Investigating the Impact of Nutrition and Oxidative Stress on Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder is one of the most common neuropsychiatric disorders affecting up to 4% of adults. ADHD is often characterized by severe symptoms during childhood that may persist and evolve with advancing age [1]. ADHD is associated with an increased risk of other psychiatric disorders, addictions, and accidents [2], prompting researchers to analyze the various risk factors involved in its pathogenesis [2,3]. Both psychostimulant and non-psychostimulant drugs are used to treat ADHD, with psychostimulant drugs showing greater efficacy over a shorter period [4].

OS induced by reactive oxygen species (ROS) and reactive nitrogen species adversely affects neuronal function and contributes to the pathogenesis of ADHD. In this context, the gut microbiota plays a crucial role in modulating OS and systemic inflammation, thereby directly impacting mental health. Dietary patterns are instrumental in regulating the microbiota and, consequently, in affecting neural function and the expression of psychiatric symptoms. Diets rich in antioxidants can mitigate OS, while foods that support microbiota health may help improve the symptoms associated with psychiatric disorders [5].

Recent studies have increasingly focused on the contribution of OS to the pathophysiology of ADHD [6,7]. OS is a biological condition characterized by an imbalance between oxidants and antioxidants, leading to excessive production of oxidants or insufficient antioxidant defenses [8]. This imbalance can cause damage to lipids, proteins, and DNA; alter cellular signaling and gene expression; inhibit protein activity; and induce apoptosis [9]. ROS, which include free radicals and non-radical compounds derived from oxygen, play a critical role in this process by degrading carbohydrates, proteins, lipids, and nucleic acids [9,10]. While low levels of ROS are necessary for normal cellular function, excessive ROS levels can lead to significant cellular damage [11].

The body’s defense against OS includes various antioxidants, some of which can cross the blood-brain barrier and protect nerve cells. Key antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) are recognized biomarkers of oxidative stress [11]. Current research also underscores the importance of diet in managing ADHD, particularly through the intake of specific micronutrients like vitamins B and D and minerals such as manganese (Mn), zinc (Zn), magnesium (Mg), copper (Cu), selenium (Se), iron (Fe), and polyunsaturated fatty acids (PUFA) [12,13]. For example, iron deficiency has been implicated in the pathophysiology of ADHD due to iron’s essential role as a cofactor of tyrosine hydroxylase in catecholamine synthesis and metabolism, as well as in oxygen transport and brain myelination [14]. However, while supplementation with certain micronutrients can significantly reduce ADHD symptoms, excessive intake may lead to adverse effects. For instance, high doses of vitamin E supplementation have been linked to an increased risk of prostate carcinoma, and long-term ω-3 PUFAs (ω-3 polyunsaturated fatty acids) supplementation may be associated with serious side effects [12].

Additionally, the gut microbiome has emerged as a significant factor in ADHD, with its composition and function also being associated with other mental disorders. The gut–brain axis facilitates bidirectional communication between the gut microbiome and the brain [12,15]. The gut microbiota produces metabolites, such as serotonin, that influence neuronal function, while the brain sends signals, including dopamine, that can directly or indirectly impact the gut microbiota [16]. Disturbances in the intestinal microbiome are correlated with several conditions, including irritable bowel syndrome, cardiovascular diseases, immune disorders, obesity, and inflammatory bowel disease [16,17,18]. Without a healthy microbiome, pathogenic bacteria like Clostridium difficile increase, leading to gastrointestinal disorders such as diarrhea [19].

In this review, we will focus on the function of oxidative stress as a factor in the pathophysiology of ADHD, examine the influence of diet on treatment, and discuss the connection to the gut microbiome in the context of ADHD.

