Research On Traditional Chinese Medicine For Gut Health And Depression.

Abstract: Post-stroke depression (PSD) is an important complication and source of distress in stroke patients, with a high prevalence, insidious onset, and easy to be overlooked, which can severely reduce the overall quality of life of patients, impede the process of post-stroke rehabilitation, and have a significant impact on the normal functioning of the nervous system. Current research has found that the occurrence of post-stroke depression is closely related to human gut microorganisms (GM). A large number of existing animal experiments and clinical studies have shown that GM affects PSD mainly through hypothalamic-pituitary-adrenal (HPA) axis function, inflammatory response, neurotransmitter transmission, vagus nerve, lipid metabolism, and brain-derived neurotrophic factor (BDNF).In this paper, we focus on PSD through the traditional Chinese medicines monomers of Bupleurum chinese DC, Polygala tenuifolia Willd, Pueraria lobata (willd), Cistanche deserticola Ma, and Schisandra chinensis (Turcz.)and the Chinese herbal medicine complexes of Shugan Jieyu capsule,Xiaoyao San (XYS), Kai-Xin-San (KXS) , Yueju Wan, Gardenia jasminoides J, Yang Xin Jie Yu decoction (YXJYD), and Shugan Hewei Decoction (SGHWD), to reveal that the Chinese medicines and the Chinese medicine compound affect GM and thus participate in the multilevel targeted treatment of depression from several aspects such as inhibiting inflammatory response, regulating the HPA axis, and increasing the secretion of neurotransmitters such as 5-hydroxytryptophan (5-HT) in the brain, in the hope that it can provide a new thought process and strategy for the prevention and treatment of depression by traditional Chinese medicines.

Cistanche For Depression

 

Keywords: Post-stroke depression; Gut microbiota; Mechanisms; Traditional Chinese medicine; Anti-depression

 

Introduction

Post-stroke depression (PSD) can be caused by a variety of factors, including cerebral hemisphere stroke or focal neurological deficits in the brainstem, leading to harmful psychological effects such as depression, suicide, and loss of interest, as well as a series of clinical manifestations [1]. PSD seriously hinders the recovery of neurological function, prolongs treatment time, reduces overall quality of life, and imposes a heavy economic burden on patients [2].
The pathophysiology of PSD mainly involves neurotransmitters and inflammatory factors, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, abnormal lipid metabolism, and decreased levels of brain-derived neurotrophic factor (BDNF). Intestinal dysfunction and gut microbiota (GM) disorders caused by stroke can participate in the pathogenesis of PSD through multiple mechanisms involving the immune, endocrine, and nervous systems (Figure 1). Studies have shown [3] that there is an imbalance between depression and GM, and improving this imbalance may benefit patients with depression. Therefore, exploring the correlation between PSD and GM and using GM as a potential therapeutic target for PSD patients can provide a reasonable and effective theoretical basis for treatment.
PSD has a high clinical incidence and seriously affects the prognosis of stroke patients. Therefore, timely and accurate diagnosis and treatment are of great clinical significance. Western medicine mainly uses oral antidepressants for treatment, but there are many adverse reactions such as long treatment cycle, poor patient compliance, and easy relapse. Modern research has conducted extensive research on PSD from the perspective of the brain-gut axis, confirming that Chinese medicine can regulate the composition and metabolism of GM and has significant efficacy in the treatment of depression. Therefore, this article aims to summarize the relationship between GM and PSD, as well as the research progress of Chinese medicine in exerting antidepressant effects by regulating GM, and look forward to the potential of Chinese medicine in the treatment of PSD in the future, in order to provide a theoretical basis for the treatment of PSD and other neurological diseases.

