Thinking on the Treatment of Lung Cancer by Regulating Lung-Intestinal Axis Microecology by Traditional Chinese Medicine

HUANG Shi-yun (黃詩云), XU Yun (許 云)

1. Chengdu University of TCM, Chengdu 611139, China

2. Oncology Department, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China

ABSTRACT The intestinal microecological disorder is closely related to the occurrence and development of lung cancer and the treatment response. This paper starts with the relationship between the lungintestinal axis, to discuss the possibility of TCM regulating the target of intestinal microecological treatment of lung cancer, so as to provide new research ideas for TCM treatment of lung cancer.

KEYWORDS lung-intestinal axis; traditional Chinese medicine; intestinal microecology; lung cancer

The intestine is a nutrient-rich environment.There are up to 1014 microorganisms in the intestine of adults, the vast majority in the colon[1], which is 10 times the size of human somatic cells, encoding 3.3 million genes, and about 150 times the number of human genes[2]. Intestine has important physiological functions, including material metabolism, promoting the development of the immune system and so on. Meanwhile, it is affected by host genetics, diet and other factors[3]. At present, the relationship and mechanism of intestinal micro-ecology and diseases have increasingly attracted the attention of many international research teams, such as "intestinalliver axis", "brain-intestinal axis", "intestinal-braincutaneous axis" and other intestinal research on the complex and interconnected axis between the organs is also underway.

Most patients with tumors have intestinal flora disturbances. The intestinal flora is involved in the development and treatment of various tumors[4], and its effects on tumors are mainly caused by several ways: Microorganisms directly contact the tumors to promote tumor development; By regulating the body's immune system, it affects tumor development; By regulating the body's metabolism,it indirectly affects the fate of tumor cells; Specific bacteria groups participate in affecting the tumor chemotherapy effects and immunotherapy effects,preventing effective tumor treatment[5-6].

With the progress of research, it has been discovered that the role of intestinal flora is not limited to digestive system tumors, but also has an important impact on the occurrence, development and treatment of lung cancer. In recent years, some scholars have proposed the concept of "lung-gut axis". The proposal of this axis has opened a new chapter for a series of research on intestinal flora and also brought about related research on lung and bowel diseases new ideas.

RELATIONSHIP BETWEEN LUNGINTESTINE AXIS AND LUNG CANCER

Embryological Links of the Lung and Bowel

The initial site of lung development is located on the ventral side of the embryonic endoderm.In the 3rdweek after pregnancy, the foregut differentiates into the peripheral mesenchyme, and then the diverticulum-like structure that bulges on the ventral side of the endoderm gradually forms a tracheal embryo. It gradually branches into 2 germs:the foregut of the gut develops into lung organs,the gut endoderm differentiates into respiratory epithelium and glands; the epidermis of the digestive tract (except oral and anal) also develops from endoderm. Therefore, the source of embryonic structure of the lung and intestine is the same[7].Some scholars have studied the expression patterns of lung and intestine genes during the embryonic period and found that there were different degrees of similarity in the expression of lung and intestine genes in the 3 stages of embryonic development.The expression of similar genes in the early stages is mainly reflected in the development of epithelial cells. The upper and middle stages are mainly in the function of the 2[8]. The same structural source is bound to determine the close relationship between function and pathology. Therefore, the homology of the source of respiration and intestinal tissues provides the basis for the pathological structure of the relationship between lung and intestinal micro ecological imbalances.