Attention deficit hyperactivity disorder is a prevalent neuropsychiatric disorder that is diagnosed based on persistent developmental levels of hyperactivity, inattention, and impulsivity [20]. ADHD is classified into three subtypes: inattentive, hyperactive-impulsive, and combined. Individuals with the inattentive subtype are often described as daydreaming, struggling to maintain focus, easily distracted, and less organized. The hyperactive-impulsive form is characterized by distractibility, reduced persistence, and lack of impulse control. The combined subtype presents with symptoms in all three categories. Additionally, there are gender differences in the subtypes: boys are more frequently diagnosed with the hyperactive-impulsive, whereas girls are more commonly diagnosed with the inattentive subtype [21]. In adults, hyperactivity often manifests as feelings of inner restlessness or agitation, incessant mental activity, excessive talking, and an inability to relax [3]. Impulsive behavior and interpersonal conflicts are correlated with negative consequences on relationships with friends, family, and colleagues. More specifically, impulsive behavior may often manifest as a coping mechanism to combat anxiety or as a result of a need for immediate gratification. Inattentiveness is characterized by distraction and slow processing speed. However, some patients, particularly those engaged in activities of interest, may exhibit hyperfocus or overconcentration [3]. ADHD frequently co-occurs with other psychiatric disorders, such as depression, anxiety, bipolar disorder, autism spectrum disorders, conduct disorder, eating disorders, and substance use disorders [22]. ADHD has a high degree of heritability, estimated at approximately 76%. Furthermore, prenatal risk factors such as alcohol and drug use, as well as hypertension, play a significant role in the pathogenesis of ADHD [3]. Moreover, maternal stress during pregnancy and premature birth are environmental factors associated with ADHD [3].

The etiology of ADHD is considered multifactorial, with genetic predisposition and biological vulnerability being the most significant contributors. Comorbidity is common among children with ADHD, with conduct disorders, depression, and anxiety being the most frequently observed conditions observed in children with ADHD [23,24]. Other disorders, such as autism spectrum disorder and exposure to environmental agents and substances, including lead (Pb), alcohol, tobacco, and other drugs, may also contribute to the symptoms and pathogenesis of ADHD [21]. While understanding the onset and progression of ADHD is important [23], no single cause has been identified, and exposure to a risk factor does not guarantee the development of ADHD. The factors contributing to the onset of ADHD may differ from those influencing its progression and outcomes. Genetic factors may exert indirect effects through interactions with environmental factors [25]. Prenatal and postnatal factors such as low birth weight, premature birth, and maternal substance use during pregnancy have been linked to an increased risk of developing ADHD [23].

In recent years, more studies have reported the influence that OS has on neuropsychiatric disorders, but its mode of action is still unclear [10]. Oxidative stress occurs when there is an imbalance characterized by the overproduction of oxidants, reduction in antioxidant levels, or both. This imbalance leads to harmful effects, as excess free radicals or a compromised antioxidant system disrupts central nervous system enzymes and alters neurotransmitter receptor functions [8]. Higher levels of OS have been observed in people with ADHD, particularly in children with this disorder, where higher levels of malondialdehyde (MDA) have been recorded compared to controls [6]. In numerous randomized, double-blind, placebo-controlled trials, participants with ADHD were found to have a lower total oxidant status (TOS) [55,56].

Key antioxidants associated with ADHD include γ-linolenic acid (GLA) [57], total antioxidant capacity (TAC) [58], antioxidant glutathione (GSH) [9], melatonin [59], and total antioxidant status (TAS) [56]. Additionally, several important enzymes work as markers of OS, including glutathione peroxidase [60], catalase (CAT) [61], superoxide dismutase (SOD) [62], and glutathione-S-transferase (GST) [63]. Oxidants such as lipid peroxidation products (LPO) [61], plasma levels of advanced oxidation protein product (AOPP) [61], nitrites + nitrates (NOx) [61], glutathione reductase activity (GRd) [61], total thiols [8], MDA [64] and TOS [56] are also critical in understanding OS in ADHD.

GPx is an antioxidant enzyme critical for combating OS and maintaining redox balance [65]. A study conducted on 35 ADHD patients from Gazi University Faculty of Medicine, Child, and Adolescent Psychiatry Clinic and 35 healthy control patients reported significantly lower plasma GPx level ADHD patients compared to the healthy group [60]. Another important enzyme, CAT, plays an essential role in the metabolism of H₂O₂ and reactive nitrogen species [66]. In this context, although CAT enzyme activity in plasma was higher compared to that in the controls, the difference was not statistically significant [60]. CAT activity in saliva was estimated in ADHD patients and controls and was found to be reduced in patients with ADHD compared to healthy controls [67]. Moreover, the mean serum TAC, GSH, and CAT levels of patients with ADHD were significantly lower than those of the healthy group [58]. However, decreases in plasma TAS levels were observed in children diagnosed with ADHD compared to the reference values in control patients [68,69].

