Depression Is More Than an Emotional Problem: Theories of Neuroinflammation and the Gut-Brain Axis

Major depressive disorder (MDD) is often understood by the general public as a psychological illness centered on low mood. From the perspective of modern biomedicine, however, it is actually a complex disorder involving multiple layers of physiological dysfunction. Research in neuroscience, immunology, and microbiology has gradually revealed that depression does not arise solely from psychological stress or adverse life circumstances. Instead, it is closely related to interactions among multiple systems, including neural signaling in the brain, inflammatory immune responses, the composition of the gut microbiota, and endocrine regulation. When the finely tuned balance among these systems is disrupted, the brain's ability to regulate mood and motivation can be impaired, leading to persistent low mood, loss of interest, reduced concentration, fatigue, and changes in sleep.

Depression affects more than mental state alone. It also leaves measurable marks on the body, including changes in body weight, chronic fatigue, and alterations in immune function. Approximately 300 million people worldwide are affected by this disorder, meaning that about 1 in every 25 to 30 people has experienced or is currently experiencing depression, and its incidence continues to rise, making it one of the most important public health issues in modern society. From an economic perspective, depression imposes an enormous social burden each year through reduced productivity and increased healthcare costs. For this reason, understanding its biological basis and identifying more effective treatments has become a major focus of medical research.

In early psychiatric research, one of the most influential explanations for depression was the Monoamine Hypothesis. This theory proposes that mood regulation depends on the balance of several key neurotransmitters in the brain, mainly serotonin, dopamine, and norepinephrine. These molecules transmit signals between neurons and are responsible for regulating mood, motivation, pleasure, and cognitive function. When their levels decrease or their signaling efficiency is reduced, low mood and reduced motivation may follow. Based on this theory, many modern antidepressants were designed to target the monoaminergic system. For example, selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin by neurons, allowing it to remain in the synaptic cleft for a longer time and thereby strengthening neural signaling (Note).

Release and reuptake of neurotransmitters（圖片來源：Lumen Learning，採用 CC BY 4.0 授權）

These drugs do improve symptoms in many patients, which is why the Monoamine Hypothesis has held an important place in psychiatry for so long. As research progressed, however, many investigators began to realize that a theory based solely on neurotransmitters could not fully explain the complexity of depression. Some patients respond only poorly to medication, while others require weeks or even longer before therapeutic effects appear. This suggests that the disorder may involve broader physiological mechanisms, including changes in neuroplasticity, inflammatory responses, and dysregulation of the body's stress system.

In recent years, particular attention has been given to the role of neuroinflammation in depression. The brain is not an organ isolated from the immune system. It contains immune cells known as microglia, which monitor the neural environment and clear damaged cells. When the body is exposed to infection, stress, or other forms of stimulation, microglia become activated and release a variety of inflammatory molecules, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). These molecules normally play important roles in fighting infection and repairing tissue, but when they are released at persistently high levels, they may interfere with neurotransmission and synaptic function. Indeed, studies have shown that patients with depression often exhibit a state of chronic low-grade inflammation, with significantly elevated levels of inflammatory markers in both blood and cerebrospinal fluid. These inflammatory signals can alter patterns of neuronal activity and push the brain's mood-regulating systems out of balance. Neuroinflammation may also reduce synaptic connectivity and impair neuroplasticity, making it harder for patients to recover from negative emotional states. These findings have helped drive the emergence of immunopsychiatry, a field that emphasizes the close relationship between the immune system and psychiatric disease.

Microglia (brown) in stained brain tissue sections（圖片來源：GrzegorzWicher，CC0 1.0 公共領域）

The effects of inflammation on the nervous system are not limited to neurons themselves. Inflammation can also alter the metabolic pathways of neurotransmitters. Tryptophan is the raw material used to synthesize serotonin, but under inflammatory conditions, the immune system activates certain enzymes that redirect tryptophan into the kynurenine pathway. This metabolic route produces a variety of neuroactive compounds, including kynurenine, kynurenic acid, and 3-hydroxykynurenine, some of which can be neurotoxic, such as quinolinic acid. When large amounts of tryptophan are consumed along this pathway, less remains available for serotonin synthesis, reducing the brain's ability to regulate mood. At the same time, neurotoxic metabolites may damage nerve cells, further worsening emotional and cognitive function.