Lung Intestinal Microbiological Connection

In the study of the lung-intestinal axis, the main concern at this stage is the microbial impact between the 2. This stems from the simple fact that the microorganisms ingested by both are reachable,that is, the microflora of the gastrointestinal tract can enter the lungs through breathing, which has a more "deep" effects[9]. Studies show that with the fecal microbiota transplantation, lung function and pathogen clearance can be improved[10];

Some lung diseases can cause patients'intestinal flora diversity and structural changes[11],GUO Na-na et al.[12]through the preparation of mice lung cancer model, verified the intestinal-lung mucosal immunology theory, and confirmed that lung cancer can cause intestinal mucosal damage and mechanism. That is the body that has an oxidativeantioxidant system disorder after hypoxia, thereby aggravating intestinal mucosal function damage etc.[13]; Based on a series of experimental studies on intestinal flora and pulmonary inflammation, it is concluded that the symbiotic microbiota in the intestine is important for the lung to resist bacterial invasion, and the pulmonary inflammation signal directly changes the structure of the intestinal bacterial community, further exacerbating lung inflammation.

Therefore, the intestinal-lung axis is bidirectional, and the intestinal flora can cause damage to the lungs and may also be changed by the lung flora. In the microbial pathogenic relationship between the intestinal axis and the lung[14], scholars pointed that the use of intestinal microbiota to treat lung diseases has great potential:the bacterial components and metabolites of the intestine and lungs have the ability to regulate local and systemic immunity, of which specific groups can affect the pathogenesis of respiratory diseases, such as asthma, chronic obstructive pulmonary disease and respiratory infections.

Intestinal Micro Ecology and Lung Cancer

Current research shows that lung cancer can cause changes in the intestinal flora. Meanwhile,changes in the lung flora are consistent with changes in the intestinal flora[15]. In a clinical and experimental study on intestinal microecology and lung cancer[16], there was an intestinal microecological disorder in elderly patients with lung cancer, mostly manifested by reduced butyric acid bacteria, increased enterococci, and intestinal flora colonization resistance decreases.

After the patients received chemotherapy and targeted therapy, the probiotics and potential pathogens were reduced, that is, the probiotic and pathogenic bacteria (B/E) values decreased,indicating that the colonic resistance to intestinal flora further decreased after chemotherapy and targeted therapy, which aggravates the intestinal flora imbalance. Microbial-derived butyrate can induce T cells to transform into Treg cells. The anti-inflammatory function of Treg cells can slow down inflammation-driven tumor formation. In addition, Treg cells can also infiltrate into the tumor microenvironment, exert immunosuppressive effects, and weaken the body's anti-tumor response[17].

The use of broad-spectrum antibiotics is related to the profound changes in the intestinal microbiota.The use of antibiotics etc. will lead to a decline in the response of lung cancer to chemotherapy and immunotherapy. The study further found that[16]: the intestinal symbiotic flora of mice treated with cisplatin combined with ABX (vancomycin,ampicillin, and neomycin) was destroyed. Tumors were larger than mice treated with cisplatin alone,and survival significantly reduced. In contrast, mice treated with cisplatin combined with lactobacillus had smaller tumors and higher survival rates.Further gene expression studies showed that the levels of IFN-γ (interferon γ), GZMB (granzyme B), and PRF1 in mouse CD8 + T cells were reduced in ABX-treated mice; But those levels were up regulated in mice, showing enhanced antitumor response. This shows that the negative impact of the destruction of the commensal flora in the treatment of lung cancer cannot be underestimated.By supplementing probiotics in an appropriate amount, the intestinal microecology destroyed by chemotherapy can be restored to achieve better efficacy. A recent noteworthy study has shown that patients with metastatic renal cell carcinoma or non-small cell lung cancer have significantly worse survival rates if they receive antibiotics before or immediately after starting treatment[18]. A total of 3 papers recently published in Science further demonstrate that the curative effects of intestinal microbiota composition can modulate anti-PD-1 and anti-PD-L1 immunotherapy in patients with epithelial tumors (including non-small cell lung cancer, renal cell carcinoma, and melanoma)[19-21].In the 3 studies, patients who received anti-PD-1 and PD-L1 treatment were divided into responders and non-responders by collecting their stools before treatment, and then transferring the stools to sterile mice. And anti-PD-1 mAbs treatment was performed. These mice reproduced the patient's response to anti-PD-1 mAbs treatment. In these mice models, mice receiving responder stool had enhanced antitumor immunity, compared to mice receiving non-responder stool.