 

 

 

1. Effect of GM on PSD

The human gastrointestinal tract contains a variety of microorganisms that maintain homeostasis by regulating immunity, digestion, metabolism, and neural function, and is often referred to as the "second brain." Disruption of GM balance can affect the central nervous system (CNS) through different conduction pathways. The brain-gut axis is a bidirectional regulatory pathway between the central nervous system and the gastrointestinal tract, connecting them through multiple mechanisms such as neurotransmission, hormonal signaling, immune response, and molecular signaling [4]. The brain-gut axis[5] involves connections between the vagus nerve, the immune system, and microbial metabolites. In the human gastrointestinal system, GM plays an important role in transmitting signals to the central nervous system directly or indirectly along the brain-gut axis [6]. Studies have found [7] that GM is associated with PSD, especially in individuals with stroke susceptibility factors such as hypertension, diabetes, and hyperlipidemia. The GM generation
The short chain fatty acids (SCFAs) metabolized by the intestine have the function of regulating blood pressure, and the gastrin secreted by the intestine helps to maintain the stability of blood sugar and blood lipid levels. The inflammatory response after stroke can disrupt the integrity of the intestinal barrier and the balance of GM[8]. In addition, inflammatory factors (including bacterial endotoxins) released by the intestinal mucosa enter the blood-brain barrier (BBB) ​​of the circulatory system, causing damage and increasing oxidative stress in the brain. Activation of the HPA axis and the sympathetic nervous system can affect intestinal function, hinder the synthesis of neurotransmitters and nerve conduction in the intestine, affect the prognosis of stroke, and thus increase the susceptibility to post-stroke mental disorders[9].
Exogenous and endogenous stress can activate the HPA axis, and activation of the sympathetic nervous system and enteric nervous system can lead to changes in intestinal motility and permeability, ultimately leading to intestinal inflammation and other forms of intestinal dysfunction. GM also plays an important role in the occurrence and development of depression by affecting key factors such as the HPA axis, neurotransmitter levels, and inflammatory mediators. Kang et al. [10] found that compared with stroke patients without depression, PSD patients had a higher incidence of harmful bacteria; compared with patients without PSD, PSD patients had higher levels of dominant bacteria (such as Bifidobacterium). Lower. Related studies have confirmed that the number of intestinal microorganisms, Clostridium, Blautia, and Streptococcus in PSD model mice was reduced, and a variety of metabolites related to lipid, amino acid, carbohydrate, and nucleotide metabolism also changed significantly. Changes in GM and lipid metabolism suggest that PSD involves disorders in GM and lipid metabolism[7,11]. In summary, the disruption of GM is closely related to the pathogenesis of PSD.

1.1 HPA axis disorder is associated with the occurrence of PSD

The HPA axis is a core component of the neuroendocrine network and plays an important role in regulating stress response, endocrine and hormone levels [11-13], and HPA axis hyperfunction is an important mechanism of depression. When faced with stress, the HPA axis is activated, first the hypothalamus releases corticotropin-releasing hormone (CRH), which then stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH).
The adrenal cortex secretes cortisol (COR) under the activation of ACTH, and a series of physiological reactions occur within the sympathetic nervous system. Once the stressor stops, these reactions are subsequently terminated by a negative feedback mechanism [14]. Throughout the cycle, COR levels decrease, thereby inhibiting the continued release of ACTH and CRH in the hippocampus, both of which play an important role in regulating emotions. The expression of glucocorticoid receptor (GR) is mediated by the hippocampus and regulates the HPA axis through negative feedback[15]. When GR protein expression is downregulated[16], its various functions are impaired, the negative feedback mechanism fails, and the HPA axis continues to be hyperactive[17]. Therefore, increased COR levels in the hippocampus lead to decreased function of the 5-HT system, thereby reducing the expression of neurotrophins, which in turn leads to hippocampal neuronal degeneration and ultimately depression[18]. Therefore, HPA axis disorders can lead to CRH, ACTH, and COR secretion disorders. Several studies have confirmed that people diagnosed with depression can show elevated CRH, COR, and ACTH levels.