In serum, MDA levels have been reported to be increased [64], although some studies have indicated statistically significantly lower values [70]. There is also evidence showing a significant decrease in TAS in one study [55], while other research indicates lower levels, but without reaching statistical significance [68,69]. At the same time, higher levels of melatonin have been observed [59].

Both SOD1 and TAC (Table 1) showed significantly lower values in the serum [58,68], while in the plasma, total thiols and GST also showed significant decreases compared to those in the control group [8,63]. Garre-Morata et al. 2024 found that after administration of MPH for three months, plasma levels of AOPP, LPO, and NOx decreased [61]. In addition, studies examining the effects of MPH on the rat brain reported a decrease in the activity of antioxidant enzymes, such as CAT and SOD [71,72,73].

Diet can affect the gut microbiome, which in turn influences a variety of physiological processes, including the immune system, appetite, metabolism, nutrient absorption, and neuronal development via GBA [76]. Additionally, high-calorie foods combined with a lack of exercise contribute to the damage of fat cells, leading to significant health problems such as obesity [77]. Ingested food causes the gastrointestinal tract to respond by signaling the brain to induce satiety [77]. The intestinal epithelium, consisting of absorptive enterocytes, proliferative stem cells, and secretory cells, including enteroendocrine cells, is the primary interface between the host and the microbiota. Enteroendocrine cells, which make up 1% of the intestinal epithelium, represent the largest network of endocrine cells in the body that express numerous hormones [78]. In response to food ingestion, L cells secrete hormones [77], such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). L cells are sensitive to short-chain fatty acids (SCFA) and secondary bile acids, but they respond most intensely to microbiota-derived nutrients and metabolites, stimulating hormone secretion [78]. GLP-1 has multiple effects, including insulin secretion and increased satiety, while PYY reduces food intake [78].

Food nutrients are known to have powerful antioxidant and anti-inflammatory properties for maintaining cellular redox homeostasis by activating antioxidant defense systems such as the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway and the phase II detoxification genes and enzymes including heme oxygenase-1 (HO-1), heat shock protein 70 (Hsp70), sirtuin-1 (Sirt1), GPx, thioredoxin (Trx), SOD, and CAT for neuroprotection during OS and neurotoxicity that lead to the onset and progression of neuropsychiatric disorders such as ADHD [79,80,81].

It is interesting to note that nutrients, particularly polyphenols, vitamins, probiotics, and PUFAs, follow the concept of hormesis, a biphasic dose-response process by which small, nontoxic stresses or mild stress are used to induce cellular adaptive responses that protect the biological system against subsequently large and potentially lethal stresses of the same, similar, or different nature. According to hormesis, low doses of food nutrients are neuroprotective by activating Nrf2 antioxidant pathways, while high doses can be toxic and induce inhibition of these protective pathways, causing brain damage. Therefore, polyphenols, but also probiotics and PUFAs, can be considered as “hormetic nutrients” since they are capable of orchestrating cellular resilience to stress and the preservation of cellular redox homeostasis as benchmarks of health by activating intracellular antioxidant enzymes such as SOD, CAT, and GPx in a dose-dependent manner. This is in line with emerging evidence [82,83,84] that shows that a low dose of hormetic nutrients upregulates antioxidant Nrf2 pathways for enhancing the stress resilience response to counteract excess free radicals in vitro and in vivo. On the other hand, high doses of natural compounds can be toxic to cells and animal models, leading to the inhibition of antioxidant pathways and the onset and progression of neurological disorders associated with OS. The field of hormetic/adaptive responses activated by food nutrients in enhancing endogenous redox defense systems and reducing OS is emerging as a promising preventive and therapeutic approach in gut–brain axis disorders [81]. In this context, the interaction between polyphenols and probiotics plays a significant role, with the potential to prevent and treat inflammation associated with changes in the intestinal microbiota, positively influencing the gut–brain axis. For instance, resveratrol, a natural polyphenol found in grape skins, not only provides antioxidant and anti-inflammatory effects, but also supports neuroprotective functions. By modulating the intestinal microbiota, resveratrol affects the GBA, contributing to the regulation of insulin sensitivity and mitochondrial biogenesis through the activation of Sirt1. Resveratrol also activates the Nrf2 pathway, offering protection against OS and reducing neuroinflammation [81]. Similarly, curcumin not only regulates the intestinal microbiota by promoting beneficial bacteria and reducing pathogenic ones but also activates the Nrf2 pathway, thereby protecting against OS and inflammation. Additionally, it influences the GBA, improving both intestinal symptoms and cognitive function by balancing neurotransmitters and modulating the microbiota [81,85].

