Irritable bowel syndrome (IBS) is one of the most common GI disorders. It is twice as frequent among women as among men. IBS is related to dysfunction of the enteral serotonin system. There are no published systematic epidemiologic studies about the occurrence of IBS among patients with RLS. In our own clinical database, GI symptoms had been tabulated from 141 RLS patients (unpublished observations). Of these patients, 17 (12 %) had GI symptoms that could be diagnosed as IBS type. Because we had not tabulated this history systematically, the true prevalence might be higher. On the other hand, about 29 % of patients with IBS have RLS [36].

Intestinal microbiota has a role as a regulator of autoimmune diabetes in animals, and probably also in humans [37]. The role of gut microbiota in other human HLA-associated autoimmune diseases, including narcolepsy, remains to be studied. Small intestine bacterial overgrowth (SIBO) is common in RLS. In a recent series, SIBO was found in almost 70 % of patients with RLS [38]. In a randomized study, all 20 patients with RLS had marked improvement in their RLS symptoms after treatment of SIBO [39]. The therapy of SIBO was based on rifaximin, which is a rifamycin-based nonsystemic antibiotic, meaning that the drug will not pass the GI wall into the circulation [39–41]. Although treatment with antibiotics may be beneficial, the spectrum of gut microbes is changed, which may be followed by various adverse effects and symptoms that may last years. Changes in the gut microbiota may be involved in many neurological and psychological symptoms [42]. The intestinal microbes are also known to be able to produce many neurotransmitters such as GABA, serotonin, melatonin, catecholamines, histamine, and acetylcholine [42–44]. Different diets have been advised for patients with IBS. Some beneficial results have been obtained by use of probiotics and by FODMAP diet. That diet is low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) that are poorly absorbed by the small intestine and fermented by bacteria in the large intestine [45].

Neurosteroids are synthesized in astrocytes, oligodendrocytes, Schwann cells, Purkinje cells, hippocampal neurons, and retinal amacrine and ganglion cells [46, 47]. Cholesterol is transported to glial mitochondria, where it is converted to pregnenolone. In the cytosol, pregnenolone is then converted to different neurosteroids such as allopregnanolone and dehydroepiandrosterone (DHEA). DHEA is a precursor of testosterone, which is converted to estradiol by an aromatase [46, 47]. Vitamin D is also an important neurosteroid [48]. Synthesis of neurosteroids is regulated by interactions between neurons and glial cells.

Neurosteroids have many important actions. Allopregnanolone activates neuronal GABA_A receptors having anxiolytic, sedative, sleep-inducing, and anticonvulsant effects. Benzodiazepines, alcohol, and γ-hydroxybutyrate increase brain levels of allopregnanolone. Thus, these drugs may potentiate GABAergic transmission directly and also by increasing allopregnanolone. Pregnenolone sulfate, DHEA, and DHEA sulfate (DHEA-S) are inhibitory, noncompetitive modulators of GABA_A and positive modulators of N-methyl-d-aspartate (NMDA) receptors by facilitating calcium influx. Estradiol inhibits NMDA receptors. Neurosteroids acting on NMDA are implicated in cognition, neuroprotection, and neurotoxicity. While pregnenolone sulfate is excitotoxic to cortical and retinal cells, DHEA and DHEA-S have neuroprotective effects against glutamate toxicity. However, the exact mechanisms of such neuroprotective effects are not clear.

Neurosteroids have been implicated in many neurologic and psychiatric disorders, including epilepsy, neurodegenerative diseases, schizophrenia, and depression. For example, depression is associated with reduced levels of allopregnanolone in cerebrospinal fluid. Antidepressant treatment with fluoxetine increases allopregnanolone levels [49]. There is also some evidence that DHEA helps in the treatment of depression. The beneficial effect of DHEA correlates with a decrease in glucocorticoids, which are increased in depression.

There is increasing evidence about many important roles of neurosteroids in regulation of vigilance as well. It remains to be studied whether nutritional factors could also play some role in this. DHEA is marketed in pharmacies and health shops. Little is known about possible positive (and, perhaps, also negative) long-term neuropsychiatric effects of nutritional factors that may cause changes in brain neurosteroids.

Several lines of evidence have shown that diets rich in fibers, vegetables, and fruits are associated with reduced risk of cardiovascular disease and many neurologic diseases [50]. There is also evidence that a vegetarian diet helps in weight control, and in this way prevents obesity and occurrence of obstructive sleep apnea. As stated previously, rapidly absorbed low-fiber carbohydrates induce sleepiness. Therefore, a vegetarian diet with a lot of fiber and slowly absorbing “good” carbohydrates is better for staying alert during waking time. Some of the positive effects are explained by antioxidant effects of different phytochemicals, but there is also evidence that some effects may be due to subtoxic effects of some neurotoxic molecules in the gut.

