Progress of Bai He Di Huang decoction on intestinal flora of mouse with depression

Dong-Xue Chen, Cun-Xia Ren, Ya-Wen Bai, Bao-Shan Rong, Xin Ding,Chang-Qing Li, Hui-Min Zhao, Zhan-Hong Qian＊

Abstract Depression is a recurrent, common, and potentially life-threatening psychiatric disease. Intestinal flora is a large number of microbial communities that are parasitic in the human digestive tract.Current evidence suggests that the occurrence of depression may be related to intestinal flora. Long time ago, Bai He Di Huang decoction was used to treat the depression. Recently, researchers found that Bai He Di Huang decoction could affect the the intestinal flora of patients with depression. This review focuses on the clinical progress of Bai He Di Huang decoction in the treatment of depression, and explores the effect and mechanism of Bai He Di Huang decoction on the intestinal flora of depressive mouse.

Key words：Depression, Bai He Di Huang decoction, Intestinal flora, Progress

Introduction

D epression is a recurrent, common, and potentially life-threatening psychiatric disease. By 2020,depression will become the second major disease causing ill and disability in the world [1]. Depression belongs to the category of Chinese medicine emotional disease. This symptom has been recorded in many ancient Chinese literatures. It is more common in"Melancholia"," manic disease","renal mass disease", "hysteria","lily disease","globus hystericus"and so on. such as, the Treatise on Cold Pathogenic and Miscellaneous Diseases, well known as the progenitor of prescriptions, mentioned that" when the woman was Zangzao,they would be sorrow and easy to cry,yawn and stretch many times. This time, she should be the owner of Gan Mai Da Zao Decoction ","if there was a foreign body sensation in her throat but it wasn' t in real, the patient should be the owner of Ban Xia Hou Pu Decoction". The clinical expression of Zangzao is the symptom of mental disorder, without reason sadness, want to cry, physically and mentally fatigued, and so on. Zaijing You's Understanding of Jin Kui Yao Lue said that plum core gas is "stagnation of qi and phlegm obstruct in the pharynx. Pinellia ternata, Magnolia officinalis, Ginger taste xin to disperse stagnation, taste bitter to regulate circulation of qi in the wrong direction;Fuling can help Pinellia ternate disperse the stagnation of qi and phlegm;and purple perilla is fragrance, and can break into the lung to publicize its gas. In the treatment of depression,Traditonal Chinese Medicine (TCM)has the advantage of "enhancing the therapeutic effect and reducing the side effect", such as Bai He Di Huang decoction in Jin Kui Yao Lue can treat Lily desease [2]. This article reviews the research progress of Bai He Di Huang decoction in treating depression and the correlation between intestinal flora and depression model.

1 Research progress of intestinal flora in patients with depression.

The composition of the genera in fecal samples was significantly different from depressed people and healthy people [3]. The proportion of pathogenic enterobacteriaceae and inflammatory bacteriain theintestinal of depressed patients was significantly higher than that of healthy people.The three most abundant intestinal flora in depression patients are firmicutes, bacteroides and fusobacteria; In the family level, the first three were bacteroidaceae, prevotella and rumen bacteriaceae. In genera level, the first three were polymorphic bacillus, prevotella and mycobacterium. The proportion of bacteroides is excessive high and the lachnospira is obvious deficiency.

Changes in gut flora have been found to trigger depression. Researchers transplanted depression patients' faeces into germ-free mouse, and then depression-like behaviors were induced in mouse. It demonstrated that "depression behavior" can transfer with the intestinal flora [4-5]. Poor diet, stress, antibiotics and other damage to the intestinal flora can also lead to abnormal distribution and metabolism of relevant neurotransmitters. It can make the intestinal microecology of healthy people tend to be the microflora structure of depressed patients, affect brain function and increase the risk of depression [6]. It is through the intestinal flora-gut-brain to adjust and control between intestinal flora and the brain. Intestinal flora can affect the absorption and metabolism of immune cells, neurotransmitters and tryptophan, etc., which further cause depression via vagus nerve, HPA axis, neuroimmune system, neurotransmitter or microbial metabolites [7]. More and more experiments have shown that there is two-way adjustment function between depression and intestinal flora [8-10], as shown in Figure 1. Intestinal flora disorder can cause the host behavior change and conduct depression behavior [6, 8,11]. However, rebuilding gut flora can help with depression symptoms. Studies show that Psychobiotics is a kind of psychoactive probiotics, which can regulate intestinal flora disorders and increase the level of 5-HT, GABA and other neurotransmitters, serving as an antidepressant [12].Messaoudi[13] randomly assigned substances containing lactobacillus and bifidobacterium for experimental groups and blank placebo for control group to patients with major depressive disorder. As a result, patients in the experimental group showed significant improvement in mental stress,depression, anxiety and gastrointestinal discomfort. In addition, studies have shown that lactobacillus rhamnosus can reduce the content of corticosterone caused by stress,and alleviate depression-like symptoms via the vagus nerve signal pathway of mice [14].

