Table of contents

Depression is one of the most common mental illnesses [1]. Its characteristic symptoms include persistent low mood, lack of motivation, inability to experience pleasure, and changes in appetite. Risk factors include a family history of mood disorders, early life trauma, female gender, recent stressors, and substance use. Other illnesses may also increase the likelihood of developing depression—particularly metabolic disorders, cardiovascular diseases, and autoimmune conditions [2]. In recent years, the impact of gut microbiome on mental health has also attracted growing interest.

Depression is accompanied by anxiety in approximately half of cases. Anxiety is a persistent state of expressed and uncontrollable worry about everyday matters, often accompanied by general restlessness, sleep disturbances, and fatigue [3]. Around 12% of people experience a depressive episode in their lifetime, while 14% experience anxiety. Depression is one of the leading causes of work-related disability worldwide [1], and in at least one-third of cases, there is no meaningful or lasting improvement with therapy. Given this, depression represents a significant public health challenge, and new treatment approaches may be required to enhance effectiveness. [4]

What are the symptoms of depression?

A range of symptoms can indicate the presence of depression. It is diagnosed using the criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [5]. Major depressive disorder is diagnosed when at least five of the following symptoms persist for at least two weeks:

  1. depressed or sad mood
  2. significant loss of interest or pleasure (anhedonia)
  3. noticeable weight or appetite changes
  4. disturbed sleep (reduced or increased sleep)
  5. restlessness or inhibition
  6. fatigue, weakness, lethargy
  7. feelings of worthlessness, self-blame, or guilt
  8. difficulty thinking, concentrating, or making decisions.
  9. preoccupation with death, suicidal ideation, or attempts

Additionally, the following four conditions must be met:

  1. the symptoms cause clinically significant distress or impairment of function in daily life
  2. the symptoms are not due to another medical condition or substance use
  3. the symptoms are not better explained by another psychiatric disorder (e.g., schizophrenia)
  4. there is no history of manic or hypomanic episodes (i.e., no symptoms of elevated mood)

The DSM-5 categorizes depression into three levels of severity based on the number and intensity of symptoms and the degree to which they disrupt daily life. If fewer than all criteria are met (but still at least five), and daily functioning is only mildly impaired, the diagnosis is mild depression. If symptoms severely interfere with daily functioning, depression is considered severe. In the most serious cases, psychotic symptoms (delusions and hallucinations) may be present. Intermediate cases are classified as moderate.

As seen from the criteria above, depression does not necessarily equate to a sad mood—it can manifest in many different ways in daily life.

Several specific subtypes of major depressive disorder are also commonly recognized:

  • Seasonal affective disorder: Typically occurs in autumn and winter and remits in spring and summer.
  • Prenatal and postpartum depression: Symptoms emerge during pregnancy or within four weeks after delivery. The DSM refers to this as “major depressive disorder with peripartum onset.”
  • Atypical depression: Also called “major depressive disorder with atypical features,” this form differs from typical depression in that mood may temporarily improve in response to positive events. Other symptoms include increased appetite and sleep, persistent fatigue, anxiety, and rejection sensitivity. [6]

If at any point in life—either currently or in the past—a person has experienced episodes of elevated mood or a naturally excitable temperament, bipolar affective disorder may be the correct diagnosis. This condition involves a different pathology and often requires a different treatment approach. Signs of elevated mood include excessive cheerfulness, irritability, talkativeness, reduced need for sleep, and high energy. This article does not address bipolar disorder; here, “depression” refers to the unipolar form.

Figure 1. Symptoms of depression

What causes depression?

Neither depression nor anxiety can be attributed to a single cause; rather, they are the result of complex, interacting processes. The most commonly discussed theories include:

This perspective explains depression through the altered functioning of central nervous system neurotransmitters. Antidepressant medications are largely designed to target these disruptions.

Neurotransmitters are chemical messengers that transmit signals between neurons and other cells—such as muscle or gland cells. Over 100 neurotransmitters have been identified in the human body. [7]

These molecules do not work in isolation; instead, they form a complex, interactive system that regulates various physiological functions. As such, depression or anxiety is not due to a single neurotransmitter abnormality but rather to an overall imbalance.

The most commonly implicated neurotransmitters in depression are serotonin, dopamine, and noradrenaline, which typically present at reduced levels [8]. Anxiety is often associated with underactivity in the gamma-aminobutyric acid (GABA) system. Other neurotransmitters also contribute to psychiatric symptoms, several of which are detailed below:

  • Serotonin regulates a number of physiological processes, including cognitive function, circadian rhythm, pain perception, gastrointestinal secretion and peristalsis, as well as blood clotting and cardiovascular function. [9]
  • Dopamine is an important mediator of the reward system. It also plays a role in maintaining motivation, concentration, attention, memory, learning, sleep and mood regulation.
  • Noradrenaline is essential for the proper functioning of alertness, attention, concentration, decision-making and memory. It is also a mediator of the acute stress response, the so-called flight or fight response. It increases blood pressure and heart rate.
  • Gamma-aminobutyric acid is the most common inhibitory neurotransmitter. It is involved in the regulation of anxiety, irritability, concentration, sleep, mood and the development of seizures. Anti-anxiety drugs, certain drugs used in epilepsy and alcohol also act on the GABA system.
  • Glutamate is the most abundant excitatory molecule in the central nervous system. It is involved in maintaining cognitive functions such as thinking, learning and memory. Glutamate also plays a key role in the cell death process that accompanies mental illness. [10]
  • Histamine is a key component of the body’s immune defences, but it also functions as a neurotransmitter. It plays a role in regulating appetite, alertness, motivation, and the sleep–wake cycle. Both deficiencies and excesses can lead to psychological symptoms. Low histamine levels may contribute to fatigue and sleepiness, while elevated levels can result in tension, anxiety, panic, sleep disturbances, or even depersonalisation and derealisation. Additionally, histamine influences programmed cell death (a natural cellular process), and can therefore affect the survival or death of nerve cells [11]. For more information on histamine, see our previous article.
  • Acetylcholine has a number of functions in both the central and autonomic nervous systems. Among others, it affects heart rate, blood pressure, bowel function, muscle function, memory, motivation, libido, sleep and learning. [7]
  • Oxytocin plays a key role in both male and female reproductive processes, triggering uterine contractions during childbirth and promoting lactation. It also helps counteract the negative effects of stress and enhances the tendency to form emotional bonds and engage in social contact. Warm, affectionate interactions and physical touch stimulate oxytocin release. A so-called ‘caring-protective’ stress response [12], regulated by oxytocin (and vasopressin), complements the well-known fight-or-flight response and includes the instinct to protect offspring. Oxytocin also underlies the separation anxiety observed in mother–child relationships and plays a significant role in adult social connections. Lower oxytocin levels have been found in individuals with depression, whereas elevated levels are more often observed in those with anxiety symptoms. [13]

Both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system are activated in response to stress.

  • Activation of the HPA axis begins with the hypothalamus releasing corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then prompts the adrenal cortex to release cortisol.
  • Meanwhile, the sympathetic nervous system stimulates the release of catecholamines (noradrenaline and adrenaline) from the adrenal glands. In mood disorders, this system becomes imbalanced, with sympathetic activity dominating over parasympathetic.

In addition to generating the stress response, both cortisol and catecholamines influence the immune system and inflammatory processes. They exert immunosuppressive effects by inhibiting the movement and activity of white blood cells and the production of inflammatory cytokines, and can even lead to the destruction of immune cells. This is a bidirectional relationship: inflammatory cytokines can also activate the HPA axis and the sympathetic nervous system, as observed in cases of infection and injury.

Depression is associated not only with elevated cortisol levels but often with glucocorticoid resistance. Stress—especially early life stress, including prenatal maternal stress—affects sensitivity to glucocorticoids including cortisol. This leads to impaired immune regulation, increasing the risk of inflammatory and autoimmune diseases in individuals with depression. [2]

In recent years, growing evidence has highlighted a link between depression and inflammation. In cases of severe depression, elevated levels of inflammatory markers and abnormal immune function have been observed, affecting both cellular and humoral immune responses [2]. Those with elevated inflammatory markers (approximately one-quarter of individuals suffering from depression) show less improvement with antidepressant therapy [14]. The source of inflammation is often an infection (either localized or systemic), an autoimmune condition, or—particularly in obesity [14–15]—metabolites released by adipose tissue.

Inflammation leads to increased levels of various mediator molecules in the bloodstream. Many of these have been identified (e.g., CRP, IL-6, TNF, IL-10, TGF-β), each with distinct roles in regulating the inflammatory process.

Interestingly, in depression, both proinflammatory and certain anti-inflammatory markers (such as TGF-β and IL-10) show increased activity. Overall, the net effect of these mediators tends to be anti-inflammatory. The role of anti-inflammatory cytokines in depression remains less clearly understood, but may be linked to reduced cellular immune function. This aligns with observations that depression is frequently accompanied by immunosuppression.

Overall, depression appears to be characterized by immune dysregulation, involving both heightened cytokine production and an insufficient cellular immune response. These processes may vary depending on the stage of the desease, preventive treatment, or age. [2]

Different subtypes of depression are associated with distinct inflammatory profiles. Higher TNF levels are linked to atypical features, greater severity, and a chronic course [2]. Elevated CRP levels are more often seen in cases involving fatigue, increased appetite, hypersomnia, and low mood, while increased IL-6 levels are more commonly associated with reduced appetite, poor sleep, fatigue, and heightened suicide risk. [14]

The association between major depression and immune system dysregulation raises the question of whether individuals with depression are more prone to infections or autoimmune diseases than the general population. The relative risk of infection may rise by up to 60% after a single depressive episode, and by more than 80% after four or more episodes [16]. The reverse is also true: various viral and bacterial infections (e.g., gastroenteritis viruses, influenza, herpes viruses, Epstein–Barr virus, cytomegalovirus, Lyme disease) have been linked to depressive symptoms. [2]

The same applies to autoimmune diseases. People with depression are at increased risk of developing conditions such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Conversely, individuals with autoimmune diseases have a particularly high prevalence of depression and often less responsive to antidepressant treatments. However, they frequently report improved mood following immunosuppressive therapy. [2]

How can inflammation affect our behaviour?

On one hand, during infections, the innate immune system produces oxidative and nitrosative radicals, which damage, among other targets, the amino acids tryptophan and tyrosine, as well as enzymes crucial for neurotransmitter synthesis, such as tryptophan hydroxylase, which is responsible for serotonin production [17–18]. As a result, the production of neurotransmitters like serotonin, dopamine, and noradrenaline—and hormones such as thyroxine and melatonin—is disrupted.

On the other hand, various cytokines trigger multiple processes in the body. Among other effects, they increase the permeability of the blood-brain barrier, allowing components from the bloodstream — including white blood cells and inflammatory mediators — to enter the brain [2]. This activates microglia (the brain’s immune cells), which release more cytokines, damage GABAergic neurons, impair serotonin synthesis [19]. Under normal circumstances, serotonin is synthesized from tryptophan via the enzyme tryptophan hydroxylase. However, if another enzyme, indoleamine-2,3-dioxygenase (IDO for short), is activated, tryptophan is diverted into an alternative metabolic pathway known as the kynurenine pathway. This pathway produces both neurotoxic and neuroprotective compounds. Inflammatory mediators, psychological stress, and cortisol can all activate IDO [2]. Prolonged activation of this pathway decreases serotonin levels and increases neurotoxic kynurenines, leading to neuronal death. GABAergic dysfunction and certain inflammatory cytokines can also contribute to nerve cell death, disrupting neural circuits involved in emotion regulation, reward system, cognitive control, and self-reflection lead to symptoms and behaviours associated with depression and anxiety.

Mood disorders often co-occur with metabolic conditions like obesity, diabetes, or cardiovascular disease [20]. This may be due to the fact that they share several common pathways in their development, including inflammation, HPA axis dysfunction, oxidative stress, altered platelet activity, peripheral hormone imbalances (e.g., serotonin, dopamine, ghrelin, leptin), sleep disruption, and gut microbiota dysbiosis. [21–22]

People with depression often consume diets high in calories, carbohydrates, and cholesterol [21], as carbohydrate-rich foods can temporarily elevate mood by activating the brain’s opioid system. Appetite increases through several pathways: sleep disturbances impair glucose metabolism and disrupt the balance of hormones that regulate appetite (ghrelin and leptin), and may also increase blood–brain barrier permeability. [20]

Inflammation reduces leptin’s appetite-suppressing effect (leptin resistance), promoting overeating. At the same time, increased fat tissue exacerbates inflammation and further stimulates appetite [14]. Gut-brain communication involving ghrelin, leptin, and other peptides reinforces this cycle, increasing the likelihood of co-occurring obesity and depression.

Obesity, persistent stress axis activation, and inflammatory cytokines all increase the risk of insulin resistance, which impairs glucose metabolism in the brain. This leads to functional glucose deficiency, neuronal damage, and sustained neuroinflammation. [15]

The possibility arises that there is a distinct metabolic subgroup within depression who are more likely to develop insulin resistance and other metabolic disorders. Markers of insulin resistance are typically abnormal in individuals exhibiting depressive symptoms such as excessive sleep, increased appetite and weight gain. Notably, insulin resistance persists in this subgroup even after antidepressant treatment—regardless of its effectiveness [23]. As a result, metabolic support strategies—involving not only pharmacological treatment, but also dietary changes and regular physical activity—may be especially beneficial for these individuals.

The connection between depression and cardiovascular disease has been well established. Platelets, which play a central role in blood clotting, are closely linked to the serotonin system. They share significant biochemical similarities with serotonergic neurons, meaning that when the serotonin system is disrupted—as is often the case in depression—platelet function may also be affected. In individuals with major depressive disorder, there is a tendency toward increased platelet activation, which may contribute to an elevated risk of cardiovascular disease. Inflammation, which is also common in depression, further promotes platelet activation. [21]

In the absence of certain micro- and macronutrients (e.g. B vitamins), the synthesis of neurotransmitters may be reduced, but levels of the harmful homocysteine are increased. Hyperhomocysteinemia is a common finding in depressed patients, which then leads to further complications, such as also increasing cardiovascular risk and further impairing metabolic processes. [21]

A diet lacking in essential nutrients can increase the risk of developing mental health disorders and is therefore an important factor in prevention [8], [24]. Below is an overview of key nutritional components relevant to mood disorders.

