The ‘Cross Talk’ Between Sleep, Nutrition, and Immunity

Sleep affects various immune parameters, is associated with reduced infection risk, and can improve infection outcome, autoimmunity, and vaccination responses[i]. Adequate nutrition is an essential factor that also supports the immune system[ii]. Not only as it provides fuel for rapidly metabolising immune cells, but also many micronutrients operate as regulators of the immune system, including the generation of cytokines, antibodies, and many immune-active proteins and metabolites.

Many modifiable factors can influence the immune system. These include sleep quality, nutrition, physical fitness, stress, and body fatness. Sleep quality is a very important factor. For example, sleep deprivation is associated with fatigue, impaired cognitive functions during daytimes, reductions in safety-related performance, increased risk of many diseases, and increased all-cause mortality. Sleep provides an immune-supportive role, enhancing host defence against various infections and inflammatory conditions, and should be regarded as a very important part of lifestyle-related health management.

Inflammation induction

In the absence of an infectious challenge, sleep appears to promote inflammatory homeostasis through effects on several inflammatory mediators, such as cytokines. This is supported by findings that prolonged sleep deficiency (e.g., short sleep duration, sleep disturbance) can lead to chronic, systemic low-grade inflammation and is associated with various diseases that have an inflammatory component, like diabetes, atherosclerosis, and neurodegeneration[iii].

The scientific analyses of these notions started way back 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[iv]. Whilst circumstantially limited in opportunity for molecular analysis, his inciteful proposition has demonstrated proven mechanistic links[v].

Internal Clocks

Sleep is regulated homeostatically, meaning that sleep increases in duration and intensity after a prolonged period without sleep. In addition to this homeostatic component, a second process that is independent of prior wakefulness modulates the timing of sleep, namely, the circadian system. This system is responsible for imposing and synchronising a close to 24h rhythm on several behaviours and body functions, including the propensity to sleep or be awake along the 24h sleep-wake cycle. The homeostatic and circadian components constitute the two factors of the so-called two-process model describing the successful regulation of sleep[vi].

The regulation of homeostasis and circadian rhythms are affected by inflammatory responses, which remain persistent. Typical are elevations of inflammatory markers of low magnitude and the cardinal signs of local inflammation are generally absent. Such mild and often chronic elevations are most frequently referred to as low-grade inflammation; sometimes terms such as unresolved, sterile, meta-, sub-, or para-inflammation[vii].

They do not appear to involve the classical inducers of the typical inflammatory response (i.e., infection or tissue injury[viii]), but rather cellular stress or malfunction that leads to activation of pattern recognition receptors by the release of damage-associated molecular patterns (DAMPs), which are released by stressed or injured cells such as heat shock proteins and sterile inflammation inducers[ix].

Additional inducers of low-grade inflammation are nutrients and metabolites acting as DAMPs (e.g., free fatty acids, oxidised lipoproteins) and commensal bacteria representing a source of pathogen-associated molecular patterns (PAMPs) from microbes like bacteria or viruses [e.g., bacterial lipopolysaccharide (LPS); viral double-stranded ribonucleic acid (RNA) sometimes also described with the more global term microbe-associated molecular patterns (MAMPs), as they are not necessarily all pathogenic[x].

Nutrition and sleep

Optimal nutrition involves providing all the necessary nutrients in order to maintain health and wellbeing. The foods that people consume can not only influence their wakefulness during the day but also their quality of sleep. Sleep is not only influenced by the energy efficiency of the diet, but also by the content of macronutrients, such as proteins, carbohydrates, and fats[xi]. Insufficient protein intake may impair sleep quality, while too much protein intake may lead to difficulties in maintaining sleep[xii].

Eating foods that are rich in tryptophan, melatonin, and serotonin (walnuts), as well as supplements, improves sleep quality. In adults, after consuming foods rich in tryptophan, a longer downtime, increased performance, and an increased total sleep time has been observed[xiii]. Vitamins and minerals (e.g., B vitamins, zinc, magnesium) influence sleep quality, and when a deficiency was compensated for, an improvement in the sleep rate and the overall sleep quality was observed[xiv].

Many food metabolites may be important in the regulation of sleep through the regulation of other related factors. Foods may also influence the commensal microbiota, which may lead to the formation of metabolites[xv]. Inadequate nutrition in the long term may contribute to inflammation, which is closely related to insomnia. Adequate nutrition that is rich in fruits, vegetables, and whole grains has a positive effect on sleep and weight[xvi].

It is easy to believe that dietary nutrition plays an important role in sleep wellness. Using diet management to improve sleep is a realisable, convenient, and inexpensive strategy. Indeed, some nutritional components or their metabolites have been experimentally proved to be beneficial[xvii]. However, many others are only hypothetical and lack solid scientific evidence. The intersection between nutrients related to sleep and immune function is clear, inflammation management, and gastrointestinal health are two areas of significant research and clinical experience[xviii].

Rather than being simply pathogen reactive, the neurally integrated immune system is regulated by sleep and nutrient dynamics such that it both seems to anticipate threats and facilitates an effective threat response[xix]. Alteration in the homeostatic, circadian, nutrient and sleep patterns alters innate and adaptive immune capability, leading to altered low levels of inflammation.

Ensuring adequate sleep, optimal nutrition and other beneficial lifestyle changes ensures that our physiological systems are appropriately ‘prepared’ to respond. Systems able to adapt to change and maintain resilience in the face of persistent and acute threats have a known survival advantage[xx].

Integrated Interventions

The use of lifestyle interventions to mediate disturbed sleep patterns, reverse inflammation, restore the homeostatic balance and coordinate circadian patterns is a core objective in the clinical strategy for NCDs and infectious diseases. Insufficient sleep leads to increased concentrations of inflammatory markers, such as C-reactive protein (CRP). Indeed, the ability of insomnia treatment to reduce levels of CRP is comparable to the anti-inflammatory effects of a healthy diet and exercise[xxi],[xxii].

Sleep patterns and nutrient intake, as well as inflammation, are influenced by environmental factors and personalised genomic factors. When non-physical threats become chronic or when disease leads to imbalanced physiological systems as can occur with inflammatory disorders, for example, sleep and nutrient need are disrupted, and the beneficial crosstalk between sleep, diet and the immune system becomes misaligned.

Such changes in sleep patterns and food intake, in response to chronic stressors, can lead to inflammation-related morbidities, including cognitive ageing and depression, while also reducing innate and adaptive antiviral defences. Therefore, the ability to harness reciprocal sleep-nutrient–immune regulation through nutritional or behavioural interventions has the potential to redirect a misaligned inflammatory transcriptional programme and to more effectively accommodate the many social threats that we now perceive and experience.

Conclusion

Findings on the sleep-nutrient-immune relationship also depend on a number of time dimensions, including time of day of assessment or experimental intervention (e.g., morning, evening, night hours), age of the participant (e.g., infancy, adolescence, older age), duration of infectious or inflammatory disease (e.g., early or late disease stages), and chronicity of sleep or nutrient deficiency (e.g., acute, sub-chronic, chronic)[xxiii]. Understanding the influence of these time dimensions on the relation between sleep nutrition and the immune system is valuable for developing nutraceutical, food, and behavioural strategies to support optimal immune and sleep health. However, whilst knowledge in these areas is still limited it is likely to expand as these areas are explored, such as in the proposed frontiers nutritional immunology research, due in Oct 2022.

References

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Key words

Immunity, Sleep, Nutrients, Walnuts, Tryptophan, Magnesium, Microbiome, Inflammation, Fatigue