Blueberries, which are rich in anthocyanins, fiber, and polyphenols, offer antioxidant and anti-inflammatory effects that support healthy intestinal microbiota and enhance brain function. They modulate the Nrf2 pathway, stimulate the production of antioxidant enzymes, and protect against OS. Regarding the gut–brain axis, blueberries improve microbiota composition by increasing beneficial bacteria such as Lactobacillus and Bifidobacterium, while reducing pathogenic bacteria [81]. Another example is Hidrox, an olive extract containing hydroxytyrosol, which activates the Nrf2 pathway to reduce OS and neuroinflammation. It improves the intestinal microbiota by increasing beneficial bacteria and supporting cognitive health [81]. Additionally, Hidrox has shown promise in reducing inflammation and managing Alzheimer ’s-like diseases [86]. Saffron also contributes to Nrf2 activation, reducing OS and inflammation in both the intestine and the brain. In the gut, saffron regulates the microbiota by decreasing pathogenic species and combating dysbiosis [81]. Moreover, polyphenols from the Hericium erinaceus mushroom stimulate the Nrf2 pathway, exhibiting similar effects in reducing OS and neuroinflammation. They enhance the intestinal microbiota by increasing beneficial bacteria and SCFAs, while protecting the brain by inhibiting amyloid-β accumulation, thereby improving both gut health and cognitive function [81,87].

The dose is a crucial determinant for inducing protective or harmful effects and should be carefully evaluated. Therefore, finding the optimal dose of dietary nutrients in order to promote healthy effects is crucial for achieving protection and/or toxicity. Numerous recent evidence [80,88,89,90] have shown that low doses of dietary nutrients promote neuroprotection via the activation of the Nrf2 pathway in order to prevent or attenuate OS and cognitive damage in vitro and in vivo.

In addition, dietary interventions can influence behavior and mental health, as supplementing or restricting certain nutrients or foods can result in positive effects on improving ADHD symptoms [91]. Nutrition plays an essential role in neuropsychiatric disorders, demonstrating that children with ADHD often present with micronutrient deficiencies [92]. Adequate vitamin and mineral intake is crucial for normal brain development, as deficiencies can impair the brain regions involved in the pathogenesis of ADHD [93]. Following a diagnosis of ADHD, the National Institute for Health and Care Excellence in the United Kingdom recommends a balanced diet and nutrition, along with regular exercise, as drug treatment is not recommended for preschoolers [94]. Additionally, to reduce ADHD symptoms, the Mediterranean diet is recommended [95], which involves a high consumption of unsaturated and monounsaturated fats and a high intake of vegetables, fruits, legumes, and cereals. Another approach is the elimination diet, which is based on the premise that adverse reactions to certain foods may be linked to ADHD and involves the elimination of food additives or products with a high degree of allergy [96].

Several studies have highlighted the potential role of micronutrients in neurodevelopmental disorders (Table 2) [97,98,99].

Mn is an essential element because it functions as a coenzyme in various biological processes [116]. It is involved in bone formation, macronutrient metabolism, and defense systems against free radicals [116] and plays a fundamental role in brain function and development [117]. Moreover, Mn acts as an activator of some antioxidants and is critical for maintaining insulin synthesis and secretion [118]. As a component of manganese superoxide dismutase (MnSOD), Mn is vital for scavenging reactive oxygen species during mitochondrial oxidative stress [118]. MnSOD is a primary antioxidant that scavenges superoxide in the mitochondria, providing protection against OS [118]. Major dietary sources of Mn include teas, juices, cereals, rice, nuts, seafood, chocolate, fruits, vegetables, seeds, and spices [100]. Mn deficiency is associated with numerous disorders, such as impaired carbohydrate metabolism and brain malfunction [119]. In addition, elevated Mn levels have been reported in children with cognitive deficits and attention and learning problems, influencing the dopaminergic system [120].

