Over the last decades, the prevalence of sleep disorders has substantially increased globally, and it is increasingly understood to have many important health and economic-related effects.[1]
A wide range of behavioural risk factors have been identified to explain, at least in part, this rise in sleep challenges. One primary driver is the evolution of the modern lifestyle which is characterised by a number of potential contributors, such as higher levels of non-resolving stress, prolonged working hours, increased nocturnal noise, and higher exposure to artificial lights[2]; moreover, over-reliance on energy-dense but nutrient-poor foods and meals and preference for low-quality ready-meals have also been hypothesised to play a role in sleep disorders.[3]
The pervasive transition from traditional dietary patterns characterised by a preference for plant-based foods toward a Western-like diet characterised by a high intake of ultra-processed food and high fat and free sugar and lack of complex carbohydrates is also identified as a possible contributor.[4] The resulting dynamic and disordered relationship between micronutrient deficiencies and sleep quality is evolving, but it is clear there are mutual relationships between key micro and macronutrients, immunity and sleep.[5]
Immune system competence relies extensively on the extraction of vital nutrients from foods. Nutrition consequently plays an essential role in the regulation of optimal immunological response, by providing adequate nutrients in sufficient concentrations to immune cells. Evidence also suggests that for certain nutrients increased intake, above currently recommended levels, may optimise immune functions including improving defence function and thus resistance to infection, while maintaining immunological tolerance. This in turn may beneficially modulate chronic inflammatory and autoimmune conditions, and decrease infection risk.
There are many micronutrients, such as minerals, and vitamins, as well as some macronutrients, such as some amino acids, cholesterol and fatty acids demonstrated to exert a very important and specific impact on appropriate immune activity.
Additionally, a wide variety of phytochemicals and other chemical biocomponents found in nutrients are also nutritional-immuno-sleep-modulators. These biocomponents are understood to affect immune function but are not crucial for maintaining normal cell metabolism and function.[6]
Sleep and Nutrition
The relationship between diet and sleep features is rather complex and is bidirectional (nutritional factors affecting sleep quality and sleeping patterns affecting calorie intake, food quality, and obesity risk) and multidimensional, involving other lifestyle aspects (i.e., level of physical activity, smoking and alcohol drinking habits, etc.) and health factors (i.e., presence of obesity and diabetes, sleep apnoea, etc.).[7],[8] This level of cross-platform variability makes the application of multiple lifestyle and nutrition factors simultaneously more likely to have a beneficial outcome than the hoped-for magic bullet approach.
Besides immunity and hormonal activities, alterations of the gut microbiota and the circadian rhythm are also important mechanisms that contribute independently and in combined form to the underlying relationship between diet and sleep. [9]
Research on this topic is thus multidisciplinary, involving social and epidemiological relations between diet and sleeping patterns, or preclinical and mechanistic studies to understand which specific components of the diet may play a role in sleep features.
What seems clear from the advances in the evidence to date is that both eating and sleeping represent two physiological processes that are more related than thought in the past, not just affecting “similar” pathways but rather being part of a unique larger mechanism necessary to the proper functioning of the human body.
Sleep and Immunity
Evidence from numerous studies supports the understanding that in terms of sleep and immune cross talk, sleep and nutritional quality is more important in terms of immune resilience than quantity. In addition, deficits in sleep and nutrient quality are cumulative and mutually destructive.[10]
Sleep-immune interactions are embedded in everyday life and folk wisdom. It is easily recognised that an infection makes us tired and increases the desire to sleep, and a good night’s sleep is commonly recommended as ‟the best medicine to recover from an infectious illness.”
Sleep and immunity, therefore, are bidirectionally linked; it is assumed and understood that prolonged sleep loss weakens our body’s defence system and renders us prone to catch a cold or any other infection. The historical scientific analyses of these notions started in 350 BC when Aristotle elaborated in his book On Sleep and Sleeplessness that sleep is induced by hot vapours that arise from the stomach during digestion, and that a similar sleep response can be observed in feverish patients.[11]
In the early 20th century, researchers postulated a hypnotoxin that increases during wakefulness, induces sleep and is cleared again during sleep.[12] The first hypnotoxin, discovered in the 1980s, turned out to be the bacterial cell wall component muramyl peptide (MP), and more than 2,000 years ago, it was assumed that it derives from the gastrointestinal tract. MPs, which are part of the peptidoglycan of cell walls of all known bacteria, are regularly formed in the body during the breakdown of gastrointestinal microflora and are considered to be natural regulators of immunity and sleep.