Hormesis refers to a paradoxical process in which low doses of a given toxic substance, or radiation, induce beneficial effects while larger doses of the same substance are toxic to cells and organisms [51–53]. Examples of endogenous molecules with neurohormetic actions are nitric oxide, carbon monoxide, glutamate, and calcium. Neuroprotective natural substances include α-tocopherol, lycopene, resveratrol (red grapes, red wine, peanuts, and soy), sulforaphanes (broccoli), catechins (green tea), allicin and allium (garlic), curcumin (turmeric), hypericin (in St. John’s wort), and many others. In randomized clinical trials, hypericin (Hypericum extracts) has shown clinical efficacy comparable with the efficacy of some commonly used antidepressants, including citalopram, paroxetine, and fluoxetine [53–60]. This is of interest to sleep specialists because antidepressants are also used in treating insomnia, especially if it is thought to be associated with underlying depression. Much more research is needed to find out if natural substances affect sleep–wake behavior.

Hot spices may disturb sleep, perhaps by a neurohormetic action. In one study on six young men, tabasco and mustard in the evening reduced slow-wave and stage 2 sleep, reduced total time awake, and prolonged sleep onset. The spicy food in the evening elevated body temperature during the first sleep cycle. It is possible that capsaicin affects sleep by its effects on body temperature [61].

Caffeine, used mainly in the form of coffee, is the world’s most common psychoactive drug. Caffeine is present in coffee, tea, cola, energy drinks, and chocolate, and it induces wakefulness. Its stimulant properties depend on its ability to reduce adenosine transmission in the brain. Caffeine acts as an antagonist to adenosine A1 and especially to adenosine A2 receptors [62]. Huang and collaborators found in knockout mice that caffeine increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2a receptor knockout mice. Thus, caffeine-induced wakefulness may be due mainly to its effects on adenosine A2a receptors [63]. Porkka-Heiskanen and her collaborators [64–66] have also recorded human sleep electroencephalograms (EEGs). The longer the previous wakefulness period is, the longer and deeper is the following sleep. The inhibitory neuromodulator adenosine is one promising candidate for a sleep-inducing factor. Its concentration is higher during wakefulness than during sleep, it accumulates in the brain during prolonged wakefulness, and local perfusions as well as systemic administration of adenosine and its agonists induce sleep and decrease wakefulness. The hypothesis is that adenosine accumulates in the extracellular space of the basal forebrain during wakefulness, increasing the sleep propensity. The increase in extracellular adenosine concentration decreases the activity of the wakefulness-promoting cell groups, especially the cholinergic cells in the basal forebrain. When the activity of the wakefulness-active cells decreases sufficiently, sleep is initiated. During sleep, the extracellular adenosine concentrations decrease, and thus, the inhibition of the wakefulness-active cells decreases, allowing awakening and a new wakefulness period [65].

One cup of coffee contains 75–125 mg of caffeine. A large amount of caffeine, usually over 300–500 mg (depending on individual sensitivity), causes restlessness, anxiety, trembling, tinnitus, and feelings of euphoria/delirium. Everyday use of more than 500 mg of caffeine leads to caffeinism with insomnia, fatigue, and different psychosomatic symptoms. It has been estimated that perhaps 10–20 % of coffee drinkers have caffeinism. Chronic coffee drinkers have often developed tolerance to caffeine, and some people may drink more than 10 cups of coffee daily. They have withdrawal symptoms if they do not have their coffee. Coffee is a well-known factor disturbing sleep [67–69]. Two or three cups of coffee (or in sensitive persons just one cup) before bedtime is followed by difficulty falling asleep and restless sleep.

Landolt et al. [70] administered 200 mg of caffeine in the morning and analyzed the sleep stages and EEG power spectra during the subsequent night in nine healthy men. They also measured caffeine levels in saliva, which decreased from a maximum of 17 μmol/L 1 h after intake to 3 μmol/L at 23:00 in the evening. Compared to placebo, sleep efficiency and total sleep time were significantly reduced after the morning intake of caffeine [70]. Slow-wave sleep decreases and amount of stage 1 sleep usually increases after drinking coffee. Insomnia and RLS are more frequent among habitual coffee drinkers than among others. Paradoxically, in some persons, one or two cups of coffee may ameliorate quality of sleep. The reason can be behavioral conditioning, but it is also known that caffeine has a stimulating effect on both breathing and cardiac function. In patients with RLS, symptoms worsen by drinking a lot of coffee. Missak postulated that the human body—in cases of iron deficiency and chronic renal failure—may produce a substance similar to caffeine [71].

