Discussion on the treatment of polycystic ovary syndrome from “spleen” based on intestinal flora

Qian Su, Xinchun Xiao＊, Hongli Zhu, Xiaona Gao, Chen Zheng

1 Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China

2 First Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province,China

Abstract

Key words: polycystic ovary syndrome; PCOS; intestinal flora imbalance; dysfunction of spleen in transportation

Introduction

The incidence of polycystic ovary syndrome (PCOS) has increased year by year[1], and the incidence rate in China is about 5.6%[2].The pathogenesis of PCOS is closely related to genetic factors, insulin resistance, hyperandrogenism,mental factors and lifestyle.Its clinical manifestations are highly heterogeneous.Early manifestations include menstrual disorders, amenorrhea, infertility, obesity,hemorrhoids and hirsutism.Its long-term complications include depression, diabetes, hypertension, cardiovascular disease and endometrial cancer, which seriously affect the physical and mental health of women of childbearing age.In recent years, many studies have found that the intestinal flora is closely related to PCOS.The intestinal flora is the largest microbiota in the human body, and its gene number is more than 100 times that of human genes[3].It can enhance immune response, promote absorption, inhibit tumors, reduce infection, and inhibit the growth of harmful microorganisms.Under normal circumstances,a dynamic balance maintains between intestinal flora,between intestinal flora and the host.When the external environment changes or the internal balance (such as dietary factors, gastrointestinal immune dysfunction)[4]is destroyed, the intestine flora type, quantity and proportion may change, resulting in intestinal flora imbalance[5],which changes the metabolism of the intestinal flora,immune response and intestinal structure and other normal metabolic activities of the human body, so that the endotoxin in the intestine enters systemic circulation,invades islet cells and results in insulin resistance,accordingly leads to the development of PCOS.Studies have shown that intestinal flora imbalance is the material basis of “ dysfunction of spleen in transportation”[6].In this study, we discusses the treatment of PCOS with“spleen” as the center, based on the mechanism of spleen governing transportation.

Correlation between Intestinal Flora and PCOS

The major pathophysiology of the pathogenesis of PCOS is insulin resistance, and changes in the intestinal flora are important factors leading to insulin resistance.An animal experiment showed that[7], intestinal flora imbalance can cause insulin resistance and ovarian polycystic changes in normal mice, revealing that the intestinal flora metabolite bile acid enters the systemic circulation and regulates the IL-22 secretion of intestinal innate immune ILC3 cells.Some scholars believe that the occurrence of PCOS is related to the increase of intestinal mucosal barrier permeability.Tremellen et al[8]pointed out that intestinal flora imbalance can cause intestinal inflammation, which destroys intestinal mucosa and increases its permeability,and then lipopolysaccharide produced by the intestinal bacteria group accelerates into the systemic circulation,activating the body’s immune response and chronic inflammation.Studies have shown that[9], the signal pathway after insulin receptors and calcium subclinical inflammatory signaling have a cross-effect, so intestinal flora alteration-mediated insulin resistance plays very important role on the pathogenesis of PCOS.A study by Lindheim[10]showed that chronic inflammation, insulin resistance, hyperandrogenism, fat accumulation are closely related to endotoxemia caused by gastrointestinal leakage in PCOS patients.Chronic inflammation causes the decline of insulin receptor function, increases insulin levels, stimulates the ovaries to produce more androgen,which accordingly affects the normal development of follicles, leading to rare ovulation and infertility[11].At the same time, various long-term complications of PCOS are associated with intestinal flora imbalance, and the formation of vascular wall plaques in cardiovascular and cerebrovascular diseases may be related to the upregulation of inflammatory factors after intestinal flora imbalance[12]; The imbalance of the flora leads to the excessive production of trimethylamine oxide, which is the material basis for the formation of hypertension and coronary heart disease[13]; the depressive symptoms may be caused by the long-term action on the adrenalpituitary-gonadal axis from inflammatory factors produced by the intestinal flora imbalance[14].