Macronutrients

Carbohydrates

Carbohydrates are crucial not only for physical energy but also for emotional well-being. Low-carbohydrate diets are associated with an increased risk of depression, as carbohydrate-rich foods help stimulate the production of serotonin and other mood-regulating molecules. Low-glycaemic carbohydrates (e.g., certain fruits and vegetables) tend to have a moderate but longer-lasting positive effect on mood, whereas high-glycaemic foods (e.g., sweets) provide immediate yet a short-lived boost. [25]

Proteins

Proteins, made up of amino acids, are fundamental building blocks in the body. 12 amino acids are synthesized by the body, while the remaining 8 (essential amino acids) must come from the diet. Good quality protein-rich foods include meats and eggs. Plant proteins do not contain all the essential amino acids in sufficient amounts. Protein intake, along with the availability of specific amino acids, can influence brain function and mental health. Many neurotransmitters and neuroactive substances are derived from amino acids: dopamine and noradrenaline from tyrosine, and serotonin and melatonin from tryptophan. A lack of tryptophan can lead to reduced serotonin synthesis and contribute to mood disorders [25]. However, because other amino acids compete with tryptophan for entry into the brain—and because tryptophan metabolism is influenced by factors like inflammation, micronutrient levels and gut microbiota composition—increased protein intake doesn’t necessarily translate to higher tryptophan levels. Thus, it cannot be claimed that increased intake of amino acids or tryptophan protects against depression [4]. In fact, excessive accumulation of amino acids may even be harmful. [25]

Fats

The effects of fatty acids vary by type. Saturated fats may impair cognitive function, while unsaturated fats are considered beneficial. [22]

Polyunsaturated fatty acids (especially omega-3 and omega-6) cannot be synthesized by the body and must be obtained from food. Omega-3 fatty acids are anti-inflammatory, protect against oxidative stress, support neuroplasticity via BDNF modulation, and enhance neurotransmitter function [26]. Low omega-3 levels are linked to increased risk of major depressive episodes and suicidal thoughts. [8], [27]

Micronutrients

Scientific evidence regarding the role of micronutrients in mental health is still developing, and findings are sometimes inconsistent due to the complexity of underlying mechanisms. Nevertheless, deficiencies in the following vitamins and trace elements may play a role in the development of depression and anxiety. [4]

B Vitamins (B6, B12, folic acid)

Low levels of B vitamins, particularly folate (vitamin B9), B6, and B12, have been observed in people with depression. These deficiencies interfere with the synthesis of serotonin, dopamine, and noradrenaline, and lead to elevated homocysteine levels, which can cause neurotoxicity [24]. Vitamin B12 also affects acetylcholine production [28] and is essential for mitochondrial health. Low folate and B12 levels have been associated with poorer antidepressant response [8]. However, some studies have found no connection, and one even linked high B12 levels with a greater risk of depression [27]. Thus, their role remains uncertain.

Vitamin D

Vitamin D, synthesised in the skin through sunlight and available in certain foods or supplements, is increasingly recognized as crucial for mental health. Deficiency is associated with a significantly increased risk of depression [27]. This may be due to the presence of vitamin D receptors in different parts of the cerebral cortex and limbic system, areas involved in memory and emotion regulation, and its influence on BDNF, serotonin, dopamine, and noradrenaline production [8]. It also protects against oxidative stress and supports anti-inflammatory processes. [29]

Vitamin E

A fat-soluble antioxidant, vitamin E usually meets requirements through diet alone. Deficiency may occur with malnutrition or fat malabsorption and can cause poor coordination, muscle weakness, and anaemia [30]. It reduces oxidative stress and supports mitochondrial function. [31–32]

Vitamin C

Vitamin C (ascorbic acid) is a water-soluble compound with antioxidant activity similar to vitamin E, and lower levels of vitamin C have been associated with depression. Vitamin C has potential antidepressant effects due to its ability to promote the recycling of vitamin E, influence the function of various neurotransmitters and contribute to the reduction of inflammatory processes. [33]

Iron

Iron deficiency is the most common nutrient deficiency worldwide and can present with symptoms such as fatigue, muscle weakness, reduced physical strength, and impairments in mood, learning, and memory. [34]

This is because iron is essential for numerous vital functions. It plays a key role in oxygen transport, DNA synthesis, mitochondrial energy metabolism, immune system function, and the proper synthesis of brain neurotransmitters [35]. Iron also contributes to the development of anxiety symptoms by influencing the GABA and glutamate systems and is required for the production of dopamine, serotonin, and noradrenaline. Additionally, it regulates BDNF production, thereby affecting neuroplasticity. During inflammatory processes, iron availability in the brain is reduced, potentially leading to a functional iron deficiency that can further exacerbate symptoms. [34]

However, excess iron can also impair brain function [35]. Iron accumulation in the brain leads to oxidative stress in neurons and may ultimately cause cell death, a process known as ferroptosis [34]. Although the blood–brain barrier usually protects the brain from excessive iron influx, the body can only compensate to a limited extent. The risk of iron overload-induced neurological damage is higher in neonates and older adults, as the rate of iron transport into the brain increases both early and late in life. [35]

The connection between psychological symptoms and iron metabolism is often overlooked, yet it may play a significant role in depression and anxiety disorders [36]. It is worth considering in cases of “brain fog” (such as during pregnancy and the postpartum period, often referred to as “mummy brain”), persistent fatigue, learning or concentration difficulties, anxiety, sleep disturbances, or mood disorders—even in the absence of anaemia. [34]

Magnesium

Magnesium is involved in more than 300 cellular processes [24]. Insufficient magnesium levels cause changes in the functioning of the central nervous system, particularly in the limbic system and glutamate systems in the cerebral cortex. Magnesium deficiency can indirectly lead to damage and even death of nerve cells. It also affects the function of the HPA axis [8]. In its absence, it can cause, among other things, mood disorders and sleep disturbances.

Zinc

The brain contains significantly higher levels of zinc than any other organ in the body. [27]

Like magnesium, zinc is essential for hundreds of cellular processes. [24]

It influences the function of the HPA axis, modulates cellular immune responses, and regulates BDNF expression in both the limbic system and the cortex. Zinc also affects serotonergic and other neurotransmitter pathways and can even function as a neurotransmitter itself. In addition, it possesses both anti-inflammatory and antioxidant properties [8]. Zinc deficiency can lead to a range of neurological and psychological symptoms, including irritability, mood swings, and cognitive dysfunction. [24]

Selenium

Selenium is an essential trace element necessary for the proper functioning of many selenoproteins. These selenoproteins also play a role in protecting the nervous system against oxidative stress [8]. Additionally, selenium influences the functioning of the serotonin, dopamine, and noradrenaline systems. It also plays a crucial role in maintaining thyroid function [27], which supports optimal metabolic processes and mental health.

Copper

Copper plays a role in energy metabolism through mitochondrial processes and also has effects on the immune and nervous systems. It is involved in histamine metabolism [37] and in defending against oxidative stress [27]. The conversion of dopamine to noradrenaline requires the presence of copper. It also supports the activity of various neural growth factors (BDNF, NGF). Through these processes, copper contributes to the proper functioning of learning and memory, as well as the maintenance of neuroplasticity. However, not only copper deficiency but also excess copper or impaired copper utilization (e.g., due to a lack of vitamin A) can impact brain function. In fact, several scientific studies have found that elevated—rather than reduced—copper levels are associated with the development of depressive symptoms. [8]

Calcium

The role of calcium in the development of depression is evident in several processes. On one hand, calcium is involved in regulating the HPA axis, i.e., the stress response, and it also influences serotonin synthesis. The concentration of calcium ions is a crucial factor in maintaining proper cellular function and stimulus-response activity. As a result, calcium has a broad impact on cellular processes, which, by extension, also affects emotion regulation [38]. Calcium deficiency is rarely observed in individuals with a balanced diet.

Lithium

Lithium is not yet classified as an essential micronutrient, yet it offers significant benefits for human health [39]. Today, it is best known for its use in psychiatry as a mood stabilizer in the treatment of bipolar disorder. In this context, the medication contains high doses of lithium (100–200 mg) [40], which require close laboratory monitoring due to its potential toxicity. However, substantial evidence suggests that at much lower doses—as a trace element—lithium may provide benefits not only for individuals with mental disorders but also for the general population. [41]

Lithium has complex and multifaceted effects on the human body, particularly on the nervous, immune, and even reproductive systems [42]. In addition to its mood-stabilizing properties, it also appears to have a suicide-preventive effect, reduce aggression and impulsivity [43], and support the resynchronization of circadian rhythms. Lithium influences various intracellular processes and modulates the function of several neurotransmitters. By stimulating the BDNF signaling pathway, it promotes the formation and growth of new neurons and contributes to the protection of neurons against oxidative stress. Its beneficial effects may also be linked to enhanced transport of vitamins—particularly B12 and folic acid—to the brain. Lithium further affects the function of the HPA axis. It also exhibits complex immunomodulatory properties, increasing cellular immune activity and enhancing the synthesis of IgG and IgM immunoglobulins. [40–41]

It should be noted that the vast majority of the associations mentioned above have been observed at high therapeutic doses. It remains unclear to what extent lithium, when consumed in trace amounts, produces these effects. Nevertheless, studies have shown that regions with lower dietary lithium intake (primarily through drinking water) tend to have higher rates of suicide, impulsive and violent crime, and drug use. [39]

The neurogenic theory of depression suggests that structural changes in the limbic system—responsible for regulating emotions and mood—play a role in symptom development. The most frequently observed changes include atrophy of the prefrontal cortex and hippocampus, which show a reduction in neurons and glial cells. These findings have led to the consideration of depression as a mild form of neurodegenerative disease. Fortunately, these changes may be reversible with effective stress reduction and treatment. [10]

Increased vulnerability of neurons results from disrupted signalling pathways combined with genetic and environmental factors. One key abnormality involves the glutamate system: stress and glucocorticoids increase glutamate release while inhibiting its removal. Excessive glutamate can damage neurons, particularly under adverse genetic or environmental conditions. [10]

Another major factor is reduced levels of growth factors. Although there are several growth factors involved in depression, most attention has focused on BDNF (brain derived neurotrophic factor) [10]. Lower levels of BDNF have been found in people with depression. [20]

BDNF plays an important role in the survival and growth of neurons, is involved in the regulation of signal transduction pathways, and is essential for learning processes and memory maintenance. It is also widely found outside the central nervous system (e.g. even in the gut), regulating metabolism and energy balance [44]. When its levels are reduced (e.g. through genetic mutation), atrophy of the hippocampus and prefrontal cortex has been observed, similar to lesions caused by chronic stress. Although BDNF mutations alone are not sufficient for the development of depression, they certainly imply an increased vulnerability to stress and carry a higher risk of developing mood and cognitive deficits (e.g. Alzheimer’s disease, Parkinson’s disease). [10]

However, the neurogenic theory has limitations. For example, depression-like symptoms can appear without neuron loss, and antidepressants don’t always restore neuron numbers. A better explanation may lie in neuroplasticity—the brain’s ability to adapt—and mitochondrial function, rather than cell count alone. [45]

Recent scientific findings suggest that disruption in the body’s energy balance—particularly at the cellular level—may be a major contributor to the development of depression. [45–47]

Our cells contain a cellular organelle called a mitochondrion. Mitochondria are the main energy storage and power plants of cells. Every cell in our body contains mitochondria, but our cells that do the intensive work need much more energy. Our brains – especially the grey matter of our brains – are made up of cells that are highly energy-intensive and have little capacity to store energy, so keeping their power plants working properly is crucial. Each nerve cell contains thousands of mitochondria. [47]

In addition to energy production, mitochondria serve several other vital functions. They contribute to maintaining cellular stability, regulating levels of reactive oxygen species, and controlling apoptosis (programmed cell death). [47]

In depression, mitochondrial function is impaired: ATP (i.e., energy) levels decrease, oxidative radical production increases, pro-inflammatory cytokines are released, and apoptosis is accelerated [45]. In addition, neuronal regeneration and the formation of new neurons are reduced, as the levels of growth factors important for neurogenesis decline. Since the release of excitatory neurotransmitters and the responses they trigger are both energy-intensive processes, communication between neurons is also disrupted [45]. All these changes lead to a decrease in the overall adaptability (neuroplasticity) of neurons. A new approach to mood disorders suggests that this reduced adaptability may underlie the development of depression. [47]

Supporting this idea, many individuals with depression exhibit mitochondrial abnormalities. Conversely, about half of people with mitochondrial disorders also have mood disorders. So the two diseases are often comorbid. However, not everyone with the same mitochondrial mutations develops depression, highlighting the influence of environmental factors in addition to genetics. [45]

Examples of such environmental effects include chronic stress. Cortisol released during HPA axis activity plays a biphasic role in the regulation of mitochondrial function. In the acute case (i.e. at the onset of a stressful event), it significantly increases mitochondrial activity, thereby helping cells and the body to adapt to changing conditions. However, in chronic situations (i.e. prolonged exposure to stress), it causes structural and functional abnormalities in mitochondria: it increases the production of reactive oxygen species and can ultimately cause cell death in neurons and other cells in the body. [47]

Micronutrient deficiencies also impair mitochondrial function. Important nutrients include B vitamins, vitamin C, vitamin E, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, lipoic acid, and taurine. Many of these support energy production, while selenium also aids mitochondrial formation [32]. Nutrition and lifestyle, therefore, play a vital role in mitochondrial health and overall mental well-being.

What is the importance of the microbiome–gut–brain axis in mental health?

The microbiome-gut-brain axis (or gut-brain axis for short) is a complex system of connections between the gut and the central nervous system that plays an important role in the development of mental illness.

In one study, when stool samples from depressed humans were transplanted into healthy germ-free mice, the animals began to display depressive behaviours. These mice also showed disruptions in carbohydrate and amino acid metabolism, as well as changes in organ function (including the brain, liver, and colon) and hormonal systems [1]. Such findings highlight the growing focus on the gut bacterial flora.

Research suggests that dysbiosis—an unhealthy composition of gut bacteria—may not only result from but also contribute to mental health problems. This is due to the microbiome’s involvement in nearly all mechanisms associated with depression. [48]

Most neurotransmitters of the central nervous system are also present in the gastrointestinal tract. They are produced partly by enteroendocrine cells in the gut and partly by gut bacteria. However, certain neurotransmitters or their precursors are not only produced but also consumed by the intestinal flora [49]. For example, GABA is produced by Bacteroides fragilis and consumed by Evtepia gabavorous [50]; noradrenaline is both produced and consumed by Escherichia coli [51]; tryptophan is consumed by Alistipes species [52]; and serotonin is produced by E. coli [53]. And the list goes on.