Figure 1 Bidirectional communication channels among gut microbiome, gut, and brain. Endocrine-, neurocrine-, and inflammation-related factors generated by the gut microbiota and reletaed cells within the gut can affect the brain. In turn, the brain can influence microbial composition and function via endocrine and neural mechanisms.

2. Clinical progress of Bai He Di Huang decoction in the treatment of depression.

2.1 Source of Bai He Di Huang decoction

Bai He Di Huang decoction is empirical prescription of lily disease recorded in the book Synopsis of Golden Chamber created by Zhang Zhongjing of the Han Dynasty.The symptoms described in this book are very similar to those of depressive symptoms such as delirium, different behaviors and so on. Zhongjing considered that the pathogenesis of depression is mostly Yin def iciency and internal heat. The composition of Bai He Di Huang is simple,which is made up of seven fruits of Lilium brownii and a liter juice of Rehmannia glutinosa. The Lilium brownii can clear heart and moisten lungs, and benefiting qi for tranquillization. The Rehmannia glutinosa has the effect of clearing heat and nourishing blood, nourishing kidney water and nutrient qi. Compatibility of the two drugs and boiled with spring water can achieve the effect of cooling blood, clearing heat and nourishing heart and lung.

2.2 Modern medicinal research

Modern pharmacological research suggests that Lilium brownii has the functions of relieving asthma and cough,calming the nerves, and resisting stress damage. The main component of anti-depression is steroidal saponins. The effective part is Lilium brownii saponin, Hu Linlin [15]found that in the experiment of behavioral and hippocampal GR/ MR expression in rats with post-traumatic stress disorder, it was concluded that Lilium brownii saponin can effectively inhibit HPA axis hyperfunction. Bai He Di Huang decoction can reduce PTSD-like anxiety level in rats, down-regulate PTSD rat hippocampus GR Level and up-regulate the MR level, thereby alleviating anxiety and restoring inquiry behavior. Yin Linglong [16] found that high-dose Bai He decoction can improve the openbox experimental evaluation and 5-HT content in rats, and has a certain effect on chronic stress depression in mice,which can increase antidepressant effect. The chemical constituent iridoid glycosides in Rehmannia glutinosa has a significant antidepressant effect on the nervous system[17]. Zhao Lei [18] construct network models for the active ingredient-targeting-disease of Bai He Di Huang decoction, as shown in Figure 2. It can be seen that the main active components of Bai He Di Huang decoction are sterol, steroidal saponin, and Rehmannioside A, which have a mechanism of action with many active components and many targets. In addition, Bai He Di Huang decoction is involved in the regulation of G-protein coupled receptor activity and neurotransmitter expression through its potential targets, and its effective active site can enhance the DA and 5-HT content of cerebral cortex, hypothalamus,hippocampus and striatal of model rats to exerts an antidepressant effect.

Figure 2：Components-targets network of major active ingredients of Bai He Di Huang Decoction main active ingredients, targets and diseases

2.3 Clinical treatment and research progress

Guan Jiaqi [19, 20] et al. observed the effect of Bai He Di Huang decoction on the solitary and chronic unpredictable mild stress (CUMS) depression mouse model. The results showed that compared with the control group, Bai He Di Huang decoction could make mice growth in quality, can increase the content of DA and 5-HT in brain tissue, and

can signif icantly reduce the concentration of serum cortisol and adrenocorticotropic hormone in mouse serum, thereby playing an antidepressant effect. Zhou Xiangle [21] found the effect of Bai He Di Huang decoction on the changes of inflammatory factors IL-1β and neuron 5-HT levels in depression rats. It showed that elevated serum cytokine IL-1β levels lead to decreased brain neurotransmitters 5-HT level. Bai He Di Huang decoction can effectively inhibit the depression-like behavioral changes and the level of serum IL-1β increasing in chronic stress and depression rats, and can increase the expression level of 5-HT in hippocampus.It demonstrated that the brain monoamine neurotransmitter has a regulatory effect. In clinical treatment, Jiang Yongxing [22] used Bai He Di Huang decoction and Gan Mai Da Zao decoction to treat depression. Before treatment, the patient had mental symptoms such as emotional apathy,hallucinations and space fear. After taking the compound for two weeks, the symptoms improved significantly.

3 Disccusion

Nowadays, the number of patients with depression is gradually increasing, and the number of patients inclined to commit suicide or self-injury is increasing, so more attention should be paied to the treatment of depression.Traditional Chinese medicine has many methods to treat depression with few side effects. Bai He Di Huang decoction is a classic traditional Chinese medicine prescription.On the other hand, intestinal flora plays an important role in human life and health, and intestinal microorganism was rated as one of the top ten scientific breakthroughs in the journal science in 2011. The research of the relevance of intestinal flora and depression also provides a new way for treating depression. However, these researches are conducted in animal models, so as to Bai He Di Huang decoction research. This article is still lack of the mechanism of Bai He Di Huang decoction' s effect on intestinal flora of depression model rats and the relationship between concrete microbiota and depression, more specific mechanism needs to be further in-depth study.