The pathophysiology of major depression has been increasing clearly following the development of neuroscience and bioinformatics. It mainly involves four aspects, the dysfunction of the brain, the hypothalamus–pituitary–adrenal (HPA) axis, the immune system, and the gut–brain axis. The brain abnormalities are mainly reflected in the unbalanced neurotransmitters, the impaired neuroplasticity, and the abnormal neural circuitry [
1,
10]. The HPA axis dysfunction is mainly manifested as a maladjustment of negative feedback mechanisms [
19,
20]. The immune changes are mainly seen as chronic inflammation [
21,
22]. The gut–brain dysfunction mainly includes gastrointestinal disorders and gut microbiota abnormalities [
1,
11,
23,
24,
25].
2.1. The Brain Dysfunction
Neurotransmitters play a crucial part in the brain and behavior. Depression is inseparable from neurotransmitter imbalance [
26,
27]. The monoaminergic neurotransmitter deficiency hypothesis posits that positive moods including happiness go hand in hand with monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and/or dopamine (DA) and that symptoms of depression arise from insufficient levels of these neurotransmitters. Recovering these neurotransmitter levels will have antidepressive effects [
26,
28]. However, most of the selective serotonin reuptake inhibitors (SSRIs) work slowly and just bring alleviations for part of the patients, indicating that there are still other mechanisms involved in depression [
9]. Subsequent research revealed that also signaling by other neurotransmitters probably changed in depression. For example, the glutamatergic system and acetylcholine system are hyperactive, while the gamma-aminobutyric acid (GABA) system is inhibited [
27,
29,
30].
The prefrontal cortex, hippocampus, and amygdala play a vital role in the regulation of emotion, stress responses, self-control, motivation, and cognitive reaction, but in depressed patients the function of the prefrontal cortex and hippocampus are impaired, while the activity of the amygdala is increased [
31]. The traditional brain-derived neurotrophic factor (BDNF) hypothesis posits that BDNF is an important regulator of neurogenesis and that depressive symptoms arise from the decrease in BDNF content and the following increase in neural apoptosis. Therefore, long-lasting antidepressant therapies increase the neurotrophic factors including BDNF, stimulate neurogenesis, reduce the hippocampus neuronal apoptosis, and improve the mood and cognition [
1,
20,
32]. Later research found that depressed patients not only present impaired neurogenesis but also present disturbed neuralgias growth, reduced synaptic plasticity, impaired myelin function, and a decrease in total neuroplasticity [
9,
10,
31]. The new neuroplasticity hypothesis posits that depressive symptoms arise from the impaired neuroplasticity, which can be induced by many risks factors, including neurotransmitter imbalance and insufficient BDNF. Antidepressant therapies focusing on neurotransmitter recovery and brain stimulation work through the increase of neuroplasticity and the decrease of neuronal apoptosis [
2,
33,
34,
35]. These theories put emphasis on the changes at the molecular and cellular level, while some other theories, including the neural circuit hypothesis point the changes in function. According to the neural circuit hypothesis, depression occurs as a result of aberrations in communication between specific neural structures of the brain, such as the DA neurons in the ventral tegmental area (VTA) and their projections and 5-HT neurons in the dorsal raphe nucleus and their projections. These abnormalities in neural circuits can be restored via therapies including deep brain stimulation [
10,
36].
2.2. The HPA Axis Dysfunction
The HPA axis is an important part of the stress response system, and dysfunction of the HPA axis is one of the most important mechanisms behind depression [
11,
21,
37,
38]. Both psychological and physiological stress activate the HPA axis and stimulate the release of corticotrophin-releasing factor (CRF) and vasopressin (AVP) by the hypothalamus. Both CRF and AVP induce the anterior pituitary gland to secrete adrenocorticotrophic hormone (ACTH), which enhances the release of adrenocortical hormones, including glucocorticoid (GC), and causes an increase in circulatory GC levels, which inhibits the secretion of CRF and AVP by the hypothalamus, forming a negative feedback circuit [
37,
39]. However, over half of the depressed patients present negative feedback dysfunction of the HPA axis, including a chronic increase in circulatory GC and ACTH, and some of the patients even suffer from hypercortisolemia [
21,
37]. One hypothesis posits that the glucocorticoid receptor (GR) plays an important role in the HPA axis function during depression; the excessive circulating GC reduces the sensitivity of GR, while antidepressant therapies increase the GR expression, enhance the GR function, and improve the negative feedback medicated by GR [
37,
38]. Later research found that HPA axis dysfunction also reduces BDNF expression [
39], inhibits 5-HT synthesis [
40], decreases Glu receptor expression [
41], and even disturbs neuroplasticity and neural circuits [
10,
42].