Intestinal neurotransmitter molecules primarily have local effects, as they cannot cross the blood–brain barrier under healthy conditions. Their signals can, however, be transmitted to the brain via the vagus nerve [53]. During inflammatory processes, the selectivity of the blood–brain barrier may become impaired, allowing a greater proportion of these circulating molecules to reach the brain. Precursor molecules, on the other hand, can cross into the central nervous system even when the blood–brain barrier is intact and can contribute to neurotransmitter synthesis [49]. The gut microbiota is associated with all neurotransmitter systems involved in the development of depression: serotonin, dopamine, noradrenaline, GABA, glutamate, histamine, and acetylcholine. Due to their significance, the serotonergic and dopamine/norepinephrine systems will be discussed in more detail.

Serotonin and the gut microbiome

About 90% of serotonin is synthesized outside the brain, mainly in the enterochromaffin cells of the intestinal epithelium. While serotonin itself cannot cross the blood-brain barrier, its precursor, tryptophan, can [49]. Tryptophan is an essential amino acid, meaning it must be obtained from the diet. Various bacterial strains can influence tryptophan availability in several ways. Some strains, like Alistipes, use tryptophan for growth or activate the kynurenine pathway, diverting tryptophan away from serotonin production and toward inflammation-related metabolites [52]. Turicibacter sanguinis uses serotonin itself for growth [54]. On the other hand, species like Clostridium and Staphylococcus can promote serotonin synthesis [49], and E. coli is capable of producing serotonin directly [53]. Given the dynamic interaction between the serotonergic system and the HPA axis, the microbiome may also influence the serotonin system indirectly through the stress axis [9]. The effects of serotonin on gut function are highly diverse. In addition to its physiological role in regulating motility and secretion, it also influences intestinal permeability: elevated levels enhance barrier function, whereas low levels impair it. [54]

Dopamine, noradrenaline and the intestinal flora

Dopamine is a key neurotransmitter involved in reward-driven behaviour and serves as a precursor to noradrenaline and adrenaline. More than 50% of the body’s dopamine is produced in the gut, where it primarily exerts local effects, such as regulating gastric emptying, gut motility, and secretion [49]. However, its influence may also be transmitted to the brain via the vagus nerve [53]. Certain bacteria can respond to these catecholamines and even synthesise them. For instance, pathogenic strains of Escherichia coli exhibit enhanced growth, increased motility, biofilm formation, and greater virulence in the presence of dopamine and noradrenaline. Other pathogens—such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Shigella sonnei, and Staphylococcus aureus—also demonstrate accelerated growth in response to noradrenaline. In addition, some bacteria, including E. coli and Bacillus subtilis, are capable of producing these catecholamines themselves. Short-chain fatty acids (SCFAs) produced by the gut microbiota may further influence the synthesis of neurotransmitters in the brain. Collectively, these findings support growing evidence that the microbiome may modulate host catecholamine production and degradation—an interaction that may play a significant role in the development of mental health disorders. [49], [51]

Short-chain fatty acids (SCFAs) are small organic compounds produced by large intestine bacteria during the fermentation of carbohydrates. The three most abundant SCFAs are acetate, butyrate, and propionate [53]. These molecules are key players in the communication between the gut and the brain.

SCFAs nourish gut bacteria and intestinal epithelial cells, helping to maintain a healthy gut environment. They support the integrity of the intestinal barrier, stimulate saliva production, reduce inflammation, promote the release of antimicrobial peptides, and even have antitumor effects [9], [54]. SCFAs also regulate enteroendocrine cells, which influence the release of molecules in the gut like ghrelin, serotonin, dopamine, and noradrenaline. [22]

Once absorbed into the bloodstream, SCFAs affect numerous body systems. For instance, they increase energy expenditure in skeletal muscle and the liver, improve insulin sensitivity, boost satiety, and support weight regulation [55]. SCFA receptors are also found on immune and nerve cells, where they regulate T and B lymphocyte function, which are important in the development of the immune response. They also affect visceral nerve fibres, which are part of the peripheral nervous system, as well as autonomic and sensory nerve fibres and influence the autonomic and sensory nervous systems. SCFAs reach specific brain regions (like the hypothalamus) via the vagus nerve and can modulate stress responses. [9]

However, they also have direct effects on the central nervous system, as well as indirect ones. They themselves can easily cross the blood-brain barrier and can influence its function by regulating the synthesis of tight junction proteins. Acetate can accumulate in the hypothalamus, thereby directly affecting the activity of the HPA axis and stimulating local GABA production. In addition, SCFAs promote microglial cell maturation and function. Microglia are responsible for brain immune defence and various developmental processes. SCFAs also act through epigenetic regulation, i.e. by stimulating the expression of certain genes relevant to depression. For example, they promote the production of dopamine in the brain, inhibit its conversion to noradrenaline and stimulate the production of BDNF. [54]

Short-chain fatty acids thus affect the central nervous system in a complex way, including mood, cognition and the response to stress. However, in addition to their many beneficial properties, they may also have adverse effects. For example, acetate may promote the secretion of the cytokine IL-6 in the gut and increase neutrophil cell recruitment [54], and may further impair fat accumulation in people with non-alcoholic fatty liver [55]. SCFAs may also cause neurochemical damage, e.g. propionic acid may impair the GABA/glutamate ratio in the brain, leading to the development of psychiatric symptoms. The biggest controversy surrounds butyrate. In addition to its anti-tumour, anti-inflammatory and cell regeneration promoting effects, the opposite has been observed: it may promote the transformation of the colon epithelium, contributing to the development of colon cancer, and it may also cause colitis, urethritis and renal pelvis inflammation, and contribute to obesity. [56]

In summary, SCFAs exert wide-ranging effects on brain function and mental health. However, their biological activity varies depending on health status and on ffactors that still require further scientific investigation. A well-functioning microbiome that produces SCFAs in the appropriate proportions is essential for mental well-being—but supplementing with SCFAs or prebiotics without knowing your current gut composition may do more harm than good.

HPA axis

The gut microbiome plays an integral role in the development and regulation of the HPA axis [57]. This connection occurs both via the enteric nervous system (which innervates the gut) and through bacterial antigens entering the bloodstream, which can activate the stress axis. Additionally, recent research shows that the microbiome can influence the synthesis of proteins related to the HPA axis function. [9]

At the same time, the stress axis also affects the enteric nervous system by altering gut motility and secretion, and circulating cortisol itself affects the composition of the gut microbiome and gut permeability [9]. Under prolonged stress, the diversity of the microbiome decreases, and the proportion of pathogenic bacteria may increase. Bacteria adhere more readily to intestinal epithelial cells, which promotes inflammation. The tight junctions between the cells are damaged and the gut can become permeable. [58–59]

Vagus nerve

The vagus nerve is the most direct signalling pathway between the gut and the brain. It plays a role in stress response, memory, anxiety, fear-based behaviours, and brain plasticity. Therefore, the gut microbiome can significantly influence brain function through this pathway. [9]

This communication is also bidirectional. The vagus nerve can modulate gut activity and appears capable of distinguishing between non-pathogenic and potentially pathogenic bacteria—even in the absence of inflammation. Specific vagal signals can initiate an anti-inflammatory reflex, causing the release of acetylcholine and other mediators that reduce inflammation by interacting with immune cells [11], [60]. This immunomodulatory effect also contributes to improved brain function and emotional regulation.

Gut hormones

Gut bacteria also affect the number and activity of enteroendocrine cells (hormone-producing cells in the gut). Enteroendocrine cells are found throughout the intestinal tract and make up about 1% of the epithelial cells. They can be divided into several types according to the hormones they produce. These hormones have multiple biological functions (e.g. regulation of food intake, gastric emptying, intestinal motility, glucose metabolism, etc [61]).

Many intestinal peptides are involved in gut-brain axis communication through indirect mechanisms, such as modulation of the gut-brain nerve, or directly across the blood-brain barrier. Their primary target is the hypothalamic region, which is responsible for feeding behaviour and the regulation of the hunger-fatigue balance [62], but they may also have protective effects against neuronal damage caused by toxic microbial metabolites. [21]

Two gut hormones especially relevant to mental health are ghrelin and leptin: Among their many functions, they play a role in appetite regulation. They regulate both homeostatic (called “physiologically necessary”, which is done to provide nutrients to the body) and hedonic, or “pleasure” eating by influencing dopamine signalling [63]. Ghrelin leads to an increase in appetite, plays a role in inflammatory processes, stimulates the stress response by increasing glucocorticoid levels, plays a role in cardiovascular function and regulates mood. Leptin has the opposite effect: it decreases both appetite and glucocorticoid levels [21]. The gut microbiota influences the secretion of both hormones, contributing to changes in both mood and metabolism. [62–63]

An imbalanced gut microbiome (dysbiosis) can compromise the integrity of the intestinal barrier, allowing bacterial components—such as endotoxins—to enter the bloodstream. Once in circulation, these antigens activate the immune system and trigger a systemic inflammatory cascade that affects the entire body, including the HPA axis and the central nervous system. This relationship is bidirectional: just as gut dysbiosis can cause systemic inflammation, existing inflammation can, in turn, impair the gut microbiota. This results in a loss of microbial diversity and the emergence of pathogenic colonies—further perpetuating the cycle.

The digestive and absorptive functions of the alimentary tract are crucial for the body’s nutrient supply. These are highly complex processes that require an adequate pH (especially an acidic stomach), the presence of various digestive enzymes, bile acids, an intact mucous membrane, the hormone system and the autonomic nervous system.

Abnormalities in the bacterial flora (e.g., SIBO, dysbiosis, or the presence of pathogenic colonies) can disrupt this process at several points. For example, Helicobacter pylori can alter stomach pH, while SIBO may impair bile acid function and fat digestion in the small intestine. Inflammation of the intestinal mucosa can also compromise epithelial cell function. Additionally, pathogenic colonies may consume dietary iron intended for the host. As a result, an imbalanced gut microbiota can significantly affect the availability of both micro- and macronutrients. [64]

However, most bacteria that are part of the normal, healthy microbiome, such as Lactobacillus and Bifidobacterium species, synthesise vitamins (especially vitamins B and K) as part of their metabolic processes. These key micronutrients have largely local effects, but can also be absorbed from the gut and thus play a role in many physiological processes. They cross the blood-brain barrier and, once they reach the central nervous system, they perform a range of functions from energy metabolism to neurotransmitter synthesis. [53]

The blood-brain barrier (BBB) is a highly selective, multi-layered shield that protects the brain by regulating which substances can pass from the bloodstream into the central nervous system. It ensures a stable environment for neurons while preventing harmful compounds from entering. [11]

When the gut microbiome is disrupted, intestinal permeability increases, allowing bacterial toxins bacteria and their various metabolites and toxins to enter circulation. These trigger systemic inflammation, releasing cytokines that weaken the BBB’s integrity. As a result, the BBB becomes more permeable and less effective at protecting the brain.

Bacteria can influence the BBB both indirectly (through inflammation and immune activation) and directly. For instance: LPS (from Gram-negative bacteria) and LTA (from Gram-positive bacteria) can bind to BBB cells, altering their function and reducing barrier selectivity. Conversely, short-chain fatty acids like acetate, butyrate, and propionate support BBB integrity by promoting the expression of tight junction proteins and reducing inflammation. [65]

In cases of intestinal dysbiosis, the function of cells in tissues associated with the gut-brain axis is altered, which is reflected, among other things, in the composition of the proteins they produce. These changes primarily affect energy metabolism processes, which are so fundamental to cellular function that their disruption is linked to impairments in numerous other biological functions. The organs most affected include parts of the brain, the liver, and the intestine. In animal studies, protein alterations caused by stress were compared with those resulting from dysbiosis. Although depressive behavior was observed in both groups, the protein profiles showed only partial overlap.

Thus, the microbiome may contribute to the development of depressive symptoms through mechanisms that are distinct from, and independent of, psychological stress. [1]

Contributing factors to depression

Figure 2. Contributing factors to depression

What are the differences in gut microbiome in depression or anxiety?

The scientific evidence on this topic should be interpreted with caution due to geographical variations and differing study methodologies. However, it can be concluded that the gut microbiome of individuals experiencing psychological distress differs significantly from that of healthy individuals [4]. In depression, a higher prevalence of Klebsiella, Prevotella, Streptococcus, Clostridium [48], and Eghertella species [4] is observed, while lower levels are found of genera such as Faecalibacterium, Coprococcus [66], Ruminococcus, Fusicatenibacter [67], and Dialister species [66]. Additionally, other bacteria may play a role, such as certain species of Alistipes [52], Sellimonas [4], and Evtepia gabavorous [50]. In patients with anxiety disorders, microbial species richness and diversity are reduced. Species such as Prevotella, Sellimonas, Streptococcus, Enterococcus, Escherichia, Shigella, Fusobacterium, and Ruminococcus have been linked to the onset of symptoms, while some short-chain fatty acid (SCFA) producers, such as Lachnospira, Faecalibacterium, and Eubacterium species, are believed to have protective effects [48], [68]. This list is not exhaustive, and research into the relationship between the microbiome and mental health is ongoing.

Do you suffer from depression?

Examining the composition of the gut microbiome can help uncover the underlying root causes behind depression.

What are the options for treating depression?

Today, the treatment of major depression is typically managed by a psychiatrist, psychologist, or psychotherapist. A wide range of antidepressant medications and psychotherapeutic approaches are available, depending on the individual’s needs. This article focuses on complementary or alternative strategies that may enhance or support traditional therapies.

Elimination of inflammatory processes

Inflammation can contribute to psychological symptoms via various mechanisms. Potential sources include chronic infections (e.g., dental or gynaecological), systemic diseases (e.g., Lyme), autoimmune conditions, or gut dysbiosis. For individuals with persistent mood symptoms, it’s important to investigate and, if possible, eliminate underlying sources of inflammation.

Adequate nutrition

Inappropriate dietary intake can lead to obesity, metabolic disorders, macro- and micronutrient deficiencies, subclinical inflammation, the development of autoimmune conditions, neuroinflammation, and the onset of psychiatric symptoms. In general, depression may benefit from a Mediterranean-style diet rich in plant fibers, minerals, and polyphenols.