Relationship between Physiological Functions of Spleen and Intestinal Flora

Traditional Chinese medicine (TCM) theory emphasizes the concept of holism, and the “spleen” plays an extremely important role in the theory of TCM visceral state.“Lingfu Benshen” points out that “spleen deficiency means the weakness of limbs and disturbance of five organs.” Zhang notes that “spleen belongs to soil, which is the foundation of all things, so it governs water transportation and body fluid to nourish the remaining organs: liver, heart, lung and kidney.” The spleen is the acquired basis, the biochemical source of qi and blood, and the rest organs could not play its normal physiological function without continuous enrichment of the acquired spleen.This physiological function of the spleen may be related to the huge gene pool of intestinal flora[15].In the past, it has been recognized that intestinal flora is closely related to the “spleen” in TCM viscera theory, such as abdominal distention, poor digestive and absorption function of gastrointestinal tract,diarrhea and other intestinal and gastric dysfunction may occur after intestinal flora disorder, which is similar to the“spleen deficiency syndrome”[11].Li pointed out that “for the emergence of various diseases, tonifying spleen is the premise of strengthening health energy.” This evidence emphasizes the importance of strengthening the qi of spleen and stomach to resist exogenous pathogens, which may be related to regulating gastrointestinal flora and enhancing the immunity of the body.In the theory of TCM visceral state, “the spleen is the master of ascension”,it governs ascending clear and transports cereal essence.When the physiological function of the spleen declines, the spleen loses its health and fails to transform cereal essence and nutrient to limbs, bones, tendons, muscles and furs.Therefore the body can not play its normal physiological function, and causes dizziness, tiredness and fatigue; clear yang fails to ascend, turbid yin fails to descend, leading to abdominal distension and loose stool.This evidence coincides with the findings of modern medical research for the digestion, absorption and excretion dysfunction caused by intestinal flora disorders.Spleen deficiency can’t transport water and fluids, and accumulates into phlegm.Spleen deficiency involves other organs for a long time, which eventually leads to phlegm-dampness blockade in Chong-Ren and formation of bursa, like “the nest of bees in the honeycomb, lotus seeds embedded in the seedpod.” This should be the earliest document to record the polycystic changes of ovary, and intestinal flora disorder may be the pathological basis of spleen deficiency syndrome[16], the “endotoxin” produced by intestinal flora is equivalent to the “phlegm-dampness” formed by spleen deficiency.Spleen is the source of phlegm.Invigorating spleen can block the production of phlegm-dampness and prevent the endotoxin produced by intestinal flora disorder from invasion into the systemic circulation,further destroy insulin receptors, and ultimately block the formation of PCOS.

Treating PCOS from the “Spleen”