Mg is the most common cation with significant physiological importance [121] and is involved in the development and functioning of the brain [122]. It is found primarily in plant foods (vegetables, legumes, grains, seeds, and nuts), the consumption of which is recommended to reduce ADHD symptoms [123]. Mg deficiency can present with symptoms such as aggression, fatigue, nervousness, and attention deficits [124]. Magnesium supplementation has also been shown to reduce ADHD symptoms in children [121]. In a study involving 148 boys aged 4 to 9 years, including 44 with ADHD, 40 with autism spectrum disorder, and 32 with both ADHD and autism spectrum disorder, the analysis of blood serum, urine, and hair samples revealed that hair Mg levels were significantly lower in children with ADHD compared to controls [92].

Zn is an essential micronutrient involved in numerous metabolic processes, including the proper functioning of the immune system, protein synthesis, DNA synthesis, and cell division [125]. Zn has also been associated with ADHD [126] and plays a role in the production of melatonin, which is necessary for dopamine metabolism [127]. Since Zn is required for melatonin metabolism, it is considered an important factor in the treatment of ADHD [128]. The main food sources of Zn are poultry, red meat, seafood, nuts, and seeds. Consumption of these foods is recommended because Zn has antioxidant properties and can protect against OS [101,102,123]. Children with ADHD have been found to have much lower serum Zn levels [129]. In 2020, Robberecht et al. observed lower Zn levels in the hair and nails of children with ADHD [121]. Another study demonstrated that 6 to 10 weeks of Zn and Fe supplementation improved ADHD symptoms [125].

Iron is another important micronutrient that is essential in various biological processes, such as oxygen transport by hemoglobin [130]. Fe is vital for basic brain function [131]. As a cofactor of tyrosine hydroxylase, its deficiency leads to lower dopamine production, resulting in increased ADHD symptoms and affecting behavior [121]. Fe supplementation shows clinical utility in patients with ADHD [132]. However, when present in excess, it disrupts redox homeostasis and catalyzes the propagation of ROS, leading to OS [130]. In the etiology of ADHD, Fe deficiency is one of the basic nutritional factors with a role in the essential functions of the brain, including myelination, the development of oligodendrocytes, and the synthesis of neurotransmitters [133]. However, there are other micronutrients that have a role in reducing ADHD symptoms, among them Se, and Cu, the latter having a role in catecholamine metabolism. Selenium is found in foods such as vegetables, fish, and meat. It functions as a cofactor of GPx enzymes, which play a role in protecting against OS [106,107], and a high Cu/Zn ratio may contribute to the risk of ADHD [121].

Vitamins are organic compounds obtained primarily through diet, except for vitamin D, which is synthesized through sun exposure [134]. Besides sunlight, vitamin D can be sourced from foods such as fish, dairy products, cereals, orange juice, and eggs [49,112]. Vitamin D deficiency has been associated with neurodevelopmental disorders, including attention deficit hyperactivity disorder, and its deficiency affects the expression of synaptic proteins [135]. On the other hand, vitamin B6 is found in meat, dairy products, nuts, fruits and vegetables [109], and vitamin B12 in meat, milk, eggs and fish [108]. Lower levels of B vitamins (B2, B6, B9, B12) have been significantly associated with ADHD. Vitamin B12 facilitates the conversion of homocysteine to methionine via methionine synthase, an essential reaction in the nucleotide synthesis process [134]. Both vitamin B6, B12, and vitamin D play a role in reducing OS [49,108,109,110,111,112].

Deficiencies in certain unsaturated fatty acids may contribute to ADHD [136]. PUFA are essential for normal neurotransmitter function [137]. ω-3 PUFAs, found in fish, microalgae, and some microorganisms, play a role in reducing the ratio of SOD/CAT enzymes [113,114,115]. Supplementation with ω-3 fatty acids can improve ADHD symptoms [95], and a balanced ratio of ω-3 to ω-6 PUFA may be even more effective [138]. More specifically, fish oil supplementation may represent a promising dietary intervention, although the common addition of vitamin E to fish oil could raise concern [54].