It is also important to ensure the intake of high-quality proteins and an adequate proportion of omega-3 fatty acids. Two omega-3 fatty acids—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have shown the greatest potential in alleviating symptoms of mood disorders. EPA is more actively involved in inflammatory processes, while DHA is a structural component of cell membranes, including mitochondrial membranes, which are essential for cell integrity, communication, receptor function, transporter activity, and energy production. The best results are typically seen when the supplement contains at least 60% EPA. While DHA is considered less effective for treating depression, it may help reduce suicidal thoughts and attempts. [69]

Various spices can also be incorporated into the diet for their anti-inflammatory, antibacterial, antifungal, and other biocidal properties. For example, Szechuan pepper, curcumin, and capsaicin have shown protective effects in anxiety and depression. [48]

Ultimately, a diet tailored to individual circumstances, current health status, genetics, and microbiome is most strongly recommended. [70]

Trace Elements and Vitamins

B Vitamins

A balanced diet generally provides the body with sufficient B vitamins. In general, B vitamin supplementation is not recommended for adults with adequate levels, either as a preventive measure or to support antidepressant therapy. [24]

However, when deficiencies are detected, supplementation may help improve psychological (and other) symptoms. This possibility is worth considering in vegetarians [8] and in women taking oral contraceptives [27], who are more likely to have low levels of vitamin B6.

Vitamin D

In cases of major depressive episodes, vitamin D may help alleviate symptoms and appears to [24], [27] reduce the risk of developing anxiety [29]. When levels are low, supplementation is strongly recommended, not only for its psychological benefits but also for its broader relevance to overall health.

Vitamin E

Vitamin E supplementation may play a role in reducing depressive symptoms and supporting cognitive function [71], although no similar association has been established for anxiety. However, when combined with omega-3 fatty acids, it has shown beneficial effects on both depression and anxiety, suggesting a potential synergistic relationship. [31]

Vitamin C

Low vitamin C levels are associated with an increased risk of depression and anxiety [72]. Supplementation may help prevent or alleviate symptoms. Notably, vitamin C appears to offer significant mood improvement in individuals with subclinical or mild symptoms, rather than in cases of severe depression. [33]

Iron

As previously discussed, iron deficiency is the most common nutrient deficiency worldwide and may occur with or without anemia. Before starting supplementation, the underlying cause of iron deficiency should be investigated and addressed if possible. Contributing factors may include dietary issues (e.g., deficiencies in vitamin A, vitamin C, B vitamins, copper), malabsorption, bleeding disorders, or genetic conditions. If blood ferritin levels remain below 30 μg/L after correcting other conditions, oral iron supplementation should be continued for at least three months. Supportive supplementation for antidepressant therapy may also be considered when ferritin levels are between 30 and 50 μg/L, although there is no international consensus [34]. For optimal absorption, a heme iron preparation is recommended, taken every other morning.

Magnesium

The relationship between dietary magnesium intake, serum levels, and the risk of depression is difficult to assess, as blood magnesium accounts for only about 1% of total body magnesium and does not reliably reflect intracellular levels [8]. In any case, lower levels of magnesium increase the risk of neurological and psychological symptoms [73]. Several reports suggest that magnesium supplementation can improve depressive symptoms. [74–75]

Zinc

Low zinc levels are frequently observed in individuals with depression [24], [76]. In such cases, supplementation can enhance the effectiveness of antidepressants [8], and some evidence suggests that zinc may even be effective as a standalone treatment [76]. Although more research is needed, current findings indicate that zinc is a promising trace element in the management of mood disorders.

Copper

Copper intake from a balanced diet is generally sufficient. Adequate copper levels are important for the prevention of depression, but supplementation is only beneficial for individuals with a dietary deficiency. Copper metabolism is closely linked to that of iron, zinc, and vitamin A, so these should be considered and corrected together if necessary to support mental health. [77]

Selenium

Studies investigating the link between selenium and depression have yielded mixed results [8]. No significant association has been found between serum selenium levels and the presence or severity of depressive symptoms. However, some studies report a reduction in depressive symptoms following selenium supplementation. [27]

Calcium

Inadequate calcium intake has been shown to worsen depressive symptoms [38]. However, a balanced diet typically meets the body’s calcium needs. Moreover, excessive calcium intake may counteract the beneficial effects of magnesium [78], making calcium supplementation unnecessary—and potentially unhelpful—when dietary intake is sufficient.

Lithium

Assessing lithium deficiency is currently challenging. Most laboratories only test for toxic lithium levels, which are relevant to high-dose psychiatric treatments and not reflective of trace-element needs in everyday life. Therefore, such tests are unsuitable for evaluating lithium status at nutritional levels.

Current research suggests a daily intake of approximately 1 mg of lithium, with potential benefits from doses up to 5 mg under certain conditions (e.g., environmental stressors, mental or other health issues) [42]. Small amounts of lithium are naturally found in oilseeds, nuts, certain leafy and root vegetables, cereals, and—depending on location—in drinking water. As a dietary supplement, lithium orotate is the recommended form [79]. In recent years, the concept of lithium-fortified foods (similar to iodized salt) has gained attention, although no such products are currently available on the market. [40]

Adaptogenic medicinal plants

Adaptogenic herbs are a group of plants with complex, non-specific effects on the human body, enhancing its ability to adapt to long-term stress [80]. They help restore the function of systems weakened by chronic stress—particularly the immune, nervous, and endocrine systems—bringing them back to a healthier state. Since these systems are also involved in depressive and anxiety disorders, the use of adaptogenic herbs may offer therapeutic benefits.

In the context of depression, the most extensively studied and supported adaptogen is St. John’s wort (Hypericum perforatum), followed by saffron (Crocus sativus L.). Other adaptogens that may alleviate psychological symptoms include ashwagandha (Withania somnifera), rose root (Rhodiola rosea), and ginseng (Panax ginseng). [81]

Their exact mechanisms of action are difficult to pinpoint, likely involving multiple pathways. These herbs reduce inflammation, including neuroinflammation, protect against oxidative stress, influence neurotransmitter systems, and support brain plasticity by regulating BDNF levels. [81]

However, adaptogens should be used with caution, as they interact with enzymatic pathways involved in the metabolism of antidepressant medications. This can lead to adverse or even life-threatening effects, such as severe bleeding or myocardial infarction [82]. Therefore, it is advisable to inform a doctor or general practitioner when using adaptogenic herbs and to carefully consider potential drug interactions.

Supporting mitochondrial function

Today, therapeutic options targeting altered mitochondrial function in mood disorders are receiving increasing attention. Mood stabilizers, antidepressants, and antipsychotics have shown benefits in this area, but there are also ways to support mitochondrial function beyond traditional medications. [26]

The roles of various vitamins, trace elements, and omega-3 fatty acids have been discussed previously. In addition, several other nutritional supplements have been found to enhance mitochondrial function and, consequently, brain energy metabolism—mainly by reducing oxidative stress. These include N-acetylcysteine, alpha-lipoic acid, acetyl-L-carnitine, S-adenosylmethionine, creatine monohydrate, and coenzyme Q10. While current evidence suggests these compounds may be beneficial in mood disorders, further clinical trials are needed to confirm their effectiveness. [26]

The hormone melatonin may also fall into this category. In addition to regulating circadian rhythms, melatonin is a powerful antioxidant. It directly supports mitochondrial function and protects mitochondrial DNA from damage. Although it is a relatively well-known compound and widely used for sleep disorders, clinical studies investigating its use in mood disorders have produced inconclusive results. It is possible that only certain subgroups of individuals may benefit from its use – particularly those with seasonal affective disorder. [26]

The ketogenic diet has also shown promise in improving mitochondrial function. It may be effective as an adjunct therapy for mood stabilization and/or epilepsy.

The ketogenic diet is a low-carbohydrate dietary approach in which ketone bodies, produced from fat breakdown, become the body’s primary energy source instead of glucose. This metabolic shift leads to changes in neurotransmitter levels and various hormones, enhances mitochondrial energy production, supports antioxidant processes, reduces neuroinflammation, and increases BDNF levels—producing an overall neuroprotective effect. Although data on its role in treating mood disorders are still limited, preliminary findings are promising. [26]

Physical activity

Physical activity: Exercise improves metabolism, reduces inflammation, enhances mitochondrial function, and positively impacts mood and cognitive function [22], [26]. It’s a valuable complementary therapy for depression.

Drugs and supplements affecting gut microbiome

A safe and beneficial influence on the composition of the gut microbiome is most effectively achieved when the baseline condition is known. Therefore, it is recommended to perform a microbiome assessment before using any preparation that affects the gut microbiome.

Antibiotics

Antibiotics have a significant impact on the gut microbiome. Whether their effects are positive or negative, they can influence the course of digestive and other disorders, including psychological conditions. Notably, some antibiotics may help alleviate psychological symptoms due to their anti-inflammatory and neuroprotective properties. Positive outcomes have been reported for certain antibiotics in relation to mood disorders and anxiety [83–84], while other commonly used antibiotics have been associated with adverse effects [68]. Overall, the wide variety of antibiotics and their differing impacts on the body suggest that their routine use cannot be recommended without further research.

Probiotics

Probiotics are living microorganisms that can provide health benefits to the human body when used appropriately. Their use has also shown promise in the treatment of mood disorders [68]. Probiotics exert their effects through various mechanisms—for example, by influencing the metabolism of neurotransmitters (such as GABA and serotonin), reducing HPA axis activity, affecting BDNF synthesis, or suppressing certain pathogenic bacterial colonies [2]. The use of Clostridium butyricum, various Lactobacillus, Bifidobacterium, Bacillus strains, and Akkermansia muciniphila, among others, has demonstrated therapeutic or preventive effects on anxiety and depressive symptoms [48]. However, not all studies have reported positive outcomes, likely due to differences in probiotic strains, the patient’s original microbial composition, concurrent medications, or other as yet unidentified factors. [68]

Prebiotics and symbiotics

Prebiotics are substrates that promote the growth of certain beneficial bacteria. Fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are the most well-documented prebiotics in the treatment of depression, though polyphenols and compounds derived from vegetables, herbs, and other plants have also been noted. Prebiotics typically do not act directly on the body, but rather exert their effects indirectly by supporting bacterial proliferation, which is why they are often used in combination with probiotics. Synbiotics combine the benefits of both prebiotics and probiotics [67]. Their impact on alleviating psychological symptoms appears to be most significant in patients with irritable bowel syndrome (IBS) [68]. However, without prior assessment of the microbiome, the long-term use of prebiotics may be risky, as their effects are not selective enough to promote the growth of only beneficial bacteria.

Postbiotics

Postbiotics are inanimate microbial cells, their components, and the beneficial metabolites they produce—such as short-chain fatty acids and bile acids. Administering live bacteria to critically ill or otherwise vulnerable individuals may carry potential risks. In such cases, postbiotics, which can offer health benefits similar to those of probiotics, may represent a safer alternative [67]. However, they are not without risk themselves, as demonstrated in certain contexts—for example, with short-chain fatty acids. Currently, there are few studies investigating postbiotic-based therapies for depression, and in the absence of robust evidence, their use requires increased caution.

Targeted products based on microbiome analysis

Knowledge of the gut microbiome’s composition may enable the identification and correction of abnormalities associated with psychological risk. Specific bacterial populations can be selectively modified through the use of natural herbal agents (e.g., quercetin, thymol, carvacrol, borage oil, cranberry), probiotics, or dietary interventions. This targeted approach can help restore the barrier function of the intestinal wall and reduce the brain’s—and the entire body’s—exposure to toxic or inflammatory metabolites, leading to improvements in both physical and psychological symptoms. As such, understanding the gut microbiome and addressing its potential imbalances offers a promising—and personalized—approach for individuals suffering from depression.

FMT (Faecal Microbiota Transplantation)

FMT involves transferring stool from a healthy donor into a recipient’s gut to rapidly reshape their microbiome. While FMT has shown benefits in various chronic conditions associated with dysbiosis – such as depression – FMT therapy can also have side effects and complications. Evidence for its use in mental health is still limited. However, in patients with IBS or other functional gut issues, FMT has been shown to alleviate depressive symptoms – even when gastrointestinal symptoms remain unchanged [67–68]. Despite growing interest, FMT is not yet routinely used to treat mood disorders.

Functional treatment options for depression

Figure 3. Functional medicine treatment options for depression

The development of depressive and anxiety symptoms is a highly complex process that is not well explained by the theory of brain neurotransmitter imbalance alone. It is a complex neuronal dysfunction, where not only neurons are involved but the whole body, including the immune system, endocrine system, gut-brain axis and metabolic processes, and even the circulatory system. An equally complex approach to treatment is needed to ensure an effective cure.

At HealWays, the problem can be addressed in its full complexity, allowing for the development of a personalized treatment plan tailored to individual circumstances, symptoms, and laboratory test results. In addition to dietary and nutritional recommendations aimed at supporting mental health, microbiome testing and targeted intervention play a key role in the effective management of depressive symptoms.

Do you suffer from depression?

Examining the composition of the gut microbiome can help uncover the underlying root causes behind depression.

References

[1] Y. Liu et al., ‘Proteomics analysis of the gut–brain axis in a gut microbiota-dysbiosis model of depression’, Transl Psychiatry, vol. 11, p. 568, Nov. 2021, DOI: https://doi.org/10.1038/s41398-021-01689-w

[2] E. Beurel, M. Toups, and C. B. Nemeroff, ‘The Bidirectional Relationship of Depression and Inflammation: Double Trouble’, Neuron, vol. 107, no. 2, pp. 234–256, July 2020, DOI: https://doi.org/10.1016/j.neuron.2020.06.002

[3] S. Munir and V. Takov, ‘Generalized Anxiety Disorder’, in StatPearls, Treasure Island (FL): StatPearls Publishing, 2025 https://www.ncbi.nlm.nih.gov/books/NBK441870/

[4] A. Kumar et al., ‘Gut Microbiota in Anxiety and Depression: Unveiling the Relationships and Management Options’, Pharmaceuticals (Basel), vol. 16, no. 4, p. 565, Apr. 2023, DOI: https://doi.org/10.3390/ph16040565

[5] ‘DSM-5 Criteria for Major Depressive Disorder’, MDCalc https://www.mdcalc.com/calc/10195/dsm-5-criteria-major-depressive-disorder

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Published On: July 15th, 2025 / Categories: Uncategorized / Tags: /

Table of contents

Depression is one of the most common mental illnesses [1]. Its characteristic symptoms include persistent low mood, lack of motivation, inability to experience pleasure, and changes in appetite. Risk factors include a family history of mood disorders, early life trauma, female gender, recent stressors, and substance use. Other illnesses may also increase the likelihood of developing depression—particularly metabolic disorders, cardiovascular diseases, and autoimmune conditions [2]. In recent years, the impact of gut microbiome on mental health has also attracted growing interest.