In the interaction between the lung and intestinal flora, the specific performance of this twoway influence mechanism in lung cancer has not been experimentally studied with large data, but according to the close relationship between the 2 inflammatory reactions, and existing experimental studies show that lung cancer can cause intestinal mucosal damage, and the destruction of commensal flora, which can have a negligible negative effects on lung cancer treatment. The intestinal flora structure of lung cancer patients is significantly different from healthy people, and the number of bifidobacteria and lactobacillus is significantly reduced, etc.

It is proposed that the intestinal flora affects the occurrence and development of lung cancer by affecting the body's immunity and regulating the metabolism of the body. It can be further speculated that the effects of the intestinal flora on lung cancer are equally close with the lung and intestinal axis.Regarding how lung diseases change the intestinal flora, most studies currently believe that it may be related to changes in the body's local and systemic immune status, but the specific mechanism is still unclear and needs further research.

TRADITIONAL CHINESE MEDICINE'S CONCEPT ON THE RELATIONSHIP BETWEEN LUNG CANCER AND THE INTESTINE

In TCM, the relationship between the lung and the intestine is mainly based on 2 aspects: the relationship between the lung and the intestine and the relationship between the lung and the spleen.

Lung and Large Intestine

It is said in The Spiritual Pivot of Inner Canon of Yellow Emperor that "the lung is paired with the large intestine. The large intestine is the fu organ of conduction. It is the first to propose the exterior and interior relationship between lung and intestine and,"The pulse of the Shou Tai Yang starts from the middle jiao in the gastral cavity, connected with the large intestine downward, coming back along the upper mouth of the stomach, passing through the diaphragm, and entering the lung; The Da Chang channel starts in the veins of Yangming channel,passes through lung and diaphragm, and entering the large intestine." Those elaborates the pulse affiliated relationship from channels. The exterior and interior relationship between the lungs and the large intestine is physiologically coordinated with each other. That is, the normal reduction of lung qi is helpful to the conduction of the large intestine.Pathologically, they affect each other. If the lung qi lowered, the body fluid cannot be delivered, the lung qi is weak, and the push is weak. It can be seen that constipation, the stasis of fu qi, which may influence lung qi lowering and lead to cough and chest stasis[22].

Mother-child Relationship Between Spleen and Lung

According to the theory of traditional Chinese medicine, the spleen in the 5 phases belongs to the soil, the lungs in the 5 phases belong to the earth.The soil can produce medal. Thus the relationship between spleen and lung is mother and son. In Treatise on the Spleen and Stomach, it is said that: "Diet enters the stomach, but the essential qi is lost to the spleen and returned to the lung". The lung governs the qi, and is in charge of breathing,and absorbing fresh air; The spleen governs transportation and transformation, dispersing the essential qi of Shui Gu. And the combination of the 2 is pectoral qi. Therefore, spleen qi is sufficient resulting in healthy spleen qi and sufficient pectoral qi. If the spleen qi is insufficient, the lung qi will be weak, with insufficient pectoral qi. The lung governs diffusion and dispersion. Diffusion can spread the body fluid to the skin and body hair, and the dispersion can regulate the water channel, so that the water from the source goes down. If the lung is stagnated, the water fluid in upper jiao cannot be dispersed and passed down, stoping gathering in the lung, and turning into phlegm-fluid retention.

The lung disease is caused by fluid retention,which is not just a disease of the lung lesion itself.The root cause is mostly due to the deficiency of spleen, which cannot transport water and dampness,and the dampness stops gathering in the lungs leading to diseases. The spleen main function is that the spleen governs transportation and transformation.The understanding of the spleen governing transportation and transformation should include its functions of digestion of dietary water valleys and liquids, absorption of fine substances, distribution,gasification, and transfer of metabolic waste[24].It can be seen that part of the spleen function is exactly the intestinal function in modern medicine,and dysfunction of the spleen is often manifested as intestinal dysfunction such as loss of appetite,bloating, stool and diarrhea etc. Therefore, traditional Chinese medicine community often uses the method of supplementing spleen to benefit lungs and used the method of banking up earth to generate metal to treat lung diseases. And by regulating the spleen and stomach of the acquired, the physiological functions of the lungs return to normal.