Regarding dietary options for ADHD, supplementation with minerals, vitamins, and PUFA is common (Table 3) [13]. Because sugar, sweets, artificial food colors, and preservatives are associated with ADHD symptoms [139,140], some authors recommend eating fruits, vegetables, fish, and other foods high in PUFA and other micronutrients to protect against OS and reduce the risk of ADHD [13].

Numerous studies (Table 3) confirm that micronutrient supplementation can improve symptoms of attention deficit hyperactivity disorder. For instance, supplementation with 150 mg Zn for 12 weeks had a positive result [63], while administration of a smaller amount (15 mg) for 13 weeks did not have a positive effect, leading researchers to not recommend this dose [63]. In another study involving 52 patients aged 7–14 years, 0.5–1 mg/kg/day of Zn was administered for 6 weeks alongside MPH treatment, confirming the positive effect of Zn [129].

Another study involving 23 participants aged 5–8 years confirmed that 80 mg/day of ferrous sulfate for 12 weeks improved ADHD symptoms in children with low serum ferritin [143]. Furthermore, supplementation with 200 mg/day of Mg for 6 months showed a positive effect on ADHD symptoms [144]. In another study, 74 participants were supplemented for 8 weeks with 50,000 IU/week of vitamin D and 6 mg/kg/day of magnesium supplements, yielding positive results, as vitamin D and magnesium supplementation in children with ADHD reduced behavioral problems, social problems, and anxiety [147]. Vitamin D supplementation also improved ADHD symptoms [146,147], as observed in a study where 96 patients were given 50,000 IU/week 25-hydroxy-vitamin D3 for 6 weeks [145], as well as in a study involving 35 patients aged between 7 and 14 years who were administered 3000 IU/day 25-hydroxy-vitamin D3 over 12 weeks [146].

The efficacy of ω-3 PUFA was tested in a study involving 40 patients aged between 8–14 years, who were given 10 g daily of margarine enriched with either 650 mg of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA), for 16 weeks, and the result was positive [148]. ω-3 PUFAs, particularly DHA and EPA, enhance cellular membrane fluidity, neurotransmission, and receptor function [149]. DHA deficiency is associated with dysfunctions in the dopaminergic system [150], but supplementation with ω-3 PUFAs has been shown to improve attention and reduce impulsivity. Additionally, these fatty acids exhibit anti-inflammatory effects, which contribute to reduced levels of proinflammatory interleukins [149].

In the last decade, researchers have focused on the connection between gut microbiota and neurodevelopmental disorders, revealing potential correlations [54]. Communication between the gastrointestinal tract and the brain is facilitated by the gut–brain axis, which includes the central nervous system, spinal cord, enteric nervous system, autonomic nervous system, and hypothalamic-pituitary-adrenal (HPA) axis [151]. The HPA axis is crucial for maintaining body homeostasis, and its regulation occurs mainly by changing cytokine secretion [5].

As stated by Gong et al. in 2023, the gut−brain-axis (GBA) links intestinal dysfunction and inflammation with brain function and neuropsychiatric disorder [152]. The interaction between GBA and gut microbiota is achieved through neural, immune, endocrine, and humoral links [153]. Furthermore, the mechanism underlying GBA communication involves neuro-immune-endocrine mediators. GBA plays the role of integrating gut function, linking the emotional and cognitive centers of the brain with gut function and mechanisms such as gut permeability, immune activation, entero-endocrine signaling, and enteric reflux [153].

The immune, neuroendocrine, and neural pathways each play distinct roles in modulating the interactions between the gut and the brain. The immune pathway is particularly crucial, with the gut microbiome being essential for maintaining and developing both the intestinal barrier and the blood-brain barrier. Alterations in the microbiome can impact the expression of tight junctions [154], potentially compromising these barriers to microorganisms and inducing neuroinflammation [149]. The microbiome influences the differentiation and maturation of immune cells [155], including microglia, which are involved in neurogenesis and the regulation of cognitive functions [149]. Disruption of the microbiome can affect microglial function [156]. Additionally, the microbiome impacts the recruitment of peripheral monocytes to the brain, mediated by tumor necrosis factor-alpha (TNF-α) and free fatty acid receptors, highlighting its role in regulating immune and neuroinflammatory responses. Furthermore, acquired immunity develops and matures in response to exposure to gut microbiota [149].