Depression is accompanied by anxiety in approximately half of cases. Anxiety is a persistent state of expressed and uncontrollable worry about everyday matters, often accompanied by general restlessness, sleep disturbances, and fatigue [3]. Around 12% of people experience a depressive episode in their lifetime, while 14% experience anxiety. Depression is one of the leading causes of work-related disability worldwide [1], and in at least one-third of cases, there is no meaningful or lasting improvement with therapy. Given this, depression represents a significant public health challenge, and new treatment approaches may be required to enhance effectiveness. [4]

What are the symptoms of depression?

A range of symptoms can indicate the presence of depression. It is diagnosed using the criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [5]. Major depressive disorder is diagnosed when at least five of the following symptoms persist for at least two weeks:

  1. depressed or sad mood
  2. significant loss of interest or pleasure (anhedonia)
  3. noticeable weight or appetite changes
  4. disturbed sleep (reduced or increased sleep)
  5. restlessness or inhibition
  6. fatigue, weakness, lethargy
  7. feelings of worthlessness, self-blame, or guilt
  8. difficulty thinking, concentrating, or making decisions.
  9. preoccupation with death, suicidal ideation, or attempts

Additionally, the following four conditions must be met:

  1. the symptoms cause clinically significant distress or impairment of function in daily life
  2. the symptoms are not due to another medical condition or substance use
  3. the symptoms are not better explained by another psychiatric disorder (e.g., schizophrenia)
  4. there is no history of manic or hypomanic episodes (i.e., no symptoms of elevated mood)

The DSM-5 categorizes depression into three levels of severity based on the number and intensity of symptoms and the degree to which they disrupt daily life. If fewer than all criteria are met (but still at least five), and daily functioning is only mildly impaired, the diagnosis is mild depression. If symptoms severely interfere with daily functioning, depression is considered severe. In the most serious cases, psychotic symptoms (delusions and hallucinations) may be present. Intermediate cases are classified as moderate.

As seen from the criteria above, depression does not necessarily equate to a sad mood—it can manifest in many different ways in daily life.

Several specific subtypes of major depressive disorder are also commonly recognized:

  • Seasonal affective disorder: Typically occurs in autumn and winter and remits in spring and summer.
  • Prenatal and postpartum depression: Symptoms emerge during pregnancy or within four weeks after delivery. The DSM refers to this as “major depressive disorder with peripartum onset.”
  • Atypical depression: Also called “major depressive disorder with atypical features,” this form differs from typical depression in that mood may temporarily improve in response to positive events. Other symptoms include increased appetite and sleep, persistent fatigue, anxiety, and rejection sensitivity. [6]

If at any point in life—either currently or in the past—a person has experienced episodes of elevated mood or a naturally excitable temperament, bipolar affective disorder may be the correct diagnosis. This condition involves a different pathology and often requires a different treatment approach. Signs of elevated mood include excessive cheerfulness, irritability, talkativeness, reduced need for sleep, and high energy. This article does not address bipolar disorder; here, “depression” refers to the unipolar form.

Figure 1. Symptoms of depression

What causes depression?

Neither depression nor anxiety can be attributed to a single cause; rather, they are the result of complex, interacting processes. The most commonly discussed theories include:

This perspective explains depression through the altered functioning of central nervous system neurotransmitters. Antidepressant medications are largely designed to target these disruptions.

Neurotransmitters are chemical messengers that transmit signals between neurons and other cells—such as muscle or gland cells. Over 100 neurotransmitters have been identified in the human body. [7]

These molecules do not work in isolation; instead, they form a complex, interactive system that regulates various physiological functions. As such, depression or anxiety is not due to a single neurotransmitter abnormality but rather to an overall imbalance.

The most commonly implicated neurotransmitters in depression are serotonin, dopamine, and noradrenaline, which typically present at reduced levels [8]. Anxiety is often associated with underactivity in the gamma-aminobutyric acid (GABA) system. Other neurotransmitters also contribute to psychiatric symptoms, several of which are detailed below:

  • Serotonin regulates a number of physiological processes, including cognitive function, circadian rhythm, pain perception, gastrointestinal secretion and peristalsis, as well as blood clotting and cardiovascular function. [9]
  • Dopamine is an important mediator of the reward system. It also plays a role in maintaining motivation, concentration, attention, memory, learning, sleep and mood regulation.
  • Noradrenaline is essential for the proper functioning of alertness, attention, concentration, decision-making and memory. It is also a mediator of the acute stress response, the so-called flight or fight response. It increases blood pressure and heart rate.
  • Gamma-aminobutyric acid is the most common inhibitory neurotransmitter. It is involved in the regulation of anxiety, irritability, concentration, sleep, mood and the development of seizures. Anti-anxiety drugs, certain drugs used in epilepsy and alcohol also act on the GABA system.
  • Glutamate is the most abundant excitatory molecule in the central nervous system. It is involved in maintaining cognitive functions such as thinking, learning and memory. Glutamate also plays a key role in the cell death process that accompanies mental illness. [10]
  • Histamine is a key component of the body’s immune defences, but it also functions as a neurotransmitter. It plays a role in regulating appetite, alertness, motivation, and the sleep–wake cycle. Both deficiencies and excesses can lead to psychological symptoms. Low histamine levels may contribute to fatigue and sleepiness, while elevated levels can result in tension, anxiety, panic, sleep disturbances, or even depersonalisation and derealisation. Additionally, histamine influences programmed cell death (a natural cellular process), and can therefore affect the survival or death of nerve cells [11]. For more information on histamine, see our previous article.
  • Acetylcholine has a number of functions in both the central and autonomic nervous systems. Among others, it affects heart rate, blood pressure, bowel function, muscle function, memory, motivation, libido, sleep and learning. [7]
  • Oxytocin plays a key role in both male and female reproductive processes, triggering uterine contractions during childbirth and promoting lactation. It also helps counteract the negative effects of stress and enhances the tendency to form emotional bonds and engage in social contact. Warm, affectionate interactions and physical touch stimulate oxytocin release. A so-called ‘caring-protective’ stress response [12], regulated by oxytocin (and vasopressin), complements the well-known fight-or-flight response and includes the instinct to protect offspring. Oxytocin also underlies the separation anxiety observed in mother–child relationships and plays a significant role in adult social connections. Lower oxytocin levels have been found in individuals with depression, whereas elevated levels are more often observed in those with anxiety symptoms. [13]

Both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system are activated in response to stress.

  • Activation of the HPA axis begins with the hypothalamus releasing corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then prompts the adrenal cortex to release cortisol.
  • Meanwhile, the sympathetic nervous system stimulates the release of catecholamines (noradrenaline and adrenaline) from the adrenal glands. In mood disorders, this system becomes imbalanced, with sympathetic activity dominating over parasympathetic.

In addition to generating the stress response, both cortisol and catecholamines influence the immune system and inflammatory processes. They exert immunosuppressive effects by inhibiting the movement and activity of white blood cells and the production of inflammatory cytokines, and can even lead to the destruction of immune cells. This is a bidirectional relationship: inflammatory cytokines can also activate the HPA axis and the sympathetic nervous system, as observed in cases of infection and injury.

Depression is associated not only with elevated cortisol levels but often with glucocorticoid resistance. Stress—especially early life stress, including prenatal maternal stress—affects sensitivity to glucocorticoids including cortisol. This leads to impaired immune regulation, increasing the risk of inflammatory and autoimmune diseases in individuals with depression. [2]

In recent years, growing evidence has highlighted a link between depression and inflammation. In cases of severe depression, elevated levels of inflammatory markers and abnormal immune function have been observed, affecting both cellular and humoral immune responses [2]. Those with elevated inflammatory markers (approximately one-quarter of individuals suffering from depression) show less improvement with antidepressant therapy [14]. The source of inflammation is often an infection (either localized or systemic), an autoimmune condition, or—particularly in obesity [14–15]—metabolites released by adipose tissue.

Inflammation leads to increased levels of various mediator molecules in the bloodstream. Many of these have been identified (e.g., CRP, IL-6, TNF, IL-10, TGF-β), each with distinct roles in regulating the inflammatory process.

Interestingly, in depression, both proinflammatory and certain anti-inflammatory markers (such as TGF-β and IL-10) show increased activity. Overall, the net effect of these mediators tends to be anti-inflammatory. The role of anti-inflammatory cytokines in depression remains less clearly understood, but may be linked to reduced cellular immune function. This aligns with observations that depression is frequently accompanied by immunosuppression.

Overall, depression appears to be characterized by immune dysregulation, involving both heightened cytokine production and an insufficient cellular immune response. These processes may vary depending on the stage of the desease, preventive treatment, or age. [2]

Different subtypes of depression are associated with distinct inflammatory profiles. Higher TNF levels are linked to atypical features, greater severity, and a chronic course [2]. Elevated CRP levels are more often seen in cases involving fatigue, increased appetite, hypersomnia, and low mood, while increased IL-6 levels are more commonly associated with reduced appetite, poor sleep, fatigue, and heightened suicide risk. [14]

The association between major depression and immune system dysregulation raises the question of whether individuals with depression are more prone to infections or autoimmune diseases than the general population. The relative risk of infection may rise by up to 60% after a single depressive episode, and by more than 80% after four or more episodes [16]. The reverse is also true: various viral and bacterial infections (e.g., gastroenteritis viruses, influenza, herpes viruses, Epstein–Barr virus, cytomegalovirus, Lyme disease) have been linked to depressive symptoms. [2]

The same applies to autoimmune diseases. People with depression are at increased risk of developing conditions such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Conversely, individuals with autoimmune diseases have a particularly high prevalence of depression and often less responsive to antidepressant treatments. However, they frequently report improved mood following immunosuppressive therapy. [2]

How can inflammation affect our behaviour?

On one hand, during infections, the innate immune system produces oxidative and nitrosative radicals, which damage, among other targets, the amino acids tryptophan and tyrosine, as well as enzymes crucial for neurotransmitter synthesis, such as tryptophan hydroxylase, which is responsible for serotonin production [17–18]. As a result, the production of neurotransmitters like serotonin, dopamine, and noradrenaline—and hormones such as thyroxine and melatonin—is disrupted.

On the other hand, various cytokines trigger multiple processes in the body. Among other effects, they increase the permeability of the blood-brain barrier, allowing components from the bloodstream — including white blood cells and inflammatory mediators — to enter the brain [2]. This activates microglia (the brain’s immune cells), which release more cytokines, damage GABAergic neurons, impair serotonin synthesis [19]. Under normal circumstances, serotonin is synthesized from tryptophan via the enzyme tryptophan hydroxylase. However, if another enzyme, indoleamine-2,3-dioxygenase (IDO for short), is activated, tryptophan is diverted into an alternative metabolic pathway known as the kynurenine pathway. This pathway produces both neurotoxic and neuroprotective compounds. Inflammatory mediators, psychological stress, and cortisol can all activate IDO [2]. Prolonged activation of this pathway decreases serotonin levels and increases neurotoxic kynurenines, leading to neuronal death. GABAergic dysfunction and certain inflammatory cytokines can also contribute to nerve cell death, disrupting neural circuits involved in emotion regulation, reward system, cognitive control, and self-reflection lead to symptoms and behaviours associated with depression and anxiety.

Mood disorders often co-occur with metabolic conditions like obesity, diabetes, or cardiovascular disease [20]. This may be due to the fact that they share several common pathways in their development, including inflammation, HPA axis dysfunction, oxidative stress, altered platelet activity, peripheral hormone imbalances (e.g., serotonin, dopamine, ghrelin, leptin), sleep disruption, and gut microbiota dysbiosis. [21–22]

People with depression often consume diets high in calories, carbohydrates, and cholesterol [21], as carbohydrate-rich foods can temporarily elevate mood by activating the brain’s opioid system. Appetite increases through several pathways: sleep disturbances impair glucose metabolism and disrupt the balance of hormones that regulate appetite (ghrelin and leptin), and may also increase blood–brain barrier permeability. [20]

Inflammation reduces leptin’s appetite-suppressing effect (leptin resistance), promoting overeating. At the same time, increased fat tissue exacerbates inflammation and further stimulates appetite [14]. Gut-brain communication involving ghrelin, leptin, and other peptides reinforces this cycle, increasing the likelihood of co-occurring obesity and depression.

Obesity, persistent stress axis activation, and inflammatory cytokines all increase the risk of insulin resistance, which impairs glucose metabolism in the brain. This leads to functional glucose deficiency, neuronal damage, and sustained neuroinflammation. [15]

The possibility arises that there is a distinct metabolic subgroup within depression who are more likely to develop insulin resistance and other metabolic disorders. Markers of insulin resistance are typically abnormal in individuals exhibiting depressive symptoms such as excessive sleep, increased appetite and weight gain. Notably, insulin resistance persists in this subgroup even after antidepressant treatment—regardless of its effectiveness [23]. As a result, metabolic support strategies—involving not only pharmacological treatment, but also dietary changes and regular physical activity—may be especially beneficial for these individuals.

The connection between depression and cardiovascular disease has been well established. Platelets, which play a central role in blood clotting, are closely linked to the serotonin system. They share significant biochemical similarities with serotonergic neurons, meaning that when the serotonin system is disrupted—as is often the case in depression—platelet function may also be affected. In individuals with major depressive disorder, there is a tendency toward increased platelet activation, which may contribute to an elevated risk of cardiovascular disease. Inflammation, which is also common in depression, further promotes platelet activation. [21]

In the absence of certain micro- and macronutrients (e.g. B vitamins), the synthesis of neurotransmitters may be reduced, but levels of the harmful homocysteine are increased. Hyperhomocysteinemia is a common finding in depressed patients, which then leads to further complications, such as also increasing cardiovascular risk and further impairing metabolic processes. [21]

A diet lacking in essential nutrients can increase the risk of developing mental health disorders and is therefore an important factor in prevention [8], [24]. Below is an overview of key nutritional components relevant to mood disorders.

