The treatment effects of Kaixin Powder on depression through heart-spleen axis

Hui-Mei Shi,Xin Li,Jia-Lin Wu,Di Zhang,Guo-Ping Zhao

Abstract:Depression is a kind of mental disorder characterized by conspicuous and persistent low mood,sustained sadness,loss of interest and forgetfulness.In traditional Chinese medicine,heart (different from the concept in Western medicine)control the emotions.Overthinking hinders the function of the spleen.Deficiency of spleen leads to lack of heart-Qi.Deficiency of the spleen also leads to dysfunction of heart.Once the heart is dysfunction,Qi will be stagnated in Danzhong(thoracic center),eventually leads to depression.In Traditional Chinese medicine,the development of depression is a heart-spleen-heart process,which can be called the "heart-spleen axis".Biomedicine studies have found that the progress of depression is mainly caused by long-term adverse stimulation of the central nervous system,which affects the Hypothalamic-pituitary-adrenal axis (HPA) to convey monoamine neurotransmitters, such as 5-hydroxytryptamine (5-HT),and further damaged the intestinal mucosal barrier,increased its permeability,and produced a large number of lipopolysaccharides (LPS) and inflammatory factors.The production of LPS and inflammatory cytokines reduces the synthesis of 5-HT by consuming tryptophan,and the decrease of 5-HT in serum results in the decrease of 5-HT levels in the brain.At the same time,changes in the intestinal microbiota alter the concentration of brain-derived neurotrophic factor (BDNF)via the vagal pathway,ultimately creating a vicious brain-gutbrain cycle.Kaixin Powder has the effect of invigorating spleen and eliminating dampness,awaking consciousness and inducing resuscitation,and can adjust the imbalance of gut microbiota and neurotransmitters to achieve the purpose of treating depression.

Keywords—Depression,Brain-gut axis,Heart-Spleen axis,Kaixin Powder,Gut microbiota

I.

Kaixin powder is derived from Sun-Simiao’s "Essential Recipes for Emergent Use Worth A Thousand Gold-Volume 14",which is a formula for treating forgetfulness.Modern biomedical research has proved the clinical effectiveness of Kaixin powder in the treatment of depression [1].The etiology and pathogenesis of depression still unclear and may involve many factors such as physiological,psychological and social influence.Modern biomedicine has confirmed that the occurrence of depression is related to the "brain-gut axis".They proved that the disturbances of intestinal microbiota could cause anxiety and depressive [2] .Brain-gut axis theory suggests that intestinal microbiota regulates brain and intestinal functions through stress,entero-neurological,braingut peptide,neuroendocrine and immune system pathways [2-4].In traditional Chinese medicine theory,the heart is the master of the mind and the spleen is the master of thoughts,and both are closely related to mental illness,so the development of depression cannot be separated from the heart and spleen.

II.THE RELATIONSHIP BETWEEN THE"HEART-SPLEEN AXIS" AND THE"BRAIN-GUT AXIS"

A.The spleen in traditional Chinese medicine and the intestine in modern biomedicine

According to the theory of visceral manifestation of traditional Chinese medicine,the spleen and stomach are the five elements of organs,and belong to the middle-jiao,andtogether they are the source of the production of Qi and blood.The major function of spleen are absorption,distribution,digestion and transformation.Spleen has the physiological function of transforming water and cereal food,which can transfer the essence to the whole body.The transporting function of the spleen can be divided into two aspects:transporting water and food,which is similar to the digestion and absorption function of the intestine in modern biomedicine.In traditional Chinese medicine,it means that after the diet,water and food enters the stomach.It is decomposed by the stomach and transformed by the spleen’s transport function into essence to nourish the limbs and bones [5].In modern biomedicine,the water and food enters the stomach through mechanical and chemical digestion,and the chyme enters the duodenum from the stomach,where it is chemically digested by pancreatic juice,bile and small intestine fluid and mechanically digested by the small intestine,while nutrients are transformed from large molecules to small molecules,which absorbed by the small intestine and transferred to the whole body for use by the body,while water and inorganic salts are absorbed mainly in the large intestine.The intestinal microbiota is involved in the absorption,digestion and metabolism of carbohydrates,fats and proteins,and can synthesize vitamin B and K.Finally,they are transformed into nutrients needed by the body and transported to the whole body through the celiac duct,intestinal mucosa and its capillaries,providing nutrients to cells,tissues and organs in order to give the body its normal needs [7].