Another crucial pathway in the interaction between the gut microbiome and the central nervous system is the neuroendocrine pathway. The gut microbiome is integral to the development and functioning of the HPA axis, which regulates neuroendocrine responses and manages stress [149]. The neural pathway in the GBA is mediated by the vagus nerve, which transmits signals between the gut and the brain. The vagus nerve influences behavior and mood by modulating the brain’s response to mechanical and chemical stimuli from the gut. Such signals can influence the release of catecholamines in the brain, thereby influencing the states of depression and anxiety. Additionally, the gut microbiome, through its interactions with vagal afferents, can modulate emotional and behavioral responses, impacting anxiety-like and depressive behaviors. The enteric nervous system, which includes the myenteric and submucosal plexuses, coordinates intestinal functions, such as motility and fluid movement [149].

The intestinal microbiome has an increasingly recognized impact on the functioning of ADHD through its ability to synthesize neurochemical substances and precursors [157], with an important role in anti-inflammatory responses, helping to reduce psychiatric symptoms caused by inflammation [158]. Precursors of monoamines, such as dopamine, serotonin, and neuroadrenaline, are produced by several members of the gut microbiota [157]. In this context, there is a close connection between the gut–brain axis and neuropsychiatric disorders, such as ADHD. Gamma-aminobutyric acid (GABA), serotonin, dopamine, and norepinephrine are produced by the gut microbiota and influence GBA [159]. Serotonin is an important factor in the pathogenesis of ADHD because approximately 90% of serotonin is produced in the gut by enterochromaffin cells and the gut microbiota. Also, GABA is another factor that can contribute to ADHD pathology; the intestinal microbiota is able to influence the availability of GABA through the absorption and secretion of this neurotransmitter. Furthermore, bacterial metabolites such as SCFA increase the rate-limiting enzymes in the synthesis of noradrenaline, dopamine, and serotonin [76].

The gut microbiota is considered an environmental factor that regulates host metabolism by interacting with different tissues via microbiota-derived signals and metabolites [78]. The gut microbiota consists of six major phyla, Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Verrucobacteria, and Fusobacteria [160], which perform complex functions, including food and drug metabolism [54]. The gut microbiota has been associated with various aspects of human health, including metabolism, gut homeostasis, brain behavior, and immune development [54]. The gut microbiota has been found to play a particular role in health and neuropsychiatric disorders, as it can affect mental health and brain activity [161]. Gut microorganisms can impact central nervous system processes through immune system modulation and communication via the vagus nerve [54]. The vagus nerve is considered a vital channel for two-way communication between the brain and gut, which can differentiate between pathogenic and non-pathogenic bacteria [96]. Microorganisms that are part of the intestinal microbiota participate in the food digestion process by secreting digestive enzymes and transforming complex nutrients into simple organic compounds. Another role of the gut microbiota is the synthesis of vitamins, especially those in the B complex [5]. Through the GBA, diet can exert its effect on ADHD; this communication system between the enteric nervous system and the central nervous system includes the emotional and cognitive centers of the brain [151]. DNA sequencing can be used to investigate microbial composition and its role in the pathogenesis of ADHD [151].

Gut microorganisms produce various metabolites such as short-chain fatty acids, including butyrate, propionic acid, and acetate, through the breakdown of fibers and undigested sugars. These acids serve as essential energy sources for the mitochondria and play a crucial role in conditions involving inflammation, hunger, and intense physical activity [149]. SCFA are considered the main class of biological products of the intestinal microbiota that can be obtained by fermentation of dietary fibers. While the fermentation process of dietary fiber is essential in regulating gut microbiota composition, SCFA can affect host health at the cellular, tissue, and organ levels. Abnormalities in the production of these metabolites have been associated with ADHD symptoms [162].