Mechanism

The spleen locates in the center and irrigates the surroundings, and the normal function of all the organs can not be separated from the continuous nutrition of the spleen.PCOS has a high degree of heterogeneity and various clinical manifestations, involving all organs of the whole body, so the spleeb can be considered as the central part in treatment of PCOS.Spleen is the source of phlegm, phlegm-dampness is closely associated with various complications of PCOS in TCM theory.Therefore,the principle of invigorating the spleen to eliminate phlegm and remove dampness is very important for PCOS treatment.TCM theory holds that “obese people have more phlegm and dampness”, and Wan points out in “Women’s Secret Section”: “Only when she is stout and full of fat, the lipid and phlegm congestion obstruct the opening of energy door, phlegm obstruction affects and delays the menstruation, even once for several months,leading to the turbidity, amenorrhea and infertility”.In the“Danxi Xinfa·Volume Five·Offspring” in Yuan Dynasty,Zhu proposed that “If you are a fat woman with stout body and irregular menstruation, indulged in alcohol, you are prone to infertility”.These famous doctors mention that spleen deficiency is prone to generate phlegm, which leads to obesity, irregular menstruation, amenorrhea even infertility.At the same time, Wang et al[17]have found that phlegm-dampness constitution is associated with the obese, susceptibility to diabetes, stroke, chest pain and infertility.In the “Shengji General Record·Volume 58·Diabetes”, “the diabetes is caused by fat food, excessive fat induces prediabetes (Pidan, heat syndrome of the spleen), and accordingly develops into the diabetes.”Immoderate diet and fatty food may cause the damage to the spleen and stomach, the accumulation of heat in the spleen and stomach may lead to diabetes, that is diabetes mellitus in modern medicine, spleen deficiency is the key pathogenesis of diabetes mellitus[18].Hypertension belongs to the category of “vertigo” in TCM theory, Zhu pointed out that “no phlegm, no vertigo”.In the “Miscellaneous Diseases Brief Summary”, as for people with qi deficiency and stout body, dampness and phlegm stagnate in the upper part, while yin heat originates from the lower part,so phlegm carries heat to invade the head, and energy qi fails to defeat the heat, so people may suddenly feel dizzy or get carsick/seasick, even faint without consciousness.Deng,a famous TCM doctor, creatively put forward the theory of“heart-spleen correlation” and “phlegm-stasis correlation” in the pathogenesis of coronary heart disease[19], which clarifies the relationship of coronary heart disease with heart and spleen.Therefore, strengthening and invigorating the spleen and stomach may eliminate the source of generating phlegm and dampness, obesity, irregular menstruation,infertility, hypertension, diabetes, coronary heart disease,thus achieving the goal of treating PCOS.

Treatment

Insulin resistance caused by intestinal flora imbalance is an important basis for the pathogenesis of PCOS.Studies have shown that Sijunzi Decoction of invigorating spleen and benefiting qi can increase the expression of intestinal mucosal protein and protect the intestinal mucosa[20].At the same time, it can inhibit the growth of pathogenic bacteria in the intestinal tract of rats and increase the level of predominant bacteria such as lactobacillus, along with the prolongation of drug administration[21].It also regulates insulin and glucagon levels in a rat model of insulin resistant type 2 diabetes[22].Shenling Baizhu Powder is a representative formula of invigorating spleen,benefiting qi and eliminating humidity, among them Ginseng and Chinese yam can invigorate spleen and benefit qi, they are rich in polysaccharides, which has good effects on lowering blood glucose, lowering blood lipid and enhancing immunity[23].Ginseng polysaccharide can protect intestinal mucosa and increase the diversity of intestinal flora[24].Yang et al[25]observed the changes in intestinal flora of spleen-deficiency rats after treatment of Shenling Baizhu Powder, results showed that the number of bacteria such as Enterobacter and Enterococcus was decreased significantly, while the number of beneficial bacteria such as lactobacilli, bifidobacteria, and bacilli was increased, which may reduce the number of harmful bacteria entering the systemic circulation and relieve the resistance to insulin.Berberine is an effective monomer component of Rhizoma Coptidis.It can be active in spleen meridian, strengthen spleen and eliminate dampness.Animal studies have shown that berberine can significantly increase the number of bifidobacteria in the intestine and reduce the number of Escherichia coli[26].At the same time, it can increase the expression of connexins in intestinal epithelial cells to repair the intestinal mucosa[27],prevent pathogens from entering the systemic circulation,thereby increasing the sensitivity of the ovary to insulin and improving the ovarian function of PCOS[28].

In summary, some active ingredients of spleeninvigorating Chinese medicine can promote the growth of beneficial bacteria in the intestine, thereby regulating the function of intestinal flora, repairing the intestinal mucosa, preventing the endotoxin produced by intestinal pathogens from entering the systemic circulation,preventing the inflammatory reaction-induced a series of reactions such as insulin resistance, restoring ovarian function and finally achieve the purpose of treating PCOS.