Epidemiologic studies have provided evidence that caffeine, an adenosine receptor antagonist, reduces the risk for PD [72–75]. There are indications of specific interactions between striatal adenosine A2a and dopamine D₂ receptors. In one study, the dopaminergic effects of caffeine were examined with [¹¹C]raclopride positron emission tomography in eight healthy habitual coffee drinkers after 24 h of caffeine abstinence. Compared to oral placebo, 200 mg of oral caffeine induced a 12 % decrease in midline thalamic binding potential (p < 0.001). These findings indicate that caffeine has effects on dopaminergic neurotransmission in the human brain, which may be different in the striatum and the thalamus [73]. Caffeine and other A(2A) receptor antagonists are also potentially neuroprotective, which may explain some of their favorable effects [74–76].

The main sources of energy for the brain are glucose and lactate. According to Magistretti’s theory, lactate may be the most important source of neuronal energy [7, 9, 77]. Most of the glucose from brain capillaries enters glial cells through the blood–brain barrier. In astrocytes, glucose is metabolized into lactate by glycolysis. The rate of lactate metabolism depends on brain activity and use of oxygen. Mitochondrial function should be intact for proper functioning.

Besides the heart, the CNS is the only part of the body that may have both functional and structural changes after hypoglycemia. However, the brain resists fasting better than other organs. The brain uses glucose at a rate of about 70 mg/min and contains about 1–2 g of glucose, which is sufficient for about 90 min if no more glucose is obtained from circulation. There are no strong associations between behavioral symptoms and plasma glucose levels, but fatigue and other symptoms usually occur when glucose levels are below 1.5–2 mmol/L. Common reasons for hypoglycemia are overdose of diabetic medications, high insulin levels, and severe malnutrition.

Glutamate, adenosine, and GABA have crucial roles in controlling brain energetics and lactate formation in the astrocytes. Monocarboxylate transporters (MCT1 and MCT4 in astrocytes and MCT2 in neuronal cells) are needed in the transfer of lactate from astrocytes to neurons [9, 78]. It is important to note that alpha- and beta-adrenoceptors exist in the surface of astrocytes [79]. Norepinephrine activates these adrenoceptors and stimulates glycogenolysis in astrocytes, which then produce lactate from glucose and release it to provide necessary energy for neurons [9, 80].

These theories also fit findings of Haydon and collaborators about the importance of glial cells in control of synaptic transmission, neuronal activity, and sleep [81–83]. Also Newman, Montana et al., and Zhang et al. have pointed out the role of astrocytes in regulation of synaptic activity [84–86], and, as Hertz and Zielke have written, astrocytes may be the “stars of the show” [87]. All functions of glutamate are regulated by astrocytes. Glutamate is the most important excitatory brain transmitter, and all is dependent on the ability of astrocytes to produce glutamate and glutamine [87]. The studies by Aubert and his collaborators of CNS lactate kinetics support these findings, indicating that neurons are lactate-consuming cells, whereas astrocytes are lactate producers [88]. Lactate production by the astrocytes increases with enhanced glutamatergic activation, and consumption of lactate by neurons also increases as a result of glutamatergic activity [8, 88]. It may well be that many neurologic and psychiatric diseases will turn out to be mainly glial diseases. This may also be true for fatigue and sleepiness. One of the main roles of sleep is to ensure sufficient energy for waking brain activity. To understand this better, the glial–neuronal network should be investigated, rather than concentrating our research efforts on neuronal synaptic relationships. If neurons do not have enough food (energy) of proper quality, they may starve and will not function normally [9].

In sum, the astrocyte-neuron lactate shuttle (ANLS) model, as Pellerin and Magistretti call it, can now be recognized as a major theory of brain energetics. The ANLS model helps to understand also neuronal plasticity, neurodegeneration, memory consolidation, and functional brain imaging [9]. The relations of sleep disturbances (sleep deprivation, fragmented sleep) and in the regulation of the ANLS need to be studied in more detail.

Effect of different nutrients on sleep has been studied in a large survey of 4500 people. Use of the following nutrients was associated with shorter sleep latency: alpha carotene, selenium, dodecanoic acid, and calcium. For example, the following nutrients were associated with better sleep and less awakenings during sleep: avoiding excessive salt, eating carbohydrates, use of vitamin D, dodecanoic acid, and lycopene [89]. Nonrestorative sleep was associated with butaneoic acid, lack of calcium, lack of vitamin C, lack of water, excess moisture, and excess cholesterol. Daytime sleepiness was associated with increased moisture, more caffeine/theobromine, less potassium, and less water [89]. These different elements will be handled in more detail below.