Macronutrients

Carbohydrates

Carbohydrates are crucial not only for physical energy but also for emotional well-being. Low-carbohydrate diets are associated with an increased risk of depression, as carbohydrate-rich foods help stimulate the production of serotonin and other mood-regulating molecules. Low-glycaemic carbohydrates (e.g., certain fruits and vegetables) tend to have a moderate but longer-lasting positive effect on mood, whereas high-glycaemic foods (e.g., sweets) provide immediate yet a short-lived boost. [25]

Proteins

Proteins, made up of amino acids, are fundamental building blocks in the body. 12 amino acids are synthesized by the body, while the remaining 8 (essential amino acids) must come from the diet. Good quality protein-rich foods include meats and eggs. Plant proteins do not contain all the essential amino acids in sufficient amounts. Protein intake, along with the availability of specific amino acids, can influence brain function and mental health. Many neurotransmitters and neuroactive substances are derived from amino acids: dopamine and noradrenaline from tyrosine, and serotonin and melatonin from tryptophan. A lack of tryptophan can lead to reduced serotonin synthesis and contribute to mood disorders [25]. However, because other amino acids compete with tryptophan for entry into the brain—and because tryptophan metabolism is influenced by factors like inflammation, micronutrient levels and gut microbiota composition—increased protein intake doesn’t necessarily translate to higher tryptophan levels. Thus, it cannot be claimed that increased intake of amino acids or tryptophan protects against depression [4]. In fact, excessive accumulation of amino acids may even be harmful. [25]

Fats

The effects of fatty acids vary by type. Saturated fats may impair cognitive function, while unsaturated fats are considered beneficial. [22]

Polyunsaturated fatty acids (especially omega-3 and omega-6) cannot be synthesized by the body and must be obtained from food. Omega-3 fatty acids are anti-inflammatory, protect against oxidative stress, support neuroplasticity via BDNF modulation, and enhance neurotransmitter function [26]. Low omega-3 levels are linked to increased risk of major depressive episodes and suicidal thoughts. [8], [27]

Micronutrients

Scientific evidence regarding the role of micronutrients in mental health is still developing, and findings are sometimes inconsistent due to the complexity of underlying mechanisms. Nevertheless, deficiencies in the following vitamins and trace elements may play a role in the development of depression and anxiety. [4]

B Vitamins (B6, B12, folic acid)

Low levels of B vitamins, particularly folate (vitamin B9), B6, and B12, have been observed in people with depression. These deficiencies interfere with the synthesis of serotonin, dopamine, and noradrenaline, and lead to elevated homocysteine levels, which can cause neurotoxicity [24]. Vitamin B12 also affects acetylcholine production [28] and is essential for mitochondrial health. Low folate and B12 levels have been associated with poorer antidepressant response [8]. However, some studies have found no connection, and one even linked high B12 levels with a greater risk of depression [27]. Thus, their role remains uncertain.

Vitamin D

Vitamin D, synthesised in the skin through sunlight and available in certain foods or supplements, is increasingly recognized as crucial for mental health. Deficiency is associated with a significantly increased risk of depression [27]. This may be due to the presence of vitamin D receptors in different parts of the cerebral cortex and limbic system, areas involved in memory and emotion regulation, and its influence on BDNF, serotonin, dopamine, and noradrenaline production [8]. It also protects against oxidative stress and supports anti-inflammatory processes. [29]

Vitamin E

A fat-soluble antioxidant, vitamin E usually meets requirements through diet alone. Deficiency may occur with malnutrition or fat malabsorption and can cause poor coordination, muscle weakness, and anaemia [30]. It reduces oxidative stress and supports mitochondrial function. [31–32]

Vitamin C

Vitamin C (ascorbic acid) is a water-soluble compound with antioxidant activity similar to vitamin E, and lower levels of vitamin C have been associated with depression. Vitamin C has potential antidepressant effects due to its ability to promote the recycling of vitamin E, influence the function of various neurotransmitters and contribute to the reduction of inflammatory processes. [33]

Iron

Iron deficiency is the most common nutrient deficiency worldwide and can present with symptoms such as fatigue, muscle weakness, reduced physical strength, and impairments in mood, learning, and memory. [34]

This is because iron is essential for numerous vital functions. It plays a key role in oxygen transport, DNA synthesis, mitochondrial energy metabolism, immune system function, and the proper synthesis of brain neurotransmitters [35]. Iron also contributes to the development of anxiety symptoms by influencing the GABA and glutamate systems and is required for the production of dopamine, serotonin, and noradrenaline. Additionally, it regulates BDNF production, thereby affecting neuroplasticity. During inflammatory processes, iron availability in the brain is reduced, potentially leading to a functional iron deficiency that can further exacerbate symptoms. [34]

However, excess iron can also impair brain function [35]. Iron accumulation in the brain leads to oxidative stress in neurons and may ultimately cause cell death, a process known as ferroptosis [34]. Although the blood–brain barrier usually protects the brain from excessive iron influx, the body can only compensate to a limited extent. The risk of iron overload-induced neurological damage is higher in neonates and older adults, as the rate of iron transport into the brain increases both early and late in life. [35]

The connection between psychological symptoms and iron metabolism is often overlooked, yet it may play a significant role in depression and anxiety disorders [36]. It is worth considering in cases of “brain fog” (such as during pregnancy and the postpartum period, often referred to as “mummy brain”), persistent fatigue, learning or concentration difficulties, anxiety, sleep disturbances, or mood disorders—even in the absence of anaemia. [34]

Magnesium

Magnesium is involved in more than 300 cellular processes [24]. Insufficient magnesium levels cause changes in the functioning of the central nervous system, particularly in the limbic system and glutamate systems in the cerebral cortex. Magnesium deficiency can indirectly lead to damage and even death of nerve cells. It also affects the function of the HPA axis [8]. In its absence, it can cause, among other things, mood disorders and sleep disturbances.

Zinc

The brain contains significantly higher levels of zinc than any other organ in the body. [27]

Like magnesium, zinc is essential for hundreds of cellular processes. [24]

It influences the function of the HPA axis, modulates cellular immune responses, and regulates BDNF expression in both the limbic system and the cortex. Zinc also affects serotonergic and other neurotransmitter pathways and can even function as a neurotransmitter itself. In addition, it possesses both anti-inflammatory and antioxidant properties [8]. Zinc deficiency can lead to a range of neurological and psychological symptoms, including irritability, mood swings, and cognitive dysfunction. [24]

Selenium

Selenium is an essential trace element necessary for the proper functioning of many selenoproteins. These selenoproteins also play a role in protecting the nervous system against oxidative stress [8]. Additionally, selenium influences the functioning of the serotonin, dopamine, and noradrenaline systems. It also plays a crucial role in maintaining thyroid function [27], which supports optimal metabolic processes and mental health.

Copper

Copper plays a role in energy metabolism through mitochondrial processes and also has effects on the immune and nervous systems. It is involved in histamine metabolism [37] and in defending against oxidative stress [27]. The conversion of dopamine to noradrenaline requires the presence of copper. It also supports the activity of various neural growth factors (BDNF, NGF). Through these processes, copper contributes to the proper functioning of learning and memory, as well as the maintenance of neuroplasticity. However, not only copper deficiency but also excess copper or impaired copper utilization (e.g., due to a lack of vitamin A) can impact brain function. In fact, several scientific studies have found that elevated—rather than reduced—copper levels are associated with the development of depressive symptoms. [8]

Calcium

The role of calcium in the development of depression is evident in several processes. On one hand, calcium is involved in regulating the HPA axis, i.e., the stress response, and it also influences serotonin synthesis. The concentration of calcium ions is a crucial factor in maintaining proper cellular function and stimulus-response activity. As a result, calcium has a broad impact on cellular processes, which, by extension, also affects emotion regulation [38]. Calcium deficiency is rarely observed in individuals with a balanced diet.

Lithium

Lithium is not yet classified as an essential micronutrient, yet it offers significant benefits for human health [39]. Today, it is best known for its use in psychiatry as a mood stabilizer in the treatment of bipolar disorder. In this context, the medication contains high doses of lithium (100–200 mg) [40], which require close laboratory monitoring due to its potential toxicity. However, substantial evidence suggests that at much lower doses—as a trace element—lithium may provide benefits not only for individuals with mental disorders but also for the general population. [41]

Lithium has complex and multifaceted effects on the human body, particularly on the nervous, immune, and even reproductive systems [42]. In addition to its mood-stabilizing properties, it also appears to have a suicide-preventive effect, reduce aggression and impulsivity [43], and support the resynchronization of circadian rhythms. Lithium influences various intracellular processes and modulates the function of several neurotransmitters. By stimulating the BDNF signaling pathway, it promotes the formation and growth of new neurons and contributes to the protection of neurons against oxidative stress. Its beneficial effects may also be linked to enhanced transport of vitamins—particularly B12 and folic acid—to the brain. Lithium further affects the function of the HPA axis. It also exhibits complex immunomodulatory properties, increasing cellular immune activity and enhancing the synthesis of IgG and IgM immunoglobulins. [40–41]

It should be noted that the vast majority of the associations mentioned above have been observed at high therapeutic doses. It remains unclear to what extent lithium, when consumed in trace amounts, produces these effects. Nevertheless, studies have shown that regions with lower dietary lithium intake (primarily through drinking water) tend to have higher rates of suicide, impulsive and violent crime, and drug use. [39]

The neurogenic theory of depression suggests that structural changes in the limbic system—responsible for regulating emotions and mood—play a role in symptom development. The most frequently observed changes include atrophy of the prefrontal cortex and hippocampus, which show a reduction in neurons and glial cells. These findings have led to the consideration of depression as a mild form of neurodegenerative disease. Fortunately, these changes may be reversible with effective stress reduction and treatment. [10]

Increased vulnerability of neurons results from disrupted signalling pathways combined with genetic and environmental factors. One key abnormality involves the glutamate system: stress and glucocorticoids increase glutamate release while inhibiting its removal. Excessive glutamate can damage neurons, particularly under adverse genetic or environmental conditions. [10]

Another major factor is reduced levels of growth factors. Although there are several growth factors involved in depression, most attention has focused on BDNF (brain derived neurotrophic factor) [10]. Lower levels of BDNF have been found in people with depression. [20]

BDNF plays an important role in the survival and growth of neurons, is involved in the regulation of signal transduction pathways, and is essential for learning processes and memory maintenance. It is also widely found outside the central nervous system (e.g. even in the gut), regulating metabolism and energy balance [44]. When its levels are reduced (e.g. through genetic mutation), atrophy of the hippocampus and prefrontal cortex has been observed, similar to lesions caused by chronic stress. Although BDNF mutations alone are not sufficient for the development of depression, they certainly imply an increased vulnerability to stress and carry a higher risk of developing mood and cognitive deficits (e.g. Alzheimer’s disease, Parkinson’s disease). [10]

However, the neurogenic theory has limitations. For example, depression-like symptoms can appear without neuron loss, and antidepressants don’t always restore neuron numbers. A better explanation may lie in neuroplasticity—the brain’s ability to adapt—and mitochondrial function, rather than cell count alone. [45]

Recent scientific findings suggest that disruption in the body’s energy balance—particularly at the cellular level—may be a major contributor to the development of depression. [45–47]

Our cells contain a cellular organelle called a mitochondrion. Mitochondria are the main energy storage and power plants of cells. Every cell in our body contains mitochondria, but our cells that do the intensive work need much more energy. Our brains – especially the grey matter of our brains – are made up of cells that are highly energy-intensive and have little capacity to store energy, so keeping their power plants working properly is crucial. Each nerve cell contains thousands of mitochondria. [47]

In addition to energy production, mitochondria serve several other vital functions. They contribute to maintaining cellular stability, regulating levels of reactive oxygen species, and controlling apoptosis (programmed cell death). [47]

In depression, mitochondrial function is impaired: ATP (i.e., energy) levels decrease, oxidative radical production increases, pro-inflammatory cytokines are released, and apoptosis is accelerated [45]. In addition, neuronal regeneration and the formation of new neurons are reduced, as the levels of growth factors important for neurogenesis decline. Since the release of excitatory neurotransmitters and the responses they trigger are both energy-intensive processes, communication between neurons is also disrupted [45]. All these changes lead to a decrease in the overall adaptability (neuroplasticity) of neurons. A new approach to mood disorders suggests that this reduced adaptability may underlie the development of depression. [47]

Supporting this idea, many individuals with depression exhibit mitochondrial abnormalities. Conversely, about half of people with mitochondrial disorders also have mood disorders. So the two diseases are often comorbid. However, not everyone with the same mitochondrial mutations develops depression, highlighting the influence of environmental factors in addition to genetics. [45]

Examples of such environmental effects include chronic stress. Cortisol released during HPA axis activity plays a biphasic role in the regulation of mitochondrial function. In the acute case (i.e. at the onset of a stressful event), it significantly increases mitochondrial activity, thereby helping cells and the body to adapt to changing conditions. However, in chronic situations (i.e. prolonged exposure to stress), it causes structural and functional abnormalities in mitochondria: it increases the production of reactive oxygen species and can ultimately cause cell death in neurons and other cells in the body. [47]

Micronutrient deficiencies also impair mitochondrial function. Important nutrients include B vitamins, vitamin C, vitamin E, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, lipoic acid, and taurine. Many of these support energy production, while selenium also aids mitochondrial formation [32]. Nutrition and lifestyle, therefore, play a vital role in mitochondrial health and overall mental well-being.

What is the importance of the microbiome–gut–brain axis in mental health?

The microbiome-gut-brain axis (or gut-brain axis for short) is a complex system of connections between the gut and the central nervous system that plays an important role in the development of mental illness.

In one study, when stool samples from depressed humans were transplanted into healthy germ-free mice, the animals began to display depressive behaviours. These mice also showed disruptions in carbohydrate and amino acid metabolism, as well as changes in organ function (including the brain, liver, and colon) and hormonal systems [1]. Such findings highlight the growing focus on the gut bacterial flora.

Research suggests that dysbiosis—an unhealthy composition of gut bacteria—may not only result from but also contribute to mental health problems. This is due to the microbiome’s involvement in nearly all mechanisms associated with depression. [48]

Most neurotransmitters of the central nervous system are also present in the gastrointestinal tract. They are produced partly by enteroendocrine cells in the gut and partly by gut bacteria. However, certain neurotransmitters or their precursors are not only produced but also consumed by the intestinal flora [49]. For example, GABA is produced by Bacteroides fragilis and consumed by Evtepia gabavorous [50]; noradrenaline is both produced and consumed by Escherichia coli [51]; tryptophan is consumed by Alistipes species [52]; and serotonin is produced by E. coli [53]. And the list goes on.