TCM TREATMENT OF LUNG CANCER BY REGULATING THE INTESTINAL MICROECOLOGY

The Central Treasury Classic said: "Large intestine is the lung organ. It is the officer, called Jian Cang, who is in charge of transportation.- Long-term lung disease will be transmitted to the large intestine,and Shou Yang Min is its channel. Coldness results in reducing and heat results in stasis. In Delving into the Profound Significance of the 'Essentials from the Golden Cabinet' there is saying that"accumulation of dampness results in sputum, which stays in the lungs, and the large intestine will not be consolidated"; In Zhengyin Maizhi · Xie Xie, it is said that sputum accumulates in the lungs and the lungs move to the large intestine. When the phlegm of the lungs is cleared, the large intestine's diarrhea stops automatically."

Lung and spleen deficiency are common in patients with lung cancer. The patient lacked of spleen qi, having poor transport, with dampturbidity down streaming. So they have loose stool. In addition, the lung and large intestine are exterior and interior parts. Lung qi deficiency and Lung deficiency could not control intestine, or the stagnation of lung can also influence the rising and fall of qi movement. The function of Shui Gu conduction is imbalanced, and down mixed with the pure and impure. Dry and thin stool can be seen. Therefore, stool traits should be treated as the junction of spleen and intestinal function for patients with lung cancer, and changes in stool traits are exactly an important clinical manifestation of intestinal microecological disorders.

Lung and spleen deficiency are common in patients with lung cancer. The patient lacked of spleen qi, having poor transport, with damp-turbidity down streaming. So they have loose stool. In addition, the lungs and large intestine are exterior and interior parts. Lung deficiency could not control intestine, or the stagnation of lung can also influence the rising and fall of qi movement. The function of Shui Gu conduction is imbalanced, and down mixed with the pure and the impure. Dry and thin stool can be seen. Therefore, stool traits should be treated as the junction of spleen and intestinal function for patients with lung cancer, and changes in stool traits are exactly an important clinical manifestation of intestinal microecological disorders.

Reinforcing the Mother-organ to Treat Deficiency—Strengthening Earth to Generate Metal (虛則補其母——培土生金)

Traditional Chinese medicine believes that the spleen is acquired foundation and vigorous spleen qi results in sufficient qi and blood. And the body's functions tend to be normal. The intestinal microecology of the human body is established after the fetus is born, explaining the scientific connotation of the spleen as the acquired foundation from the perspective of flora. Studies have shown that[25],the fetal intestine in the mother's body is in a sterile state. Through the process of childbirth, the mother transmits bacteria to the newborn and gradually establishes a relatively stable flora pattern by the age of 2-3 years. Among them, the time and method of delivery, mother's age, hospitalization, body mass index, and socioeconomic conditions etc. will all affect the development of the baby's microbiome.The Complete Works of Zhang Jing-yue, The diseases of the five internal organs, although they can all produce sputum, can't help the spleen."The diseases of the five organ, although they can lead to phlegm, are all due to spleen. "The spleen is the source of sputum and the lung is the device for storing sputum." Although lung cancer is originated in the Zangfu viscera, its "sputum stasis" nature,at the beginning of onset, must be on the spleen.Spleen deficiency results in phlegm stagnated in lung channel, stagnated with blood, and resulting in phlegm stasis. And then it became cancer toxin.Studies[26]have shown that the incidence of spleen deficiency in patients with lung cancer is higher, and the corresponding syndrome is more common in the deficiency of the lung and spleen. Therefore, in the treatment of lung cancer, the most commonly used method is to strengthen the spleen and supplement the lungs, that is, to bank up earth to generate metal[27-29]. YOU Jian-liang et al.[30]combined with many years of clinical experience under the guidance of the theory of "cultivating soil and producing medal"formed a "Traditional Chinese Medicine Fine-tuning No. 3 Mixture (WD-3)". The clinical experiments of this mixture have confirmed that it can inhibit S-180 sarcoma growth in mice, significantly increase the levels of cytokines IL-2, IL-4, IFN-γ. These cytokines can stimulate the body's immune function and significantly inhibit the tumor tube endothelial factor,with anti-cancer metastasis. The anti-metastatic effects are better; BU Xu-hai[31], HUANG Xiaona[32]etc. used Peitu Shengjin Formula combined with chemotherapy to treat patients with advanced lung cancer. From their treatment it have shown that the method of strengthening soil to produce medal plus chemotherapy group has obvious treatment efficiency,symptom improvement rate, and incidence of adverse reactions, which were better than the control group.