The traditional Chinese medicine mentions that Ying and Wei Qi (defense Qi) are all produced by the middle-jiao.Wei Qi has the ability to protect body from Wai Xie (exogenous evil).If the spleen and stomach function normally and produce enough Qi and blood,then the Ying and Wei Qi are abundant and harmonious[5],[7].In modern biomedicine,the intestinal mucosa-associated lymph nodes in the intestine,as the first defense barrier in the body’s defense system,constitute an important defense barrier for the body.The intestinal microbiota stimulates the body to produce natural antibodies,which play an important role in resisting the invasion of pathogenic bacteria into the body.The intestinal microbiota can also resist the colonization or direct inactivation of other pathogenic bacteria through competition and production of harmful substances [6].Thus,the defense function of the spleen in Chinese medicine has some degree of similarity to the immune function of the intestine in modern medicine[7].

B.Spleen deficiency and intestinal microbiota imbalance

The treatise on the spleen and stomachby Li Dongyuan,a Jin Dynasty doctor,mentions "internal impairment of the spleen and stomach causes various diseases".If the spleen is deficient,the spleen will lose its ability to transport and transform,and if the disease is internalized,all diseases will arise.The spleen and stomach are injured when people overeating,which makes spleen lose transportation and transformation,there is no source for the generation of essence.Deficiency of spleen leads to abnormal metabolism of water,phlegm and turbidity will be generated,phlegm move with the Qi,can be up to the Dianding acupiont,down to the Yongquan acupiont,the limbs and bones,the viscera are affected.The movements of phlegm that follow the rise and fall of Qi,all around the body inside and outside,also into viscera.So phlegm is pathological factors about all disease including difficult miscellaneous diseases.Therefore,it is also said that "the spleen is the source of phlegm production"and " internal impairment of the spleen and stomach causes various diseases[8]."In modern medical research,imbalanced intestinal microbiota is strongly associated with metabolic diseases,intestinal disorders,behavioral and cognitive disorders,cancer and autoimmune diseases [8].It has been shown that high-fat diet can lead to increased permeability of the intestinal mucosa by altering the structure of the intestinal microbiota,mediating a chronic and long-term inflammatory response in the host,resulting in symptoms such as insulin resistance,dyslipidemia and reduced levels of short-chain fatty acids and abnormal metabolism of sugars and lipids.That is leading to the development of obesity ultimately [9].By sequencing the 16SrDNA genes in the feces of mice with spleen deficiency and diarrhea type irritable bowel syndrome,Ding-Hengyue et al [10] found that the beneficial bacteria in the intestine of spleen-deficient IBS-D mice were significantly decreased compared with healthy mice,indicating a correlation between spleen deficiency and intestinal microbiota dysbiosis.Although the intestinal microbiota is settled in the intestine,its imbalance can affect all organs of the body.In Traditional Chinese medicine,it means "the spleen is in the middle of the earth and nourishes all organs".It is similar to the function of Chinese medicine,which regards the spleen as the foundation of the latter and affects the healthy.