Intestinal neurotransmitter molecules primarily have local effects, as they cannot cross the blood–brain barrier under healthy conditions. Their signals can, however, be transmitted to the brain via the vagus nerve [53]. During inflammatory processes, the selectivity of the blood–brain barrier may become impaired, allowing a greater proportion of these circulating molecules to reach the brain. Precursor molecules, on the other hand, can cross into the central nervous system even when the blood–brain barrier is intact and can contribute to neurotransmitter synthesis [49]. The gut microbiota is associated with all neurotransmitter systems involved in the development of depression: serotonin, dopamine, noradrenaline, GABA, glutamate, histamine, and acetylcholine. Due to their significance, the serotonergic and dopamine/norepinephrine systems will be discussed in more detail.

Serotonin and the gut microbiome

About 90% of serotonin is synthesized outside the brain, mainly in the enterochromaffin cells of the intestinal epithelium. While serotonin itself cannot cross the blood-brain barrier, its precursor, tryptophan, can [49]. Tryptophan is an essential amino acid, meaning it must be obtained from the diet. Various bacterial strains can influence tryptophan availability in several ways. Some strains, like Alistipes, use tryptophan for growth or activate the kynurenine pathway, diverting tryptophan away from serotonin production and toward inflammation-related metabolites [52]. Turicibacter sanguinis uses serotonin itself for growth [54]. On the other hand, species like Clostridium and Staphylococcus can promote serotonin synthesis [49], and E. coli is capable of producing serotonin directly [53]. Given the dynamic interaction between the serotonergic system and the HPA axis, the microbiome may also influence the serotonin system indirectly through the stress axis [9]. The effects of serotonin on gut function are highly diverse. In addition to its physiological role in regulating motility and secretion, it also influences intestinal permeability: elevated levels enhance barrier function, whereas low levels impair it. [54]

Dopamine, noradrenaline and the intestinal flora

Dopamine is a key neurotransmitter involved in reward-driven behaviour and serves as a precursor to noradrenaline and adrenaline. More than 50% of the body’s dopamine is produced in the gut, where it primarily exerts local effects, such as regulating gastric emptying, gut motility, and secretion [49]. However, its influence may also be transmitted to the brain via the vagus nerve [53]. Certain bacteria can respond to these catecholamines and even synthesise them. For instance, pathogenic strains of Escherichia coli exhibit enhanced growth, increased motility, biofilm formation, and greater virulence in the presence of dopamine and noradrenaline. Other pathogens—such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Shigella sonnei, and Staphylococcus aureus—also demonstrate accelerated growth in response to noradrenaline. In addition, some bacteria, including E. coli and Bacillus subtilis, are capable of producing these catecholamines themselves. Short-chain fatty acids (SCFAs) produced by the gut microbiota may further influence the synthesis of neurotransmitters in the brain. Collectively, these findings support growing evidence that the microbiome may modulate host catecholamine production and degradation—an interaction that may play a significant role in the development of mental health disorders. [49], [51]

Short-chain fatty acids (SCFAs) are small organic compounds produced by large intestine bacteria during the fermentation of carbohydrates. The three most abundant SCFAs are acetate, butyrate, and propionate [53]. These molecules are key players in the communication between the gut and the brain.

SCFAs nourish gut bacteria and intestinal epithelial cells, helping to maintain a healthy gut environment. They support the integrity of the intestinal barrier, stimulate saliva production, reduce inflammation, promote the release of antimicrobial peptides, and even have antitumor effects [9], [54]. SCFAs also regulate enteroendocrine cells, which influence the release of molecules in the gut like ghrelin, serotonin, dopamine, and noradrenaline. [22]

Once absorbed into the bloodstream, SCFAs affect numerous body systems. For instance, they increase energy expenditure in skeletal muscle and the liver, improve insulin sensitivity, boost satiety, and support weight regulation [55]. SCFA receptors are also found on immune and nerve cells, where they regulate T and B lymphocyte function, which are important in the development of the immune response. They also affect visceral nerve fibres, which are part of the peripheral nervous system, as well as autonomic and sensory nerve fibres and influence the autonomic and sensory nervous systems. SCFAs reach specific brain regions (like the hypothalamus) via the vagus nerve and can modulate stress responses. [9]

However, they also have direct effects on the central nervous system, as well as indirect ones. They themselves can easily cross the blood-brain barrier and can influence its function by regulating the synthesis of tight junction proteins. Acetate can accumulate in the hypothalamus, thereby directly affecting the activity of the HPA axis and stimulating local GABA production. In addition, SCFAs promote microglial cell maturation and function. Microglia are responsible for brain immune defence and various developmental processes. SCFAs also act through epigenetic regulation, i.e. by stimulating the expression of certain genes relevant to depression. For example, they promote the production of dopamine in the brain, inhibit its conversion to noradrenaline and stimulate the production of BDNF. [54]

Short-chain fatty acids thus affect the central nervous system in a complex way, including mood, cognition and the response to stress. However, in addition to their many beneficial properties, they may also have adverse effects. For example, acetate may promote the secretion of the cytokine IL-6 in the gut and increase neutrophil cell recruitment [54], and may further impair fat accumulation in people with non-alcoholic fatty liver [55]. SCFAs may also cause neurochemical damage, e.g. propionic acid may impair the GABA/glutamate ratio in the brain, leading to the development of psychiatric symptoms. The biggest controversy surrounds butyrate. In addition to its anti-tumour, anti-inflammatory and cell regeneration promoting effects, the opposite has been observed: it may promote the transformation of the colon epithelium, contributing to the development of colon cancer, and it may also cause colitis, urethritis and renal pelvis inflammation, and contribute to obesity. [56]

In summary, SCFAs exert wide-ranging effects on brain function and mental health. However, their biological activity varies depending on health status and on ffactors that still require further scientific investigation. A well-functioning microbiome that produces SCFAs in the appropriate proportions is essential for mental well-being—but supplementing with SCFAs or prebiotics without knowing your current gut composition may do more harm than good.

HPA axis

The gut microbiome plays an integral role in the development and regulation of the HPA axis [57]. This connection occurs both via the enteric nervous system (which innervates the gut) and through bacterial antigens entering the bloodstream, which can activate the stress axis. Additionally, recent research shows that the microbiome can influence the synthesis of proteins related to the HPA axis function. [9]

At the same time, the stress axis also affects the enteric nervous system by altering gut motility and secretion, and circulating cortisol itself affects the composition of the gut microbiome and gut permeability [9]. Under prolonged stress, the diversity of the microbiome decreases, and the proportion of pathogenic bacteria may increase. Bacteria adhere more readily to intestinal epithelial cells, which promotes inflammation. The tight junctions between the cells are damaged and the gut can become permeable. [58–59]

Vagus nerve

The vagus nerve is the most direct signalling pathway between the gut and the brain. It plays a role in stress response, memory, anxiety, fear-based behaviours, and brain plasticity. Therefore, the gut microbiome can significantly influence brain function through this pathway. [9]

This communication is also bidirectional. The vagus nerve can modulate gut activity and appears capable of distinguishing between non-pathogenic and potentially pathogenic bacteria—even in the absence of inflammation. Specific vagal signals can initiate an anti-inflammatory reflex, causing the release of acetylcholine and other mediators that reduce inflammation by interacting with immune cells [11], [60]. This immunomodulatory effect also contributes to improved brain function and emotional regulation.

Gut hormones

Gut bacteria also affect the number and activity of enteroendocrine cells (hormone-producing cells in the gut). Enteroendocrine cells are found throughout the intestinal tract and make up about 1% of the epithelial cells. They can be divided into several types according to the hormones they produce. These hormones have multiple biological functions (e.g. regulation of food intake, gastric emptying, intestinal motility, glucose metabolism, etc [61]).

Many intestinal peptides are involved in gut-brain axis communication through indirect mechanisms, such as modulation of the gut-brain nerve, or directly across the blood-brain barrier. Their primary target is the hypothalamic region, which is responsible for feeding behaviour and the regulation of the hunger-fatigue balance [62], but they may also have protective effects against neuronal damage caused by toxic microbial metabolites. [21]

Two gut hormones especially relevant to mental health are ghrelin and leptin: Among their many functions, they play a role in appetite regulation. They regulate both homeostatic (called “physiologically necessary”, which is done to provide nutrients to the body) and hedonic, or “pleasure” eating by influencing dopamine signalling [63]. Ghrelin leads to an increase in appetite, plays a role in inflammatory processes, stimulates the stress response by increasing glucocorticoid levels, plays a role in cardiovascular function and regulates mood. Leptin has the opposite effect: it decreases both appetite and glucocorticoid levels [21]. The gut microbiota influences the secretion of both hormones, contributing to changes in both mood and metabolism. [62–63]

An imbalanced gut microbiome (dysbiosis) can compromise the integrity of the intestinal barrier, allowing bacterial components—such as endotoxins—to enter the bloodstream. Once in circulation, these antigens activate the immune system and trigger a systemic inflammatory cascade that affects the entire body, including the HPA axis and the central nervous system. This relationship is bidirectional: just as gut dysbiosis can cause systemic inflammation, existing inflammation can, in turn, impair the gut microbiota. This results in a loss of microbial diversity and the emergence of pathogenic colonies—further perpetuating the cycle.

The digestive and absorptive functions of the alimentary tract are crucial for the body’s nutrient supply. These are highly complex processes that require an adequate pH (especially an acidic stomach), the presence of various digestive enzymes, bile acids, an intact mucous membrane, the hormone system and the autonomic nervous system.

Abnormalities in the bacterial flora (e.g., SIBO, dysbiosis, or the presence of pathogenic colonies) can disrupt this process at several points. For example, Helicobacter pylori can alter stomach pH, while SIBO may impair bile acid function and fat digestion in the small intestine. Inflammation of the intestinal mucosa can also compromise epithelial cell function. Additionally, pathogenic colonies may consume dietary iron intended for the host. As a result, an imbalanced gut microbiota can significantly affect the availability of both micro- and macronutrients. [64]

However, most bacteria that are part of the normal, healthy microbiome, such as Lactobacillus and Bifidobacterium species, synthesise vitamins (especially vitamins B and K) as part of their metabolic processes. These key micronutrients have largely local effects, but can also be absorbed from the gut and thus play a role in many physiological processes. They cross the blood-brain barrier and, once they reach the central nervous system, they perform a range of functions from energy metabolism to neurotransmitter synthesis. [53]

The blood-brain barrier (BBB) is a highly selective, multi-layered shield that protects the brain by regulating which substances can pass from the bloodstream into the central nervous system. It ensures a stable environment for neurons while preventing harmful compounds from entering. [11]

When the gut microbiome is disrupted, intestinal permeability increases, allowing bacterial toxins bacteria and their various metabolites and toxins to enter circulation. These trigger systemic inflammation, releasing cytokines that weaken the BBB’s integrity. As a result, the BBB becomes more permeable and less effective at protecting the brain.

Bacteria can influence the BBB both indirectly (through inflammation and immune activation) and directly. For instance: LPS (from Gram-negative bacteria) and LTA (from Gram-positive bacteria) can bind to BBB cells, altering their function and reducing barrier selectivity. Conversely, short-chain fatty acids like acetate, butyrate, and propionate support BBB integrity by promoting the expression of tight junction proteins and reducing inflammation. [65]

In cases of intestinal dysbiosis, the function of cells in tissues associated with the gut-brain axis is altered, which is reflected, among other things, in the composition of the proteins they produce. These changes primarily affect energy metabolism processes, which are so fundamental to cellular function that their disruption is linked to impairments in numerous other biological functions. The organs most affected include parts of the brain, the liver, and the intestine. In animal studies, protein alterations caused by stress were compared with those resulting from dysbiosis. Although depressive behavior was observed in both groups, the protein profiles showed only partial overlap.

Thus, the microbiome may contribute to the development of depressive symptoms through mechanisms that are distinct from, and independent of, psychological stress. [1]

Contributing factors to depression

Figure 2. Contributing factors to depression

What are the differences in gut microbiome in depression or anxiety?

The scientific evidence on this topic should be interpreted with caution due to geographical variations and differing study methodologies. However, it can be concluded that the gut microbiome of individuals experiencing psychological distress differs significantly from that of healthy individuals [4]. In depression, a higher prevalence of Klebsiella, Prevotella, Streptococcus, Clostridium [48], and Eghertella species [4] is observed, while lower levels are found of genera such as Faecalibacterium, Coprococcus [66], Ruminococcus, Fusicatenibacter [67], and Dialister species [66]. Additionally, other bacteria may play a role, such as certain species of Alistipes [52], Sellimonas [4], and Evtepia gabavorous [50]. In patients with anxiety disorders, microbial species richness and diversity are reduced. Species such as Prevotella, Sellimonas, Streptococcus, Enterococcus, Escherichia, Shigella, Fusobacterium, and Ruminococcus have been linked to the onset of symptoms, while some short-chain fatty acid (SCFA) producers, such as Lachnospira, Faecalibacterium, and Eubacterium species, are believed to have protective effects [48], [68]. This list is not exhaustive, and research into the relationship between the microbiome and mental health is ongoing.

Do you suffer from depression?

Examining the composition of the gut microbiome can help uncover the underlying root causes behind depression.

What are the options for treating depression?

Today, the treatment of major depression is typically managed by a psychiatrist, psychologist, or psychotherapist. A wide range of antidepressant medications and psychotherapeutic approaches are available, depending on the individual’s needs. This article focuses on complementary or alternative strategies that may enhance or support traditional therapies.

Elimination of inflammatory processes

Inflammation can contribute to psychological symptoms via various mechanisms. Potential sources include chronic infections (e.g., dental or gynaecological), systemic diseases (e.g., Lyme), autoimmune conditions, or gut dysbiosis. For individuals with persistent mood symptoms, it’s important to investigate and, if possible, eliminate underlying sources of inflammation.

Adequate nutrition

Inappropriate dietary intake can lead to obesity, metabolic disorders, macro- and micronutrient deficiencies, subclinical inflammation, the development of autoimmune conditions, neuroinflammation, and the onset of psychiatric symptoms. In general, depression may benefit from a Mediterranean-style diet rich in plant fibers, minerals, and polyphenols.