MPs are involved in the stimulation of all forms of anti-infectious defence processes of the body: phagocytosis, cellular and humoral immunity, and they also take part in ensuring immunological tolerance and haematopoiesis, regulating immune homeostasis. The use of selected probiotics to enhance sleep, whilst early in terms of data, aligns with the notion of inducing eubiosis as well as being a source of MPs.[13]
Gut-Derived Sleep Factors
Intestinal bacteria, and/or bacteria cell wall degradation products, such as MPs or lipopolysaccharide (LPS), translocate across the intestinal epithelial barrier. Depending on their frequency and concentration, and the viability of the gastrointestinal barrier, these will impact the sleep process.
Sleep loss and conditions that affect sleep, e.g., injury, food intake, stress, circadian rhythm, and exercise, also affect bacteria and their cell wall fragments translocation. Bacteria are engulfed by phagocytes, such as macrophages or neutrophils, and digested; their digest products (e.g., MPs, LPS) are released into the surrounding intercellular fluid.
MPs and LPS in turn activate phagocytes that then release cytokines such as interleukin-1 and tumour necrosis factor. These and other systemic cytokines are then able to access the brain through at least two routes.
Cytokines can signal the brain via vagus nerve afferents whose action potentials induce further cytokine production in the brain by glia and neurons. Cytokines can also cross the blood–brain barrier (BBB) to induce their own and other cytokine productions.
Brain cytokines at low concentrations enhance sleep, while at high concentrations fragment sleep. The same pattern is seen in mild to chronic infections. Other microbes, e.g., viruses, and their components also enhance cytokine production via endogenous receptors that recognise pathogen-associated molecular patterns (PAMPs), e.g., Toll-like receptors, to affect sleep.
Recent work has also shown that the gut microbiota and its metabolites exhibit diurnal rhythmicity which predominantly responds to the feeding/fasting cycle. Persistent jet lag, an obesogenic diet, and clock gene deficiency can dampen the natural circadian oscillatory nature of gut bacterial composition affecting sleep quality, which can subsequently be rescued by time-restricted feeding.
Contrastingly, gut microbial metabolites including MP and LPS, can positively influence central and hepatic clock gene expression and sleep duration and regulate body composition through circadian transcription factors.
A study published in SLEEP found that sleep loss initiates, amplifies, and extends blood levels of a chemical signal endocannabinoid 2-arachidonoylglycerol (2-AG) that enhances the pleasure we experience whenever we eat sweet, salty, or high-fat snacks and is just what you do not need circulating late at night when standing in front of the fridge.[14]
Both sleep fragmentation and short sleep duration are associated with gut dysbiosis which may be due to the activation of the HPA-axis. Metabolic disturbances associated with sleep loss may in fact be mediated through the overgrowth of specific gut bacteria. Reciprocally, the end products of bacterial species which grow in response to sleep loss are able to induce fatigue, demonstrating the intersecting and potentially self-setting role the microbiome plays in the core elements of sleep and immunity and nutrition.[15]
Comment
Many people battle with sleep and feel their lives are dominated by the related loss of focus and energy. Yet rarely are long-term sleep problems the result of one event, rather they are the reflection of numerous intersecting mechanistic processes that require careful unwinding to achieve the therapeutic threshold effect of somnolence and the regular nocturnal visit from Morpheus.
References
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[2] Grandner MA. Sleep, health, and society. Sleep Med Clin. (2017) 12:1–22.
[3] Godos J, Currenti W, Angelino D, Mena P, Castellano S, Caraci F, et al. Diet and mental health: review of the recent updates on molecular mechanisms. Antioxidants (Basel). (2020) 9:346
[4] Godos J, Grosso G, Castellano S, Galvano F, Caraci F, Ferri R. Association between diet and sleep quality: A systematic review. Sleep Med Rev. (2021) 57:101430.
[5] Ikonte CJ, Mun JG, Reider CA, Grant RW, Mitmesser SH. Micronutrient Inadequacy in Short Sleep: Analysis of the NHANES 2005-2016. Nutrients. 2019 Oct 1;11(10):2335
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[10] Besedovsky L, Lange T, Haack M. The Sleep-Immune Crosstalk in Health and Disease. Physiol Rev. 2019 Jul 1;99(3):1325-1380.
[11] Aristotle On Sleep and Sleeplessness. http://classics.mit.edu//Aristotle/sleep.html.
[12] Ishimori K. True cause of sleep – a hynogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igaku Zasshi 23: 423–457, 1909
[13] Lee L, Letchumanan V, Law JW, et al IDDF2022-ABS-0241 Exploring the potential role of probiotics in alleviating insomnia Gut 2022;71:A65
[14] Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, de Wit H, Hillard CJ, Van Cauter E. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol. Sleep. 2016 Mar 1;39(3):653-64.
[15] Matenchuk BA, Mandhane PJ, Kozyrskyj AL. Sleep, circadian rhythm, and gut microbiota. Sleep Med Rev. 2020 Oct;53:101340.