Evolution of TCM Syndromes of PCOS Centered on “Spleen”

The normal human intestinal flora is in a stable state.When affected by the internal and external environment,the structure of the intestinal flora is gradually changing,like the syndrome emphasized by Chinese medicine,reflecting the pathological features of the disease in different stage of development.In the process of disease evolution, with the changes in the structure of a certain flora in the intestine at a certain stage, intestinal flora imbalance in patients with PCOS gradually forms different TCM syndromes[29].Some scholars have pointed out that[30]TCM syndrome varies in different structure of intestinal flora in patients with ulcerative colitis.In the analysis of intestinal flora in elderly patients, the structure of the flora in the feces of spleen qi deficiency and spleen and kidney yang deficiency patients was significantly different[31].Studies have also shown that Enterobacter,Enterococcus and other aerobic bacteria increased significantly in spleen-stomach damp-heat type patients,yeast increased in spleen deficiency syndrome patients,anaerobic bacteria in spleen deficiency syndrome patients was more obviously decreased compared spleen-stomach damp-heat type patients[32].

An et al[33]have summarized the law of drug use in the TCM treatment of dysbacteriosis during 2005-2016.Results showed that the treatment principle of intestinal flora imbalance is mainly to benefit qi, invigorate spleen,clear damp and promote diuresis, the syndromes of dysbacteriosis predicted by cluster analysis include spleen and kidney yang deficiency, liver station and spleen involvement, spleen deficiency and dampness, which is similar to the common syndrome of PCOS: (1) spleen and kidney deficiency syndrome: kidney is congenital origin, spleen is acquired origin.Under the influence of internal and external environment, the intestinal flora is deteriorating, and the deficient spleen is not able to provide nutrients, thus forming a syndrome of spleen and kidney deficiency.The disease that occurs before the baby is born is mostly attributed to the kidney deficiency.Studies have shown that prophylactic use of antibiotics during perinatal period increases the intestinal Enterobacteria in infants[34].Prophylactic use of antibiotics during birth delivery also significantly reduces the number of bifidobacteria in neonatal intestinal tract[35].(2) Spleen deficiency liver stagnation syndrome: manifested by unhealthy spleen and liver dysfunction, liver stagnation involves spleen and further develops emotional depression,bloating, loose stools.Studies have shown that depression and anxiety were related with intestinal flora imbalance[36],the application of Bifidobacterium triple viable capsules can effectively improve the gastrointestinal function of patients with anxiety-induced irritable bowel syndrome,which is conducive to emotional recovery[37].(3) Spleen deficiency and dampness syndrome: spleen deficiency produces phlegm, phlegm and dampness are abundant,body becomes fat and stout, uterine vessel is obstructed,Chong Ren is stagnated, causing obesity, irregular menstruation and infertility.Some studies[38]found that the metabolic syndrome based on spleen deficiency and dampness syndrome may be related to the imbalance of intestinal flora, suggesting that invigorating spleen and removing humidity can treat various metabolic diseases by improving intestinal flora imbalance.(4) Qi stagnation and blood stasis syndrome: spleen is the source of qi and blood biochemistry, qi deficiency can not promote blood circulation and cause blood stasis, coupled with low emotion, liver depression and qi stagnation in the majority of modern population, it leads to qi stagnation and blood stasis, and gradually involves the kidney, ultimately the liver, spleen and kidney are affected.However, further study is required to explore whether the different syndrome types of PCOS also have a corresponding relationship with different intestinal flora, and which type of syndrome corresponds to which colony.

Shortcoming and Outlook

At present, TCM treatment of PCOS from the spleencentered regulation of intestinal flora is rarely investigated.Due to high heterogeneity of PCOS, it is difficult to judge the curative effect of spleen-invigorating drugs in PCOS patients from certain clinical symptom, only clinical complications and accompanying symptoms are available for observations, in order to comprehensively understand PCOS and provide a new direction for future research on PCOS drugs.