Disruption of the gut microbiota caused by antibiotics, infections, poor diet, or stress can lead to dysbiosis [158]. This imbalance results in the growth of inflammatory microorganisms, which can affect intestinal permeability and causie systemic inflammation through microbial translocation. Systemic inflammation can disrupt the blood-brain barrier and elevate the levels of proinflammatory cytokines, contributing to oxidative stress and impacting neurotransmitters associated with ADHD [151]. However, further studies are needed to understand how the gut microbiota regulates proinflammatory cytokines, given the established link between the inflammatory process and pathogenesis of ADHD [151]. Moreover, the gut microbiome regulates the maturation and differentiation of macrophages, innate lymphoid cells, and dendritic cells. Macrophages constitute microglia [149], immune cells that represent 10% of the central nervous system [163], with an important role in the modeling and neurogenesis of neuronal circuits, having implications in the subsequent development of social behavior and cognitive function [149]. An altered gut microbiome leads to the pathogenesis of neurodegenerative diseases by modulating and activating microglial functions. The pathological hallmarks of neurodegenerative diseases are neuroinflammation and microglial activation [163].

Ribosomal 16S RNA sequencing and metagenomics have significantly advanced our understanding of the gut microbiome by allowing the identification of various microorganisms and analysis of their biological pathways. Techniques such as metatranscriptomics and metaproteomics provide a comprehensive view of the microbiome, while culturomics aid in identifying specific microbial species. Various factors, including medications, diet, lifestyle, and genetics, influence the gut microbiome, with medications having a particularly notable impact [164]. Previous research has highlighted the difference between the gut microbiome of patients with ADHD and that of controls [165,166]. In a study evaluating the differences between the gut microbiome of ADHD patients and healthy controls, stool samples from 209 patients were analyzed, and it was found that there was a significant difference in the composition of the fecal microbiome between adult ADHD patients and controls [166].

Another study in which the composition of the gut microbiota was analyzed found that drugs administered to treat ADHD could affect the gut microbiota. The most numerous genus of bacteria associated with ADHD symptoms is the genus Coproccocus [165]. On the other hand, in a study conducted by Aarts and colleagues in 2017, 96 participants were considered, 19 of whom had ADHD and 77 were healthy. The microbiome of people with ADHD was compared to that of healthy individuals by analyzing the 16S microbiome, and the results showed that the genus Bifidobacterium is significantly higher in those with ADHD [157]. Bifidobacterium is one of the many bacteria capable of producing GABA [82]. In addition, in a study conducted by Sukmajaya et al. in 2021, 49 bacterial taxa were differentiated between individuals with ADHD and healthy people; therefore, it is difficult to say which taxa differ the most in ADHD [151].

ADHD can coexist with other mental and physical disorders, such as anxiety, depression, or sleep disorders, and these comorbidities can complicate the assessment of nutrition and oxidative stress in ADHD. Additionally, sleep, physical activity, and other lifestyle factors may interact with food and oxidative stress, making it more difficult to analyze study outcomes. Cultural and regional factors can influence lifestyle and diet, thereby affecting how nutrition and oxidative stress impact ADHD symptoms. Moreover, the studies reviewed vary significantly in terms of the type and duration of nutritional interventions, ranging from ω-3 supplements to specific diets, which may affect the comparability and applicability of the results. However, more research is needed to understand the impact of diet and oxidative stress on ADHD.

According to our analysis, further research is needed on the diagnosis of ADHD in adults. Although most studies have focused on micronutrient supplementation in children and adolescents, a healthy diet is necessary to reduce ADHD symptoms. A healthy diet refers to eating fruits, vegetables, legumes, and other foods rich in dietary fiber, which play a role in maintaining a balanced microbiota. Dietary approaches, such as the Mediterranean diet and the elimination diet of certain foods that can cause side effects, have also been shown to improve ADHD symptoms. It is especially important to maintain healthy microbiota to prevent the onset of neuropsychiatric disorders.

Conceptualization, M.V. and V.R.; validation, V.B. and A.C.; formal analysis, G.H.; investigation, M.V., V.R., A.-M.S. and R.D.; resources, M.V. and V.R.; data curation, M.V. and V.R.; writing—original draft preparation, M.V. and V.R.; writing—review and editing: M.V., V.R., V.B., G.H., A.C., A.-M.S., R.D., I.M. and A.T.; visualization, A.C. and R.D.; supervision, A.C. and R.D. All authors have read and agreed to the published version of the manuscript.

The authors declare no conflicts of interest.

This research received no external funding.