro-Diehl et al found that a Mediterranean-style diet was associated with adequate sleep duration and fewer insomnia symptoms.^23,24 This cross-sectional, multi-ethnic study of 2,068 adults with atherosclerosis found that compared with individuals who currently reported a low aMed score, those with a moderate-high aMed score were more likely to sleep 6-7 vs. <6 hr/night (p <0.01) and less likely to report insomnia symptoms occurring with short sleep (vs. no insomnia or short sleep alone; p <0.05). An increase in aMed score over the preceding 10 years was not associated with sleep duration or insomnia symptoms. However, compared with those with decreasing aMed score, individuals with an unchanging score reported fewer insomnia symptoms (p ?0.01).^23,24

• In a 2019 cross-sectional study of 1,314 Southern Italian adults, a higher adherence to the Mediterranean diet was associated with a higher likelihood of adequate overall sleep quality (highest vs. lowest quartile, OR=1.82, 95% CI: 1.32, 2.52).²⁵ Interestingly, in a sub-analysis of this study, researchers found the benefit of the Mediterranean diet on sleep latency was observed in normal and overweight individuals (highest vs. lowest quartile of adherence score, OR=2.30, 95% CI: 1.49, 3.54) but was not evident in the obese (highest vs. lowest quartile of adherence score, OR=1.12, 95% CI: 0.33, 3.79).^22,25

• In a 2021 cross-sectional study of 2,169 Costa Rican adults (1,600 men and 569 women), the association between sleep duration and adherence to the Mediterranean diet differed between men and women. In women only, a lower adherence to the Mediterranean diet was associated with shorter sleep duration, a finding that researchers say was primarily driven by lower consumption of fruits, vegetables, and legumes.²⁶ However, the literature is inconsistent regarding whether associations between sleep and diet are gender based. For example, a 2020 study conducted among young adults 21 to 30 years old found that men with lower fruit and vegetable intake had a higher risk of insomnia as compared to women.^26,27

Functional Medicine Considerations

Taken together, these studies illustrate the important connection between the gut microbiome and sleep patterns. Screening patients for sleep disorders is encouraged as a regular practice in functional medicine, and there are a range of effective lifestyle interventions for patients suffering from poor sleep. A close working relationship between clinician and patient can help identify sleep troubles early on so that they may be targeted with behavioral and lifestyle therapies to prevent or reverse further damage.

The IFM Toolkit contains a patient education handout illustrating the effects of poor sleep throughout the body, an outline of the signs and symptoms of poor sleep, and tips for improving sleep. The IFM Toolkit is one of the most robust collections of functional medicine resources available to practitioners and offers a variety of dynamic, clinical resources to use in practice. IFM continually updates the toolkit resources with the latest evidence-based research and considerations. All practitioners who complete IFM’s premier course, Applying Functional Medicine in Clinical Practice (AFMCP), have access to the IFM Toolkit, which contains a wealth of information for new and seasoned practitioners alike. With IFM membership, the toolkit can be accessed anytime.

To learn more about sleep and the microbiome, consider attending IFM’s GI Advanced Practice Module (APM). This course takes a whole systems approach to evaluating and treating not only local gastrointestinal disease but many systemic diseases that are linked to GI dysfunction. It supplies practitioners with the foundational background, insight, and in-depth clinical thinking to confidently work up and treat patients who may present with conditions, signs, and symptoms indicative of gastrointestinal dysfunction. Discussions will include important laboratory evaluations to be considered, the appropriate clinical connections that must be made, and the treatment approaches that should be used.