It is also important to ensure the intake of high-quality proteins and an adequate proportion of omega-3 fatty acids. Two omega-3 fatty acids—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have shown the greatest potential in alleviating symptoms of mood disorders. EPA is more actively involved in inflammatory processes, while DHA is a structural component of cell membranes, including mitochondrial membranes, which are essential for cell integrity, communication, receptor function, transporter activity, and energy production. The best results are typically seen when the supplement contains at least 60% EPA. While DHA is considered less effective for treating depression, it may help reduce suicidal thoughts and attempts. [69]

Various spices can also be incorporated into the diet for their anti-inflammatory, antibacterial, antifungal, and other biocidal properties. For example, Szechuan pepper, curcumin, and capsaicin have shown protective effects in anxiety and depression. [48]

Ultimately, a diet tailored to individual circumstances, current health status, genetics, and microbiome is most strongly recommended. [70]

Trace Elements and Vitamins

B Vitamins

A balanced diet generally provides the body with sufficient B vitamins. In general, B vitamin supplementation is not recommended for adults with adequate levels, either as a preventive measure or to support antidepressant therapy. [24]

However, when deficiencies are detected, supplementation may help improve psychological (and other) symptoms. This possibility is worth considering in vegetarians [8] and in women taking oral contraceptives [27], who are more likely to have low levels of vitamin B6.

Vitamin D

In cases of major depressive episodes, vitamin D may help alleviate symptoms and appears to [24], [27] reduce the risk of developing anxiety [29]. When levels are low, supplementation is strongly recommended, not only for its psychological benefits but also for its broader relevance to overall health.

Vitamin E

Vitamin E supplementation may play a role in reducing depressive symptoms and supporting cognitive function [71], although no similar association has been established for anxiety. However, when combined with omega-3 fatty acids, it has shown beneficial effects on both depression and anxiety, suggesting a potential synergistic relationship. [31]

Vitamin C

Low vitamin C levels are associated with an increased risk of depression and anxiety [72]. Supplementation may help prevent or alleviate symptoms. Notably, vitamin C appears to offer significant mood improvement in individuals with subclinical or mild symptoms, rather than in cases of severe depression. [33]

Iron

As previously discussed, iron deficiency is the most common nutrient deficiency worldwide and may occur with or without anemia. Before starting supplementation, the underlying cause of iron deficiency should be investigated and addressed if possible. Contributing factors may include dietary issues (e.g., deficiencies in vitamin A, vitamin C, B vitamins, copper), malabsorption, bleeding disorders, or genetic conditions. If blood ferritin levels remain below 30 μg/L after correcting other conditions, oral iron supplementation should be continued for at least three months. Supportive supplementation for antidepressant therapy may also be considered when ferritin levels are between 30 and 50 μg/L, although there is no international consensus [34]. For optimal absorption, a heme iron preparation is recommended, taken every other morning.

Magnesium

The relationship between dietary magnesium intake, serum levels, and the risk of depression is difficult to assess, as blood magnesium accounts for only about 1% of total body magnesium and does not reliably reflect intracellular levels [8]. In any case, lower levels of magnesium increase the risk of neurological and psychological symptoms [73]. Several reports suggest that magnesium supplementation can improve depressive symptoms. [74–75]

Zinc

Low zinc levels are frequently observed in individuals with depression [24], [76]. In such cases, supplementation can enhance the effectiveness of antidepressants [8], and some evidence suggests that zinc may even be effective as a standalone treatment [76]. Although more research is needed, current findings indicate that zinc is a promising trace element in the management of mood disorders.

Copper

Copper intake from a balanced diet is generally sufficient. Adequate copper levels are important for the prevention of depression, but supplementation is only beneficial for individuals with a dietary deficiency. Copper metabolism is closely linked to that of iron, zinc, and vitamin A, so these should be considered and corrected together if necessary to support mental health. [77]

Selenium

Studies investigating the link between selenium and depression have yielded mixed results [8]. No significant association has been found between serum selenium levels and the presence or severity of depressive symptoms. However, some studies report a reduction in depressive symptoms following selenium supplementation. [27]

Calcium

Inadequate calcium intake has been shown to worsen depressive symptoms [38]. However, a balanced diet typically meets the body’s calcium needs. Moreover, excessive calcium intake may counteract the beneficial effects of magnesium [78], making calcium supplementation unnecessary—and potentially unhelpful—when dietary intake is sufficient.

Lithium

Assessing lithium deficiency is currently challenging. Most laboratories only test for toxic lithium levels, which are relevant to high-dose psychiatric treatments and not reflective of trace-element needs in everyday life. Therefore, such tests are unsuitable for evaluating lithium status at nutritional levels.

Current research suggests a daily intake of approximately 1 mg of lithium, with potential benefits from doses up to 5 mg under certain conditions (e.g., environmental stressors, mental or other health issues) [42]. Small amounts of lithium are naturally found in oilseeds, nuts, certain leafy and root vegetables, cereals, and—depending on location—in drinking water. As a dietary supplement, lithium orotate is the recommended form [79]. In recent years, the concept of lithium-fortified foods (similar to iodized salt) has gained attention, although no such products are currently available on the market. [40]

Adaptogenic medicinal plants

Adaptogenic herbs are a group of plants with complex, non-specific effects on the human body, enhancing its ability to adapt to long-term stress [80]. They help restore the function of systems weakened by chronic stress—particularly the immune, nervous, and endocrine systems—bringing them back to a healthier state. Since these systems are also involved in depressive and anxiety disorders, the use of adaptogenic herbs may offer therapeutic benefits.

In the context of depression, the most extensively studied and supported adaptogen is St. John’s wort (Hypericum perforatum), followed by saffron (Crocus sativus L.). Other adaptogens that may alleviate psychological symptoms include ashwagandha (Withania somnifera), rose root (Rhodiola rosea), and ginseng (Panax ginseng). [81]

Their exact mechanisms of action are difficult to pinpoint, likely involving multiple pathways. These herbs reduce inflammation, including neuroinflammation, protect against oxidative stress, influence neurotransmitter systems, and support brain plasticity by regulating BDNF levels. [81]

However, adaptogens should be used with caution, as they interact with enzymatic pathways involved in the metabolism of antidepressant medications. This can lead to adverse or even life-threatening effects, such as severe bleeding or myocardial infarction [82]. Therefore, it is advisable to inform a doctor or general practitioner when using adaptogenic herbs and to carefully consider potential drug interactions.

Supporting mitochondrial function

Today, therapeutic options targeting altered mitochondrial function in mood disorders are receiving increasing attention. Mood stabilizers, antidepressants, and antipsychotics have shown benefits in this area, but there are also ways to support mitochondrial function beyond traditional medications. [26]

The roles of various vitamins, trace elements, and omega-3 fatty acids have been discussed previously. In addition, several other nutritional supplements have been found to enhance mitochondrial function and, consequently, brain energy metabolism—mainly by reducing oxidative stress. These include N-acetylcysteine, alpha-lipoic acid, acetyl-L-carnitine, S-adenosylmethionine, creatine monohydrate, and coenzyme Q10. While current evidence suggests these compounds may be beneficial in mood disorders, further clinical trials are needed to confirm their effectiveness. [26]

The hormone melatonin may also fall into this category. In addition to regulating circadian rhythms, melatonin is a powerful antioxidant. It directly supports mitochondrial function and protects mitochondrial DNA from damage. Although it is a relatively well-known compound and widely used for sleep disorders, clinical studies investigating its use in mood disorders have produced inconclusive results. It is possible that only certain subgroups of individuals may benefit from its use – particularly those with seasonal affective disorder. [26]

The ketogenic diet has also shown promise in improving mitochondrial function. It may be effective as an adjunct therapy for mood stabilization and/or epilepsy.

The ketogenic diet is a low-carbohydrate dietary approach in which ketone bodies, produced from fat breakdown, become the body’s primary energy source instead of glucose. This metabolic shift leads to changes in neurotransmitter levels and various hormones, enhances mitochondrial energy production, supports antioxidant processes, reduces neuroinflammation, and increases BDNF levels—producing an overall neuroprotective effect. Although data on its role in treating mood disorders are still limited, preliminary findings are promising. [26]

Physical activity

Physical activity: Exercise improves metabolism, reduces inflammation, enhances mitochondrial function, and positively impacts mood and cognitive function [22], [26]. It’s a valuable complementary therapy for depression.

Drugs and supplements affecting gut microbiome

A safe and beneficial influence on the composition of the gut microbiome is most effectively achieved when the baseline condition is known. Therefore, it is recommended to perform a microbiome assessment before using any preparation that affects the gut microbiome.

Antibiotics

Antibiotics have a significant impact on the gut microbiome. Whether their effects are positive or negative, they can influence the course of digestive and other disorders, including psychological conditions. Notably, some antibiotics may help alleviate psychological symptoms due to their anti-inflammatory and neuroprotective properties. Positive outcomes have been reported for certain antibiotics in relation to mood disorders and anxiety [83–84], while other commonly used antibiotics have been associated with adverse effects [68]. Overall, the wide variety of antibiotics and their differing impacts on the body suggest that their routine use cannot be recommended without further research.

Probiotics

Probiotics are living microorganisms that can provide health benefits to the human body when used appropriately. Their use has also shown promise in the treatment of mood disorders [68]. Probiotics exert their effects through various mechanisms—for example, by influencing the metabolism of neurotransmitters (such as GABA and serotonin), reducing HPA axis activity, affecting BDNF synthesis, or suppressing certain pathogenic bacterial colonies [2]. The use of Clostridium butyricum, various Lactobacillus, Bifidobacterium, Bacillus strains, and Akkermansia muciniphila, among others, has demonstrated therapeutic or preventive effects on anxiety and depressive symptoms [48]. However, not all studies have reported positive outcomes, likely due to differences in probiotic strains, the patient’s original microbial composition, concurrent medications, or other as yet unidentified factors. [68]

Prebiotics and symbiotics

Prebiotics are substrates that promote the growth of certain beneficial bacteria. Fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are the most well-documented prebiotics in the treatment of depression, though polyphenols and compounds derived from vegetables, herbs, and other plants have also been noted. Prebiotics typically do not act directly on the body, but rather exert their effects indirectly by supporting bacterial proliferation, which is why they are often used in combination with probiotics. Synbiotics combine the benefits of both prebiotics and probiotics [67]. Their impact on alleviating psychological symptoms appears to be most significant in patients with irritable bowel syndrome (IBS) [68]. However, without prior assessment of the microbiome, the long-term use of prebiotics may be risky, as their effects are not selective enough to promote the growth of only beneficial bacteria.

Postbiotics

Postbiotics are inanimate microbial cells, their components, and the beneficial metabolites they produce—such as short-chain fatty acids and bile acids. Administering live bacteria to critically ill or otherwise vulnerable individuals may carry potential risks. In such cases, postbiotics, which can offer health benefits similar to those of probiotics, may represent a safer alternative [67]. However, they are not without risk themselves, as demonstrated in certain contexts—for example, with short-chain fatty acids. Currently, there are few studies investigating postbiotic-based therapies for depression, and in the absence of robust evidence, their use requires increased caution.

Targeted products based on microbiome analysis

Knowledge of the gut microbiome’s composition may enable the identification and correction of abnormalities associated with psychological risk. Specific bacterial populations can be selectively modified through the use of natural herbal agents (e.g., quercetin, thymol, carvacrol, borage oil, cranberry), probiotics, or dietary interventions. This targeted approach can help restore the barrier function of the intestinal wall and reduce the brain’s—and the entire body’s—exposure to toxic or inflammatory metabolites, leading to improvements in both physical and psychological symptoms. As such, understanding the gut microbiome and addressing its potential imbalances offers a promising—and personalized—approach for individuals suffering from depression.

FMT (Faecal Microbiota Transplantation)

FMT involves transferring stool from a healthy donor into a recipient’s gut to rapidly reshape their microbiome. While FMT has shown benefits in various chronic conditions associated with dysbiosis – such as depression – FMT therapy can also have side effects and complications. Evidence for its use in mental health is still limited. However, in patients with IBS or other functional gut issues, FMT has been shown to alleviate depressive symptoms – even when gastrointestinal symptoms remain unchanged [67–68]. Despite growing interest, FMT is not yet routinely used to treat mood disorders.

Functional treatment options for depression

Figure 3. Functional medicine treatment options for depression

The development of depressive and anxiety symptoms is a highly complex process that is not well explained by the theory of brain neurotransmitter imbalance alone. It is a complex neuronal dysfunction, where not only neurons are involved but the whole body, including the immune system, endocrine system, gut-brain axis and metabolic processes, and even the circulatory system. An equally complex approach to treatment is needed to ensure an effective cure.

At HealWays, the problem can be addressed in its full complexity, allowing for the development of a personalized treatment plan tailored to individual circumstances, symptoms, and laboratory test results. In addition to dietary and nutritional recommendations aimed at supporting mental health, microbiome testing and targeted intervention play a key role in the effective management of depressive symptoms.

Do you suffer from depression?

Examining the composition of the gut microbiome can help uncover the underlying root causes behind depression.

References

[1] Y. Liu et al., ‘Proteomics analysis of the gut–brain axis in a gut microbiota-dysbiosis model of depression’, Transl Psychiatry, vol. 11, p. 568, Nov. 2021, DOI: https://doi.org/10.1038/s41398-021-01689-w

[2] E. Beurel, M. Toups, and C. B. Nemeroff, ‘The Bidirectional Relationship of Depression and Inflammation: Double Trouble’, Neuron, vol. 107, no. 2, pp. 234–256, July 2020, DOI: https://doi.org/10.1016/j.neuron.2020.06.002

[3] S. Munir and V. Takov, ‘Generalized Anxiety Disorder’, in StatPearls, Treasure Island (FL): StatPearls Publishing, 2025 https://www.ncbi.nlm.nih.gov/books/NBK441870/

[4] A. Kumar et al., ‘Gut Microbiota in Anxiety and Depression: Unveiling the Relationships and Management Options’, Pharmaceuticals (Basel), vol. 16, no. 4, p. 565, Apr. 2023, DOI: https://doi.org/10.3390/ph16040565

[5] ‘DSM-5 Criteria for Major Depressive Disorder’, MDCalc https://www.mdcalc.com/calc/10195/dsm-5-criteria-major-depressive-disorder

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Published On: July 15th, 2025 / Categories: Uncategorized / Tags: /

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