Modern research has found that most of the spleen-invigorating Chinese medicines have good effects on the intestinal microecology. For example, polysaccharides is one of the active ingredients of many traditional Chinese medicines,which can promote the growth of probiotics such as Bifidobacterium and Lactobacillus, and inhibit pathogenic bacteria such as Enterobacter,Enterococcus, and Bacteroides, and other pathogenic bacterium, to maintain the intestinal microecological homeostasis. Supplementary traditional Chinese medicines containing polysaccharides have a supportive effects on probiotics and pathogenic microorganisms, but the supportive effects on probiotics are significantly better than pathogenic microorganisms[33]. Nano-yam polysaccharides can improve intestinal disorders and bacterial translocation in rats with acute liver failure[34]. YANG Xudong et al.[35]established a mice model of spleen deficiency and treated it with Shenling Baizhu powder. The number of various flora in the mice gradually returned to normal levels after treatment;DING Wei-jun et al[36]. Used the same modeling and treatment to get the results that Shenling Baizhu Powder was able to support anaerobic bacteria and inhibit aerobic bacteria, thereby adjusting the intestinal dysbacteria. After treating mice with the spleen deficiency model by Sijunzi polysaccharide,the number of Bifidobacterium, Lactobacillus,Bacteroides fragile, and Escherichia coli colonies and B/E values of the mice's intestines tended to return to normal[37]. Recent studies[38,39]have shown that the microecological structure and functional metabolic pathways of the intestinal flora of patients with nonsmall cell lung cancer have significantly changed,and that the intestinal flora is closely related to the host's inflammatory state and immune response. The method of cultivating soil and medal is likely to play a role in treating lung cancer by improving the intestinal microecology.

Purging Child Viscera for Treating Excess of Mother Viscera—Pulling the Plug (實則瀉其子——釜底抽薪)

In the verification of lung cancer, "phlegm,stasis, and poison" are the main factors. The pathgen toxin invades the lungs, leading to lung dispersion qi stagnation, and blood and phlegm stasis and cancer stasis was formed. The lungs pulses are in the large intestine. When lung pathogen was accumulated, the lung pathogen is vigorous and accumulated, and the qi movement stagnated. When the lung qi diffuses,it easily lead to fu qi stagnation and turbidity in the intestine blocking. The turbidity qi is blocked in lung,resulting in severe cough. Therefore, the method of diffusion is used to regulate qi, with apparent efficacy,often effective[38,39]. By dredging the intestine, it can not only promote defecation and exhaustion of the body,reduce abdominal pressure, thereby increasing the range of body chest movement, improving the patient's respiratory system function, but also enhancing gastrointestinal motility and improving digestive system function. When the intestinal barrier is dysfunctional,a large number of bacteria and endotoxins enter the blood through the portal vein and mesentery, forming intestinal endotoxemia and bacterial translocation,and triggering a chain reaction of cytokines and other inflammatory mediators. Dredging the intestines can also excrete harmful microorganisms accumulated in the gastrointestinal tract and various toxins released from it, promote the recovery of the intestinal flora and the circulatory metabolism of the body, thereby effectively protecting the body.