III.THE DUAL RELATIONSHIP BETWEEN THE"HEART-SPLEEN AXIS" AND DEPRESSION

In Chinese medicine,deficiency of the spleen leading to deficiency of heart-Qi(function of heart)is the pathological basis of depression;deficiency of the spleen leads to deficiency of heart-Qi,and child-organ disorder involving its motherorgan.Based on this,the human body is stressed by strong mental stimulation.The emotions emanate from the heart,so excessive thinking will lead to the inability to regulate the heart’s Qi,and the heart’s function as the master of the mind will not function normally,and the Qi in the mahjong will not be able to enter and exit normally,leading to the onset of depression,and because excessive thinking hurts the spleen,the generation of qi and blood will be impaired,eventually leading to the loss of nourishment of the heart and mind.Han Jingjie [11] proposed the "theory of spleen-sense regulation",which holds that the qi and blood produced by the spleen and stomach in the middle-jiao are the material basis for the functional activities of emotions and that the circulation of Qi is a prerequisite for the normal expression of emotions.A Jin Dynasty’s doctor Li Dongyuan,proposed in his treatise on the spleen and stomach that "the spleen unifies the four organs"."Thinking" is the basis of other emotional activities,and other emotional changes need to be generated by "thinking".If dysfunction of spleen in transport,phlegm is produced and then in turn affects the normal function of the spleen and stomach,resulting in the inability of the spleen to generate qi and blood to nourish the heart,which is the center of emotion,thus causing emotional disorders.It is said that the heart is the only one that is responsible for all emotion.This means that the heart is responsible for the mental activities of the body,including the spirit,emotions,consciousness and thinking,as well as for the life activities of the whole body.Dysfunction of spleen in transport and heart in the mind can lead to injury to both heart and spleen,which can lead to various depressive symptoms such as depressed mood,lack of pleasure,loss of interest,depression,loss of appetite and forgetfulness,etc.Therefore,the development of depression is the result of the stimulation of the all emotions,which first injury to the heart and cannot regulate the spleen.Then,it is a heart-spleen-heart process in which the spleen does not nourish the heart.

First of all,in modern medicine,the development of depression is due to a state of stress caused by long-term mental stimulation.When the stressor acts excessively on the organism,it can activate the HPA axis.This further cause abnormal release of hormones such as adrenocorticotropic hormone,which leads to the down-regulation of the expression level of glucocorticoid receptor protein and reduces the negative feedback regulation of the HPA axis,making the axis continuously hyperactive and thus leading to depression and other psychiatric disorders [13].At the same time,prolonged exposure to stressors causes the adrenal medulla to secrete a large amount of catecholamine,which damages the integrityof the barrier against pathogenic bacteria made up of mucin and antimicrobial peptides.Negative emotions also cause a redistribution of immune cells,resulting in a decrease in immunity and a severe inflammatory response,leading to a disturbance of the intestinal microbiota and an increase in harmful bacteria [14-15].On this basis,intestinal microbiota dysbiosis and intestinal mucosal injury are more likely to lead to bacterial endotoxin translocation,produce large amounts of LPS,reduce blood-brain barrier tight junction proteins[16].Dysbiosis of intestinal gut microbiota causes an overactive immune response,and LPS also leads to activation of TAK1 through activation of IRAK4 followed by activation of TRAF6,which ultimately phosphorylates IKK,and transcriptionfactor NFκB.This further leads to expression of inflammatory factor genes such as IL-1,TNF-α,affecting the enteric nervous system,which in turn leads to brain dysfunction and triggers changes in the body’s mood and behavior.In addition,TAK1 activates MKK and thus phosphorylates P38/MAPK and JNK,and the phosphorylated P38/MAPK and JNK,in turn,phosphorylate AP-1,ultimately produces a large amount of inflammatory factors[17-19],At the same time,the increase in inflammatory factors activates indoleamine 2,3-dioxygenase1 (IDO1),which in turn turns tryptophan into kynurenic acid(KYNA)via the kynurenine pathway,which in turn depletes tryptophan (TRP) so that tryptophan cannot be produced via the serotonin pathway.This in turn depletes TRP so that TR P cannot produce 5-HT via the serotonin pathway,thereby reducing 5-HT levels [20].

Besides,changes in the intestinal microbiota are transmitted to the brain through the vagus nerve,and the brain issues instructions to change the concentration of BDNF,which is widely distributed in the central nervous system and plays an important role in maintaining the survival,differentiation,growth and development of brain neurons.The BDNF mRNA or the protein expression will be inhibited under stressful conditions,and the decrease will cause brain neurons to atrophy or apoptosis,which will lead to related anxiety and depression symptoms,and then lead to depression[21].

