Narrative Review: Pathogenesis of the Inflammatory Response and Intestinal Flora in Depression

Figures & data

Figure 1 NLRP3 activation induces the cleavage of pro-Caspase-1, activates the effector protein Caspase-1, shears and activates interleukin (IL)-1β and IL-18, and activates the downstream signaling pathways to produce inflammatory mediators; NLRP3 activation induces microglia to synthesize and release inflammatory mediators, which induce inflammatory responses and ultimately lead to neurotransmitter changes in the brain and depressive-like behaviors. (Blue line) TLR4 is ultimately involved in the neuroinflammatory response by promoting the expression of transcription factors such as nuclear transcription factor-kappa-B (NF-κB) and interferon regulatory factor 3, which, in turn, induce the production and release of inflammatory factors such as IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and also upregulate the expression of proteins such as cyclooxygenase-2. (Orange line) IDO is overactivated and the kynurenine metabolic pathway is enhanced, producing several cytotoxic products that cause neurotoxicity and ultimately lead to neurological disorders such as depression. Inflammatory factors such as interferon-γ, TNF-α, and IL-1 also augment the overexpression of IDO. (Green line).

Figure 2 Schematic of the pathogenesis of inflammatory response in depression. Inflammatory response exacerbates abnormal HPA axis function; intestinal flora activates the HPA axis through microbial antigens, prostaglandins, and other mediators, all of which eventually lead to depression (Green line). Inflammatory response decreases the synthesis and thus the levels of monoamine neurotransmitters; some flora in the intestine (anaerobic bacteria, streptococci) can affect the metabolism or synthesis of monoamine neurotransmitters, all of which eventually lead to the onset of depression (Blue line). Inflammatory factors reduce the expression of BDNF and thus its levels, leading to depression (Yellow line). Metabolites of the intestinal flora (short-chain fatty acids, neurotransmitters) enter the brain via blood circulation to aggravate the neuroinflammatory response, and other metabolites activate inflammatory cells to produce inflammatory factors that aggravate the neuroinflammatory response in the brain. The inflammatory factors that are produced in turn lead to an imbalance of the intestinal flora and dysregulation of metabolites (Red line).

Table 1 Partial List of the Medications Available to Treat Depression

Antidepressants	Type of Antidepressant	Dosage	Mechanism	Efficacy	Side Effects
Amitriptyline	Tricyclic antidepressants	25 mg/once, 3 times/d	Inhibit the reuptake of 5-HT and norepinephrine (NE) by the presynaptic membrane of nerve endings to increase the concentration of 5-HT and NE in the synaptic gap and promote neurotransmitter release to achieve antidepressant effects.	Response rate 90.0%^Citation80	Drowsiness, constipation, excessive sweating and dry mouth, ect.^Citation80,Citation81
Clomipramine		25 mg/once, 2–3 times/d		Response rate 70.0%^Citation82	Dry mouth, headache, blurred vision, insomnia, etc.^Citation82
Doxepin		25 mg/once, 2 times/d		Response rate 76.0%^Citation83	Drowsiness, rash, dizziness, headache, etc.^Citation83
Moclobemide	Monoamine oxidase A inhibitors	300–600 mg/d, 2–3 times/d	Inhibits the degradation of monoamine neurotransmitters in the synaptic gap, thereby increasing the concentration of monoamine neurotransmitters in the synaptic gap producing antidepressant effects.	Response rate 83.25%^Citation84	Dry mouth, palpitations, sweating, insomnia, etc.^Citation84
Fluoxetine	Selective 5-hydroxytryptamine reuptake inhibitors	20–80 mg/d, once/d	Inhibits the reuptake of 5-HT in the presynaptic membrane and increases the concentration of 5-HT in the interstitial space to achieve antidepressant effects.	Response rate 92.0^Citation85	Dizziness and nausea, insomnia or tremors, etc.^Citation81,Citation85
Paroxetine		20–50 mg/d, initial dose 10–20 mg/d, Increase dose by 10 mg per week		Response rate 96.0%^Citation85	Drowsiness, dry mouth, headache, dizziness, gastrointestinal reactions, ect.^Citation80,Citation85
Sertraline		50–200mg/d, Start from 50mg, Increase dose by 50 mg per week		Response rate 87.88%^Citation86	Nausea and vomiting, insomnia, headache, drowsiness, ect.^Citation86,Citation87
Escitalopram		20–60 mg/d, initial dose 20 mg/d, Increase slowly		Response rate 90.91%^Citation86	Headache, drowsiness, insomnia, etc.^Citation86
Bifidobacterium breve CCFM1025	Probiotics	4 weeks, 1×10^10 CFU/d	Balance gut flora and ease inflammatory responses to treat depression	Significant decrease in HDRS-24 score over 4 weeks^Citation88	Without side effects
Lacticaseibacillus paracaseiYIT 9029		9 weeks, 1×10^10 CFU/d		Significant decrease in BDI score over 9 weeks^Citation89	Without side effects

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