The intestinal flora can directly induce tumors in the digestive and blood systems through chronic inflammation or genotoxicity. Imbalanced intestinal flora and bacterial translocation can also promote tumor cell proliferation and invasion. A large number of bacteria and endotoxins enter the blood through the portal vein and mesentery, forming intestinal endotoxemia and bacterial translocation, and triggering a chain reaction of cytokines and other inflammatory mediators. Some studies[40]found that the traditional Chinese medicine Herba Taraxaci (Pu Gong Ying), Lonicera japonica Thunb (Jin Yin Hua), Herba Andrographis (Chuan Xin Lian), Herba Houttuyniae (Yu Xing Cao), Herba Patriniae (Bai Jiang Cao), Radix Isatidis (Ban Lan Gen), Fructus Forsythiae (Lian Qiao) have obvious proliferation effects on lactobacillus acidophilus,while another study[41]showed that Lactobacillus KLDS1.0901 and KLDS1.1003 have high ability to inhibit human colon cancer HT-29 cell proliferation and good probiotic function. XUAN Hong-yuan et al.[42]used the Oxford Cup method to detect the inhibition function of 42 kinds of Chinese medicine water decoction on Escherichia coli and Pseudomonas aeruginosa before and after transformation by intestinal flora, and found the main components of the 19 Chinese herbal medicines, Radix et Rhizoma Rhei (Da Huang), Radix Gentianae (Long Dan Cao), Radix Pulsatillae (Bai Tou Weng), Radix Sophorae Flavescentis (Ku Shen),Fructus Forsythiae (Lian Qiao), Radix Scutellariae(Huang Qin), Rhizoma Coptidis (Huang Bai), Cortex Phellodendri (Ju Hua), Flos Chrysanthemi (Ju Hua),Herba Taraxaci (Pu Gong Ying) etc. After intestinal microorganisms transformation, their main components can improve the intestinal flora disturbance caused by lincomycin in mice[43]. Treatment by Rhubarb polysaccharide for TNBS-induced ulcerative colitis model mice can promote probiotics and inhibit the proliferation of pathogenic bacteria, and can reverse the intestinal flora imbalance[44]. Traditional Chinese medicine of clearing heat and removing toxicity type,such as Radix et Rhizoma Rhei (Da Huang), Fructus Forsythiae (Lian Qiao), and Herba Taraxaci (Pu Gong Ying) have certain direct antitumor effects, and the regulation of intestinal flora during metabolism in the body may also be involved.

SUMMARY

In recent years, the relationship between intestinal microecology and diseases and treatment has gradually become a hot issue of research,and it has also opened a door for the study of the effects mechanism of traditional Chinese medicine.The lung-instestinal axis is closely linked to lung health and intestianl function. Changes in the microecological structure of the intestinal flora can promote the occurrence and progression of many diseases,including lung inflammatory diseases and lung cancer.In a disease state, the imbalance of the intestinal micro-ecological structure has a huge impact on lung immunity, or can promote the formation of lung cancer, and also affect the response of lung cancer to treatment. Multiple studies[45-47]have found that the microecological structure and functional metabolic pathways of the intestinal flora of patients with nonsmall cell lung cancer have significantly changed, and that the intestinal flora is closely related to the host's inflammatory state and immune response. The mutual regulating effects of traditional Chinese medicine and intestinal microecology has been confirmed.Intestinal microorganisms can promote the absorption of traditional Chinese medicine and improve the efficacy of traditional Chinese medicine. Traditional Chinese medicine can also achieve the purpose of treating diseases by regulating the imbalance of intestinal flora[48]. Combined with the influence of the lung-instestinal axis and intestinal micro-ecological imbalance on the occurrence and development of lung cancer in modern medical research, it is worth further exploring to study the relevant mechanism of traditional Chinese medicine for treating lung cancer by improving the intestinal micro-ecology.