Kynurenine Pathway（圖片來源：Grant RS, Coggan SE, Smythe GA，採用 CC BY 3.0 授權）

Beyond neurochemical alterations, observable changes in brain structure are also common in patients with depression. The hippocampus is an important region involved in memory and emotional regulation, but in people with depression it often shows atrophy. This may be related to neuronal injury caused by long-term stress and inflammatory responses. The prefrontal cortex, which is involved in rational decision-making and emotional control, may lose function as well, making it harder for individuals to suppress negative thoughts and emotional reactions. In contrast, the amygdala often becomes hyperactive in depression, increasing sensitivity to negative stimuli. Imbalances among these brain regions can leave patients trapped in a prolonged state of low mood and helplessness.

Another major factor is the body's stress-regulation system, namely the hypothalamic-pituitary-adrenal (HPA) axis. Under normal conditions, when a person faces stress, this system releases stress hormones such as cortisol to help the body cope with challenges. If stress persists for a long time, however, this mechanism may remain chronically overactivated, leading to sustained elevation of cortisol. Excessively high cortisol can suppress neurogenesis and make immune cells less sensitive to cortisol itself, weakening its anti-inflammatory effects and thereby potentially increasing inflammatory responses. It can also impair the function of the hippocampus and prefrontal cortex. This stress-inflammation-neural injury cascade may drive depressive symptoms to become progressively more severe. In addition, certain gene variants may make some individuals more sensitive to stress, including PCLO, DRD2, GRIK5, CACNA1E, and SST. As a result, the interaction between genetic susceptibility and environmental stress is often an important background factor in the development of depression.

Hypothalamic–pituitary–adrenal axis（圖片來源：Ross AP, Ben-Zacharia A, Harris C and Smrtka J，採用 CC BY 3.0 授權）

Another rapidly developing area of research in recent years is the gut-brain axis. The human gut contains trillions of microorganisms that form a complex and dynamic ecosystem. These microbes can break down dietary fiber and produce short-chain fatty acids, and they can also synthesize or regulate a variety of neuroactive molecules, including gamma-aminobutyric acid (GABA), serotonin precursors, and dopamine-related metabolites. Through the vagus nerve, immune signaling, and metabolic products, the gut microbiota can communicate bidirectionally with the central nervous system. When the microbial community remains balanced, it helps maintain immune stability and neural function. When dysbiosis occurs, however, the intestinal barrier may become more permeable, allowing bacterial components to pass from the gut into the bloodstream and trigger inflammatory responses. These inflammatory signals may ultimately affect brain function and thereby alter emotional state.

Gut–brain axis（圖片來源：Chao Yin-Xia, Gulam Muhammad Yaaseen, Chia Nicholas Shyh Jenn, Feng Lei, Rotzschke Olaf, Tan Eng-King，採用 CC BY 4.0 授權）

Multiple studies have shown that the gut microbiota of patients with depression does indeed differ from that of healthy individuals. For example, Faecalibacterium, which has anti-inflammatory properties, is often markedly reduced in patients with depression, while certain inflammation-associated microbial groups are increased. Even more compelling is the evidence from animal experiments: when researchers transplant gut microbiota from patients with depression into mice, the animals develop depression-like behaviors, such as reduced activity and loss of interest in reward. These findings suggest that the gut microbiota may influence the brain's mood-regulating systems through immune and metabolic pathways.

This newer understanding of depression has also opened new therapeutic possibilities. In addition to traditional antidepressants, researchers are now exploring anti-inflammatory drugs, probiotics, dietary modification, and other methods aimed at regulating the gut microbiota. If future research can identify the biological mechanisms operating in different groups of patients with greater precision, treatment for depression may eventually shift away from a single-drug model toward a more personalized medical approach that integrates neural, immune, and metabolic regulation.

Note: When a neuron transmits an electrical signal to the next neuron, it releases neurotransmitters into the synaptic cleft between them, allowing receptors on the postsynaptic neuron to be activated. These neurotransmitters are then normally taken back up by the presynaptic neuron, broken down by enzymes, or allowed to diffuse away from the synaptic cleft, which terminates signal transmission. If the reuptake mechanism is inhibited, the duration of stimulation on the next neuron is prolonged.

Author: Shui-Ye You

References:

1. Cui L et al. (2024). Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal transduction and targeted therapy.

2. Liu P et al. (2025). Decoding the gut-brain axis in depression: mechanistic insights and functional microbiota-based interventions. Journal of Functional Foods.

3. Réus GZ et al. (2023). Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities. Neurosci Biobehav Rev.

4. Sălcudean A et al. (2025). Neuroinflammation—A Crucial Factor in the Pathophysiology of Depression—A Comprehensive Review. Biomolecules.