1.2 Inflammatory response is associated with the occurrence of PSD and affects GM

Inflammatory factors are associated with the occurrence of depression, and there is a correlation between GM and inflammatory factors. Studies have shown [19-23] that an increase in the number of enterobacteria can stimulate the production of inflammatory factors, including interleukin-6 (IL-6), interleukin-22 (IL-22), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ). Beneficial intestinal bacteria can reduce the release of inflammatory factors and improve inflammatory responses. Intestinal immune-mediated inflammation after stroke may lead to brain neurotoxicity, thereby triggering depressive symptoms [24]. Escherichia coli and enterococci can penetrate the circulatory system and produce bacterial endotoxins. These endotoxins release cytokines[20-22], including proinflammatory cytokines such as TNF-α, IFN-γ, interleukin-1β (IL-1β) and interleukin-18 (IL-18), which can enter the brain through body fluids or neural pathways, stimulate microglial M1 subtype transformation, and ultimately cause neuroinflammation and depression. Under pathological conditions, inflammatory factors such as IL-1, IL-2, IL-6 and high-sensitivity C-reactive protein (hs-CRP) can enter the central nervous system through the blood and transmit inflammatory signals to the central nervous system[25-27]. These signals then activate glial cells through the NF-κB pathway and may lead to the onset of depression. Therefore, inflammation may be related to the occurrence and development of PSD. Studies have shown[22,24] that there is a correlation between microbiota imbalance and inflammatory markers in patients with depression. In susceptible mice, IL-6 can induce depressive symptoms by changing the composition of GM. After inhibiting peripheral IL-6 receptors, it was found that the ratio of sessile bacteria/Bacteroides was significantly reduced [28-29]. This intervention may show a rapid and lasting antidepressant effect. Kang et al. [10] found that there is an imbalance in the GM ecology in PSD patients, which affects the growth of bifidobacteria, which may lead to overexpression of serum inflammatory factors. Therefore, the above research results show that GM disorder caused by inflammatory response is involved in the occurrence and development of PSD.

 

1.3 The relationship between GM, neurotransmitters and PSD

Studies have shown [28,30] that PSD patients have GM imbalance and changes in the monoamine neurotransmitter system. Damage to GM after stroke can affect the production of neurotransmitters and nerve conduction, which may affect the occurrence of depression. GM is involved in the synthesis of important neurotransmitters, including gamma-aminobutyric acid (GABA), serotonin (5-HT), dopamine (DA) and norepinephrine (NE). These neurotransmitters are likely to affect the host's mood, behavior and cognitive function [31-32], and affect the central and peripheral nervous systems through direct and indirect mechanisms involved in regulating neurotransmitter levels [10]. Loubinoux et al. [1] demonstrated that patients diagnosed with PSD showed reduced 5-HT levels compared with non-depressed patients. GM disorder can disrupt peripheral 5-HT levels, thereby affecting the glutamate-glutamine-GAB cycle in the hippocampus and leading to mood disorders[33].

After stroke, an increased prevalence of Pepticoccaceae was observed in the cecum of mice, while the proportion of Prevotella SPP decreased. This change may be caused by increased NE release and decreased mucin-producing cells, suggesting that there may be a relationship between GM and neurotransmitters in the development of PSD[34]. Ji et al.[31] found that the levels of serotonin, DA, and NE in the frontal lobe and hippocampus of PSD rats were significantly lower than those in non-depressed rats with stroke. The expression of fibroblast growth factor-2 (FGF-2) protein and mRNA in the frontal lobe was significantly decreased, while there was no significant difference in the expression in the hippocampus.
These results indicate that the disorder of monoamine neurotransmitters and the decreased expression of FGF-2 in PSD rats may be related to the onset of PSD. Savignac et al. [35] found that bifidobacteria can effectively achieve antidepressant effects by increasing the concentration of monoamine neurotransmitter 5-hydroxytryptamine in the brain. Liu et al. [36] observed that mice subjected to restraint stress showed depressive-like behaviors and elevated serum corticosterone levels. Therefore, it can be proved that GM and neurotransmitters are closely related to PSD.