2.3. Immune System Abnormalities
Inflammation is also an important pathological feature of depression. A subpopulation of depressed patients present immune dysregulation and chronic inflammation [
21,
43,
44]. The cytokine hypothesis posits that in depression the proinflammatory cytokines, including IL-6 and TNF-α, increase in amount while the anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), decrease, making the holistic immune response tend to inflammation. The excessive proinflammatory cytokines inhibit the negative feedback of the HPA axis, increase the permeability of the blood–brain barrier, reduce the synthesis of 5-HT, disturb the glutamatergic systems, and result in depression [
40,
43,
45,
46,
47,
48]. The early theories mainly focus on peripheral inflammation, but new theories, such as the neuroinflammation hypothesis and inflammasome hypothesis pay more attention to central inflammation [
42,
47]. The neuroinflammation hypothesis emphasizes the adverse effects on the central nervous system (CNS) exerted by excessive proinflammatory cytokines released by microglia, which can be induced by various factors such as psychological stress, disease, and infection [
42]. The inflammasome hypothesis puts emphasis on the influences of neuroinflammation induced by the inflammasome [
49,
50]. Neuroglia cells play a vital part in the regulation of neuro immune and neuroplasticity. Although different theories focus on different aspects, all of them hypothesize that the neuroinflammation and neuroplasticity impairment induced by neuroglia dysfunction results in depression [
42]. The anti-inflammatory effect of traditional antidepressant therapies is not obvious [
44], and combining antiinflammation methods with antidepressive therapies will probably give better results [
47].
2.4. Gut Brain Dysfunction
The gut of mammals is also called gut brain because it has its own nervous system (enteric nervous system) and can make relatively independent responses to external signals [
18,
51]. The gut brain is a microbial organ, 90–95% of the total cells of which are microorganisms including bacteria, archaea, fungi, viruses, and some protozoa, and the metabolism, immune system, and signal transmission are all closely related with microbiota. Thus, the gut and gut microbiota can serve as a whole to respond to and influence other organs [
52,
53,
54,
55]. Depressed patients often have gut brain dysfunction, such as appetite disturbances, metabolic disturbances, functional gastrointestinal disorders, and gut microbiota abnormalities [
15,
23,
25,
56,
57,
58].
Major depression is not just a simple mental disorder or brain disease, but also a systemic disease. Patients often suffer from various disorders simultaneously, such as brain dysfunction and periphery dysfunction, such as HPA axis disturbances, immune dysregulation, and gut brain disturbances. These disturbances interplay with each other. For example, chronic stress reduces the 5-HT content in the brain; the synthesis and secretion of 5-HT are also influenced by various factors including the HPA axis, immune system, and gut brain, and in turn the 5-HT content affects the function of these organs [
20,
40,
59]. As shown in
Figure 1, taking both central and periphery abnormalities into account will facilitate the research of depression, and brain–gut axis dysfunction will explain the pathological basis better.
The brain-gut axis is the bidirectional message transformation pathway between brain and gut in mammals. It connects the brain and gut through several pathways including nerves, the HPA axis, and the immune system [
14,
18]. Factors such as psychological stress and disease impairing one or more pathways of the brain–gut axis probably induce brain–gut axis dysfunction and result in depression [
25,
60,
61]. Following the development of gut microbiota, researchers not only focus on the top–down effects of the brain–gut axis (from brain to gut), but they also pay close attention to the down–top influences (from gut to brain) [
23,
25,
62]. The functions of many a system, including metabolism, the immune system, the endocrine system, and the nervous system, are all closely related with the gut brain. Changes of the gut brain such as gut microbiota abnormalities influence the brain and behavior, and brain changes regulate the function and construction of the gut brain. Combining the brain and gut brain will probably become the new tendency of neuroscience, and targeting the gut microbiota will possibly be a promising area for the therapy of mental disorders and neurological diseases [
18,
63,
64,
65,
66,
67,
68,
69,
70,
71].
According to the gut microbiota hypothesis, the gut microbiota can influence the brain and behavior through the gut–brain axis, which is also called microbiota–gut–brain axis to emphasize the importance of the microbiota. It plays a crucial part in mental disorders [
64,
65]. Gut microbiota is a key component of the gut brain. It regulates the common functions and build-up of the gut brain [
52,
53,
54,
55], influences the development and maturation of the HPA axis [
72,
73,
74,
75], affects the development and function of the immune system [
76,
77,
78], regulates the construction of the blood–brain barrier [
79], influences the synthesis and recognition of neurotransmitters [
59,
72,
80], affects neurogenesis [
81], the development and function of neuralgias [
82,
83], and the formation of myelination [
84], and impresses the development and function of the brain [
66,
78,
85,
86]. Thus, regulating gut microbiota cannot only improve gut brain dysfunction but also alleviate abnormalities in the immune system, HPA axis, and brain. All these results are in line with the gut microbiota hypothesis, which will probably be the promising direction of mental disorder therapy and prevention.