The "brain-gut axis" is a bidirectional regulatory pathway linking the cognitive and emotional centers to the entericneurological,neuroendocrine and immune systems.The"brain-gut axis" is a bidirectional regulatory pathway linking the cognitive and emotional centers with the enteric-neural system,neuroendocrine and immune systems.There-fore,under stressful conditions,the brain is stimulated to influence the structure of the intestinal microbiota through the downstream pathway of the "brain-gut axis",and the imbalance or translocation of the intestinal microbiota,which secretes LPS and systemic inflammatory factors,leads to abnormal expression of monoamines and neurotransmitters and brain-derived trophic factors through the upstream pathway of the "brain-gut axis".The expression of neurotransmitters and brain-derived trophic factors is abnormal,leading to depressive symptoms.Therefore,emotional stimulation and stress can affect the microecology of intestinal microbiota,leading to dysbiosis or translocation of intestinal microbiota,which can then affect the host’s emotion,cognition and behavior.In traditional Chinese medicine,the heart is the master of the emotions and thoughts,and it regulates the functional activities of the internal organs and maintains the balance and coordination between the internal organs to adapt to the needs of the internal and external environment and produce various emotional changes.The clinical manifestations of intestinal microbiota disorders are similar to those of spleen deficiency in traditional Chinese medicine.Most patients with spleen deficiency have intestinal microbiota disorders,so intestinal microbiota disorders or translocations can be regarded as spleen deficiency and dysfunction.The dysfunction of spleen transportation and transformation of refined substances is disturbed,and the resulting depression is a manifestation of heart and mind lack of nutrition,which coincides with the development of the heart-spleen-heart process,and also provides theoretical support for the "heart-spleen axis" in Chinese medicine.

IV.THE TREATMENT OF DEPRESSION WITH KAIXIN POWDER-HARMONIZING THE SPLEEN AND AWAKE CONSCIOUSNESS

A.Invigorating the spleen and eliminating dampness -regulates the imbalance of intestinal microbiota

Kaixin powder,originally fromEssential Recipes for Emergent Use Worth A Thousand Gold– Volume 14 ",written by Sun Simiao,consists of four classical medicines:Ginseng,Poria,Yuan Zhi and Acorus calamus,which was used to treat amnesia.Depression are always caused by exogenous evil or emotions injures the spleen,so deficiency of spleen leading to malnutrition of heart minds.At the same time,deficiency of spleen in transportation leads to generate phlegm and make heart spirit confused by it.Renshen(Panax ginseng) invigorates the spleen and nourishes the heart;Fuling(Poria cocos) invig-orating the spleen,calming the heart and invigorating heart Qi.At the same time,Poria eliminating dampness,diuresis and phlegm which confuse heart spirit.In modern biomedical research,Sun,et al.,was isolated Water insoluble polysaccha-ride (WIP) from the nucleus of Fuling(Poria cocos),finding that it could significantly increase the number of butyrate-producing intestinal microbiota,raise intestinal butyrate levels.This in turn improved intestinal mucosal integrity,activated the intestinal PPAR-γ pathway[22].Xu Yan et al.,discovered that Fuling(Poria cocos) micropower improved the dysbiosis of intestinal microbiota of depressed rats caused by chronic unpredictable mild stress (CUMS),mainly by decreasing the levels of Phylum Bacteroidetes and Phylum Aspergillus while restoring the levels of Phylum Thick-walled and Lactobacillus spp [23] .Dong et al.,found that the intestinal microbiota metabolites of Renshen(Panax ginseng).Ginsenoside Rb1,depended on the composition of the intestinal microbiota,such as Rumenococci,Bacteroides and Bifidobacteria,and that Rb1 was metabolized by the intestinal microbiota into bioactive compounds which could promote the growth of probiotic bacteria [24].Therefore,Ginseng and Poria have been shown restore the normal structure of the intestinal microbiota by increasing probiotics,thus preventing the decrease in serum 5-HT and the increase in pro-inflammatory factors caused by the increase in LPS due to intestinal microbiota translocation,blocking the process of depression.

B.Awaking consciousness and inducing resuscitation -regulating the central neurotransmitters

Depression has symptoms such as depression,depressed mood,lack of pleasure,diminished interest and forgetfulness due to confuse heart spirit by phlegm and dampness as well as deficiency of heart Qi and blood,malnutrition of heart minds,and the heart can’t govern the ethereal soul and corporeal soul.Ginseng can awake consciousness and enhance intelligence,Yuan Zhi (Polygala tenuifolia)can calm the heart mind and Changpu(Acorus calamus) can eliminate phlegm for inducing resuscitation,through nourishing the heart Qi to calm the ethereal soul and corporeal soul.