 

1.4 The vagus nerve is the medium between GM and PSD

Related studies have shown [37-38] that the vagus nerve drives the communication between GM and CNS by neuroactive substances produced by intestinal microorganisms. Depressive and anxious behaviors are regulated by the vagus nerve [39]. GM plays an important role in the production of neurotransmitters, enabling it to communicate with the brain through the vagus nerve. Damage to the central nervous system can lead to the loss of neurons between the intestinal mucosa and muscles, resulting in reduced synaptic connections and impaired signals from the vagus nerve, which may induce depressive symptoms [37,39,40]. The vagus nerve is involved in the two-way communication between the brain and the GM system, which may be related to the occurrence of depression.
The diaphragm between the brain and the cerebral cortex is controlled by the vagus nerve. Studies have shown that subphrenic vagotomy (SDV) has an effect on GM production in mice that develop depression-like symptoms after injection of lipopolysaccharide (LPS).

 

Depression has a certain impact on LPS-induced depression in mice[39], while no depressive-like symptoms were observed in SDV mice. SDV prevented depressive-like behavior in Chrna7 KO mice and reduced the expression of synaptic proteins in the medial prefrontal cortex (mPFC). These findings suggest that Chrna7 KO mice display depressive-like behaviors via the vagus nerve, a part of the gut-microbe-brain axis[41]. Thus, there is a clear correlation between the GM and the vagus nerve, suggesting that both may play a role in the development and progression of PSD.

 

1.5 Relationship between lipid metabolism disorders and GM and PSD

GM is involved in the occurrence and development of PSD, and its mechanism may be related to the regulation of lipid metabolism. Significant differences in microbial and metabolic profiles were observed in PSD rats, including glutamate, maleate, 5-methyluridine, cyanamide, acetylalanine, and 5-methoxytryptamine. Studies have found that the fecal metabolomics disturbances in PSD rats are mainly due to abnormal metabolism of lipids, amino acids, carbohydrates and nucleotides[32,42]. Liquid chromatography-mass spectrometry analysis showed that 10 bacterial genera (mostly belonging to sterol bacteria) were significantly changed in stroke rats compared with control rats, and three SCFAs (butyrate, acetate, and valerate) were significantly increased. is decreasing. Jiang et al. [43] showed that the changes in GM of PSD rats related to these SCFAs were more obvious. Fifty-seven lipid metabolites were significantly altered in the PFC of PSD rats compared with control and stroke rats. PSD Large
Alterations in SCFAs in mice were also significantly associated with most of the disturbed lipid metabolites in PFC. These findings suggest that SCFAs may play a mediating role in communication between the gut and the brain. Exploring the relationship between fungi, SCFAs, and lipid metabolism may provide new ideas for further studying the underlying mechanisms of the brain-gut axis and PSD.

1.6 Correlation between BDNF levels and GM and PSD

BDNF is a member of the neurotrophic factor family and acts through the neurotrophic factor receptor tyrosine kinase B (TrkB). BDNF and TrkB jointly promote adhesion, migration, proliferation, and activation of angiogenesis and apoptosis pathways[5]. Yang et al.[44] found that stroke can lead to GM disorders, and GM disorders can induce depression by affecting BDNF levels. BDNF and TrkB are present in intestinal epithelial cells, intestinal glial cells, and neurons, and play a role in regulating intestinal sensation and movement. GM disorders caused by stroke affect the expression levels of BDNF and TrkB, and these two factors are closely related to the occurrence of depression[45]. Jiang et al. [42] observed that the activity of the transcription factor cAMP response element binding protein (CREB) and its related BDNF/TrkB signaling pathway was reduced in hippocampal cells of PSD rats. 17-Estrogen treatment significantly improved depressive behavior and enhanced the activity of CREB and BDNF/TrkB signaling pathways. These results indicate that the CREB/BDNF/TrkB signaling pathway may be involved in the formation of PSD in rats. In summary, stroke can change the composition and metabolism of GM. GM establishes a complex ecosystem through its metabolites and immune activity as well as its interaction with the host, which ultimately affects the occurrence, development and prognosis of stroke and its concurrent mental illnesses.