Related Articles

The Gut-Brain Axis & Systems Biology

The Microbiome, Stress Hormones, & Gut Function

Prebiotic Foods for Postbiotic Abundance

References

1. Wang Z, Wang Z, Lu T, et al. The microbiota-gut-brain axis in sleep disorders. Sleep Med Rev. 2022;65:101691. doi:1016/j.smrv.2022.101691
2. Sen P, Molinero-Perez A, O’Riordan KJ, et al. Microbiota and sleep: awakening the gut feeling. Trends Mol Med. 2021;27(10):935-945. doi:1016/j.molmed.2021.07.004
3. Han M, Yuan S, Zhang J. The interplay between sleep and gut microbiota. Brain Res Bull. 2022;180:131-146. doi:1016/j.brainresbull.2021.12.016
4. Haarhuis JE, Kardinaal A, Kortman GAM. Probiotics, prebiotics and postbiotics for better sleep quality: a narrative review. Benef Microbes. 2022;13(3):169-182. doi:3920/bm2021.0122
5. Wang Y, van de Wouw M, Drogos L, et al. Sleep and the gut microbiota in preschool-aged children. Sleep. 2022;45(6):zsac020. doi:1093/sleep/zsac020
6. Grosicki GJ, Riemann BL, Flatt AA, Valentino T, Lustgarten MS. Self-reported sleep quality is associated with gut microbiome composition in young, healthy individuals: a pilot study. Sleep Med. 2020;73:76-81. doi:1016/j.sleep.2020.04.013
7. Agrawal R, Ajami NJ, Malhotra S, et al. Habitual sleep duration and the colonic mucosa-associated gut microbiota in humans—a pilot study. Clocks Sleep. 2021;3(3):387-397. doi:3390/clockssleep3030025
8. Matenchuk BA, Mandhane PJ, Kozyrskyj AL. Sleep, circadian rhythm, and gut microbiota. Sleep Med Rev. 2020;53:101340. doi:1016/j.smrv.2020.101340
9. Simkin DR. Microbiome and mental health, specifically as it relates to adolescents. Curr Psychiatry Rep. 2019;21(9):93. doi:1007/s11920-019-1075-3
10.  Zhang X, Wang S, Xu H, et al. Metabolomics and microbiome profiling as biomarkers in obstructive sleep apnoea: a comprehensive review. Eur Respir Rev. 2021;30(160):200220. doi:1183/16000617.0220-2020
11.  Valentini F, Evangelisti M, Arpinelli M, et al. Gut microbiota composition in children with obstructive sleep apnoea syndrome: a pilot study. Sleep Med. 2020;76:140-147. doi:1016/j.sleep.2020.10.017
12.  Ko CY, Liu QQ, Su HZ, et al. Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities. Clin Sci (Lond). 2019;133(7):905-917. doi:1042/cs20180891
13.  Li Q, Xu T, Shao C, et al. Obstructive sleep apnea is related to alterations in fecal microbiome and impaired intestinal barrier function. Sci Rep. 2023;13(1):778. doi:1038/s41598-023-27784-0
14.  Rastogi S, Singh A. Gut microbiome and human health: exploring how the probiotic genus Lactobacillusmodulate immune responses. Front Pharmacol. 2022;13:1042189. doi:3389/fphar.2022.1042189
15.  Wang Q, Chen B, Sheng D, et al. Multiomics analysis reveals aberrant metabolism and immunity linked gut microbiota with insomnia. Microbiol Spectr. 2022;10(5):e0099822. doi:1128/spectrum.00998-22
16.  Liu B, Lin W, Chen S, et al. Gut Microbiota as an objective measurement for auxiliary diagnosis of insomnia disorder. Front Microbiol. 2019;10:1770. doi:3389/fmicb.2019.01770
17.  Li Y, Zhang B, Zhou Y, et al. Gut microbiota changes and their relationship with inflammation in patients with acute and chronic insomnia. Nat Sci Sleep. 2020;12:895-905. doi:2147/nss.s271927
18.  Mazziotta C, Tognon M, Martini F, Torreggiani E, Rotondo JC. Probiotics mechanism of action on immune cells and beneficial effects on human health. Cells. 2023;12(1):184. doi:3390/cells12010184
19.  Takada M, Nishida K, Gondo Y, et al. Beneficial effects of Lactobacillus casei strain Shirota on academic stress-induced sleep disturbance in healthy adults: a double-blind, randomized, placebo-controlled trial. Benef Microbes. 2017;8(2):153-162. doi:3920/bm2016.0150
20.  Nakagawa M, Yamamoto H, Kawaji M, Miura N, Wakame K, Endo T. Effects of lactic acid bacteria-containing foods on the quality of sleep: a placebo-controlled, double-blinded, randomized crossover study. Funct Foods Health Dis. 2018;8(12):579-596. doi:31989/ffhd.v8i12.572
21.  Chu A, Samman S, Galland B, Foster M. Daily consumption of Lactobacillus gasseri CP2305 improves quality of sleep in adults – a systematic literature review and meta-analysis. Clin Nutr. 2023;42(8):1314-1321. doi:1016/j.clnu.2023.06.019
22.  Scoditti E, Tumolo MR, Garbarino S. Mediterranean diet on sleep: a health alliance. 2022;14(14):2998. doi:10.3390/nu14142998
23.  Qi X, Ye J, Wen Y, et al. Evaluating the effects of diet-gut microbiota interactions on sleep traits using the UK Biobank Cohort. Nutrient 2022;14(6):1134. doi:10.3390/nu14061134
24.  Castro-Diehl C, Wood AC, Redline S, et al. Mediterranean diet pattern and sleep duration and insomnia symptoms in the Multi-Ethnic Study of Atherosclerosis. Sleep. 2018;41(11):zsy158. doi:1093/sleep/zsy158
25.  Godos J, Ferri R, Caraci F, et al. Adherence to the Mediterranean diet is associated with better sleep quality in Italian adults. 2019;11(5):976. doi:10.3390/nu11050976
26.  Gupta K, Jansen EC, Campos H, Baylin A. Associations between sleep duration and Mediterranean diet score in Costa Rican adults. 2022;170:105881. doi:10.1016/j.appet.2021.105881
27.  Jansen EC, She R, Rukstalis MM, Alexander GL. Sleep duration and quality in relation to fruit and vegetable intake of US young adults: a secondary analysis. Int J Behav Med. 2021;28(2):177-188. doi:1007/s12529-020-09853-0