Fig.1.The interaction between depression and bidirectional pathway of"brain-gut axis"

In modern studies,Ginseng Rb1 exhibited antidepressant effects in a chronic unpredictable mild stress model,mainly by upregulating monoamine neurotransmitters,modulating BDNF and its downstream protein TrkB,affecting levels of proadrenocorticotropic hormone as well as cortisol.Increased expression of both pro-inflammatory and anti-inflammatory factors was also detected in the cerebral cortex and hippocampus to enhance the anti-inflammatory response in the brain [26].In addition,Renshenzaogan (Ginsenoside Re) can also inhibit inflammation such as systemic inflammation by regulating NF-κB signaling pathway [27].Ji N.D.et al studied that high dose of Acorus calamus alcoholic sediment enhanced 5-HTPinduced heads tossing behavior in mice,suggesting that through blocking the reuptake of central 5-HT and other monoamine transmitters,the level of 5-HT in the central nervous system increased,thus exerting an antidepressant effect [28].The main active con-stituents of Changpu(Acorus calamus) are the fine ether com-ponents.Dong H et al constructed a chronic unpredictable mild stress (CUMS)depression rat model,finding that β-cosyl ether promoted hippocampal neuronal protection and increased the expression of brain-derived neurotrophic factor BDNF [29].Zhu Cai-xia demonstrated that β-caryophyllene improved the performance of depressive behavior disorder in mice and increased the levels of 5-HT,5-HIAA and DA in the cortex,midbrain,striatum as well as serum of mice in a depression model [30].Liu Ping,et al,found significant antidepressant effects of 3,6’-diacetyldeuconoyl sucrose in Jianzhu(Fargesia spathacea Franch),which was associated with enhancement of 5-HT and noradrenergic nerve function [31].Renshen (Panax ginseng),Changpu(Acorus calamus) and Yuan Zhi (Polygala tenuifolia)has been proved to affect the expression of pro-inflammatory factors,anti-inflammatory factors,monoamine neurotransmitters and brain-derived neurotrophic factors.

V.CONCLUSION

Depression in Chinese medicine occurs and develops in the order of heart-spleen-heart,i.e.,the "heart-spleen axis",and its traditional Chinese medicine pathological basis of depression is deficiency of spleen leads to lack of heart-Qi,on the basis of which the emotions stimulate the heart first,and the heart then injures the spleen,and then the spleen does not nourish the heart,i.e.,the heart-spleen-heart.If the spleen functions normally,the Ying organs will function normally.Invigorating the spleen is a prerequisite for treating depression.Invigorating the spleen is the prerequisite for treating depression.On this basis,it is supplemented by calming the heart,nourishing the mind,awakening the consciousness,inducing resuscitation and enhancing intelligence,etc.Therefore,the treatment for depression is to invigorate the spleen and nourish the mind,and the treatment is to invigorate the spleen,eliminate dampness,awaking consciousness and inducing resuscitation.The effect of Kaixin powder is to invigorate the spleen,eliminate dampness,and awaken consciousness and inducing resuscitation.It is to treat depression by regulating intestinal microbiota,neurotransmitters and neurotrophic factors.The"brain-gut axis" in modern biomedicine is a dual pathway for the treatment of depression,through which Kaixin powder regulate the intestinal microbiota and thus treat depression,with a view to providing a new approach to the clinical management of depression.

Competing interests:

The authors declare no conflicts of interest.

Abbreviations:

HPA,axis;5-HT,5-hydroxytryptamine;LPS,lipopollysaccharides;BDNF,brain-derived factor;TRP,tryptophan.

Citation:

Shi HM,Li X,Wu JL,Zhang D,Zhao GP.The treatment effects of Kaixin Powder on depression through heart-spleen axis.Drug Comb Ther.2021;3(3):14.doi:10.53388/DCT202 1080504.

Executive editor:Na Liu.

Submitted:19 April 2020,Accepted:17 June 2021,On-line:26 July 2021.

© 2021 By Authors.Published by TMR Publishing Group Limited.This is an open access article under the CC-BY license(http://creativecommons.org/licenses/BY/4.0/).